@article{gonzalez_small_green_akhtari_motsinger-reif_quintanilha_havener_reif_mcleod_wiltshire_2023, title={MKX-AS1 Gene Expression Associated with Variation in Drug Response to Oxaliplatin and Clinical Outcomes in Colorectal Cancer Patients}, volume={16}, ISSN={["1424-8247"]}, url={https://doi.org/10.3390/ph16050757}, DOI={10.3390/ph16050757}, abstractNote={Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene MKX-AS1 and partnered sense gene MKX could impact the response of genetically varied cell lines to OXAL treatment. This study found that the expression levels of MKX-AS1 and MKX in lymphocytes (LCLs) and CRC cell lines differed between the rs11006706 genotypes, indicating that this gene pair could play a role in OXAL response. Further analysis of patient survival data from the Cancer Genome Atlas (TCGA) and other sources showed that patients with high MKX-AS1 expression status had significantly worse overall survival (HR = 3.2; 95%CI = (1.17-9); p = 0.024) compared to cases with low MKX-AS1 expression status. Alternatively, high MKX expression status had significantly better overall survival (HR = 0.22; 95%CI = (0.07-0.7); p = 0.01) compared to cases with low MKX expression status. These results suggest an association between MKX-AS1 and MKX expression status that could be useful as a prognostic marker of response to OXAL and potential patient outcomes in CRC.}, number={5}, journal={PHARMACEUTICALS}, author={Gonzalez, Ricardo D. and Small, George W. and Green, Adrian J. and Akhtari, Farida S. and Motsinger-Reif, Alison A. and Quintanilha, Julia C. F. and Havener, Tammy M. and Reif, David M. and McLeod, Howard L. and Wiltshire, Tim}, year={2023}, month={May} }
 @article{small_akhtari_green_havener_sikes_quintanhila_gonzalez_reif_motsinger-reif_mcleod_et al._2023, title={Pharmacogenomic Analyses Implicate B Cell Developmental Status and MKL1 as Determinants of Sensitivity toward Anti-CD20 Monoclonal Antibody Therapy}, volume={12}, ISSN={["2073-4409"]}, url={https://doi.org/10.3390/cells12121574}, DOI={10.3390/cells12121574}, abstractNote={Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene MKL1 displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of MKL1 by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated TGFB1I1 as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG+ cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the MKL1 gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy.}, number={12}, journal={CELLS}, author={Small, George W. and Akhtari, Farida S. and Green, Adrian J. and Havener, Tammy M. and Sikes, Michael and Quintanhila, Julia and Gonzalez, Ricardo D. and Reif, David M. and Motsinger-Reif, Alison A. and McLeod, Howard L. and et al.}, year={2023}, month={Jun} }
 @article{gonzalez_small_green_akhtari_havener_quintanilha_cipriani_reif_mcleod_motsinger-reif_et al._2023, title={RYK Gene Expression Associated with Drug Response Variation of Temozolomide and Clinical Outcomes in Glioma Patients}, volume={16}, ISSN={["1424-8247"]}, url={https://doi.org/10.3390/ph16050726}, DOI={10.3390/ph16050726}, abstractNote={Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the RYK (receptor-like kinase) gene with TMZ drug response. Functional validation of RYK using lymphocytes and glioma cell lines resulted in gene expression analysis indicating differences in expression status between genotypes of the cell lines and TMZ dose response. We conducted univariate and multivariate Cox regression analyses using publicly available TCGA and GEO datasets to investigate the impact of RYK gene expression status on glioma patient overall (OS) and progression-free survival (PFS). Our results indicated that in IDH mutant gliomas, RYK expression and tumor grade were significant predictors of survival. In IDH wildtype glioblastomas (GBM), MGMT status was the only significant predictor. Despite this result, we revealed a potential benefit of RYK expression in IDH wildtype GBM patients. We found that a combination of RYK expression and MGMT status could serve as an additional biomarker for improved survival. Overall, our findings suggest that RYK expression may serve as an important prognostic or predictor of TMZ response and survival for glioma patients.}, number={5}, journal={PHARMACEUTICALS}, author={Gonzalez, Ricardo D. and Small, George W. and Green, Adrian J. and Akhtari, Farida S. and Havener, Tammy M. and Quintanilha, Julia C. F. and Cipriani, Amber B. and Reif, David M. and McLeod, Howard L. and Motsinger-Reif, Alison A. and et al.}, year={2023}, month={May} }
 @article{lloyd_skinner_maguire_murphy_motsinger-reif_hoyo_house_2022, title={Clomifene and Assisted Reproductive Technology in Humans Are Associated with Sex-Specific Offspring Epigenetic Alterations in Imprinted Control Regions}, volume={23}, ISSN={["1422-0067"]}, url={https://doi.org/10.3390/ijms231810450}, DOI={10.3390/ijms231810450}, abstractNote={Children conceived with assisted reproductive technology (ART) have an increased risk of adverse outcomes, including congenital malformations and imprinted gene disorders. In a retrospective North Carolina-based-birth-cohort, we examined the effect of ovulation drugs and ART on CpG methylation in differentially methylated CpGs in known imprint control regions (ICRs). Nine ICRs containing 48 CpGs were assessed for methylation status by pyrosequencing in mixed leukocytes from cord blood. After restricting to non-smoking, college-educated participants who agreed to follow-up, ART-exposed (n = 27), clomifene-only-exposed (n = 22), and non-exposed (n = 516) groups were defined. Associations of clomifene and ART with ICR CpG methylation were assessed with linear regression and stratifying by offspring sex. In males, ART was associated with hypomethylation of the PEG3 ICR [β(95% CI) = -1.46 (-2.81, -0.12)] and hypermethylation of the MEG3 ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the NNAT ICR [-5.25 (-10.12, -0.38)]. In female offspring, ART was associated with hypomethylation of the IGF2 ICR [-3.67 (-6.79, -0.55)]. Aberrant methylation of these ICRs has been associated with cardiovascular disease and metabolic and behavioral outcomes in children. The results suggest that the increased risk of adverse outcomes in offspring conceived through ART may be due in part to altered methylation of ICRs. Larger studies utilizing epigenome-wide interrogation are warranted.}, number={18}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Lloyd, Dillon T. and Skinner, Harlyn G. and Maguire, Rachel and Murphy, Susan K. and Motsinger-Reif, Alison A. and Hoyo, Cathrine and House, John S.}, year={2022}, month={Sep} }
 @article{wolkin_collier_house_reif_motsinger-reif_duca_sharpe_2022, title={Comparison of National Vulnerability Indices Used by the Centers for Disease Control and Prevention for the COVID-19 Response}, volume={137}, ISSN={0033-3549 1468-2877}, url={http://dx.doi.org/10.1177/00333549221090262}, DOI={10.1177/00333549221090262}, abstractNote={Vulnerability indices use quantitative indicators and geospatial data to examine the level of vulnerability to morbidity in a community. The Centers for Disease Control and Prevention (CDC) uses 3 indices for the COVID-19 response: the CDC Social Vulnerability Index (CDC-SVI), the US COVID-19 Community Vulnerability Index (CCVI), and the Pandemic Vulnerability Index (PVI). The objective of this review was to describe these tools and explain the similarities and differences between them.We described the 3 indices, outlined the underlying data sources and metrics for each, and discussed their use by CDC for the COVID-19 response. We compared the percentile score for each county for each index by calculating Spearman correlation coefficients (Spearman ρ).These indices have some, but not all, component metrics in common. The CDC-SVI is a validated metric that estimates social vulnerability, which comprises the underlying population-level characteristics that influence differences in health risk among communities. To address risk specific to the COVID-19 pandemic, the CCVI and PVI build on the CDC-SVI and include additional variables. The 3 indices were highly correlated. Spearman ρ for comparisons between the CDC-SVI score and the CCVI and between the CCVI and the PVI score was 0.83. Spearman ρ for the comparison between the CDC-SVI score and PVI score was 0.73.The indices can empower local and state public health officials with additional information to focus resources and interventions on disproportionately affected populations to combat the ongoing pandemic and plan for future pandemics.}, number={4}, journal={Public Health Reports}, publisher={SAGE Publications}, author={Wolkin, Amy and Collier, Sarah and House, John S. and Reif, David and Motsinger-Reif, Alison and Duca, Lindsey and Sharpe, J. Danielle}, year={2022}, month={May}, pages={803–812} }
 @article{mandal_levy_ives_hwang_zhou_motsinger-reif_pan_huggins_hamilton_wright_et al._2022, title={Correlation Analysis of Variables From the Atherosclerosis Risk in Communities Study}, volume={13}, ISSN={["1663-9812"]}, DOI={10.3389/fphar.2022.883433}, abstractNote={The need to test chemicals in a timely and cost-effective manner has driven the development of new alternative methods (NAMs) that utilize in silico and in vitro approaches for toxicity prediction. There is a wealth of existing data from human studies that can aid in understanding the ability of NAMs to support chemical safety assessment. This study aims to streamline the integration of data from existing human cohorts by programmatically identifying related variables within each study. Study variables from the Atherosclerosis Risk in Communities (ARIC) study were clustered based on their correlation within the study. The quality of the clusters was evaluated via a combination of manual review and natural language processing (NLP). We identified 391 clusters including 3,285 variables. Manual review of the clusters containing more than one variable determined that human reviewers considered 95% of the clusters related to some degree. To evaluate potential bias in the human reviewers, clusters were also scored via NLP, which showed a high concordance with the human classification. Clusters were further consolidated into cluster groups using the Louvain community finding algorithm. Manual review of the cluster groups confirmed that clusters within a group were more related than clusters from different groups. Our data-driven approach can facilitate data harmonization and curation efforts by providing human annotators with groups of related variables reflecting the themes present in the data. Reviewing groups of related variables should increase efficiency of the human review, and the number of variables reviewed can be reduced by focusing curator attention on variable groups whose theme is relevant for the topic being studied.}, journal={FRONTIERS IN PHARMACOLOGY}, author={Mandal, Meisha and Levy, Josh and Ives, Cataia and Hwang, Stephen and Zhou, Yi-Hui and Motsinger-Reif, Alison and Pan, Huaqin and Huggins, Wayne and Hamilton, Carol and Wright, Fred and et al.}, year={2022}, month={Jul} }
 @article{jima_skaar_planchart_motsinger-reif_cevik_park_cowley_wright_house_liu_et al._2022, title={Genomic map of candidate human imprint control regions: the imprintome}, volume={6}, ISSN={["1559-2308"]}, url={https://doi.org/10.1080/15592294.2022.2091815}, DOI={10.1080/15592294.2022.2091815}, abstractNote={Imprinted genes – critical for growth, metabolism, and neuronal function – are expressed from one parental allele. Parent-of-origin-dependent CpG methylation regulates this expression at imprint control regions (ICRs). Since ICRs are established before tissue specification, these methylation marks are similar across cell types. Thus, they are attractive for investigating the developmental origins of adult diseases using accessible tissues, but remain unknown. We determined genome-wide candidate ICRs in humans by performing whole-genome bisulphite sequencing (WGBS) of DNA derived from the three germ layers and from gametes. We identified 1,488 hemi-methylated candidate ICRs, including 19 of 25 previously characterized ICRs (https://humanicr.org/). Gamete methylation approached 0% or 100% in 332 ICRs (178 paternally and 154 maternally methylated), supporting parent-of-origin-specific methylation, and 65% were in well-described CTCF-binding or DNaseI hypersensitive regions. This draft of the human imprintome will allow for the systematic determination of the role of early-acquired imprinting dysregulation in the pathogenesis of human diseases and developmental and behavioural disorders.}, journal={EPIGENETICS}, author={Jima, Dereje D. and Skaar, David A. and Planchart, Antonio and Motsinger-Reif, Alison and Cevik, Sebnem E. and Park, Sarah S. and Cowley, Michael and Wright, Fred and House, John and Liu, Andy and et al.}, year={2022}, month={Jun} }
 @article{lewis_thomas_breen_peden_teferedegne_foseh_motsinger-reif_rotroff_lewis_2022, title={The AGMK1-9T7 cell model of neoplasia: Evolution of DNA copy-number aberrations and miRNA expression during transition from normal to metastatic cancer cells}, volume={17}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0275394}, abstractNote={To study neoplasia in tissue culture, cell lines representing the evolution of normal cells to tumor cells are needed. To produce such cells, we developed the AGMK1-9T7 cell line, established cell banks at 10-passage intervals, and characterized their biological properties. Here we examine the evolution of chromosomal DNA copy-number aberrations and miRNA expression in this cell line from passage 1 to the acquisition of a tumorigenic phenotype at passage 40. We demonstrated the use of a human microarray platform for DNA copy-number profiling of AGMK1-9T7 cells using knowledge of synteny to ‘recode’ data from human chromosome coordinates to those of the African green monkey. This approach revealed the accumulation of DNA copy-number gains and losses in AGMK1-9T7 cells from passage 3 to passage 40, which spans the period in which neoplastic transformation occurred. These alterations occurred in the sequences of genes regulating DNA copy-number imbalance of several genes that regulate endothelial cell angiogenesis, survival, migration, and proliferation. Regarding miRNA expression, 195 miRNAs were up- or down-regulated at passage 1 at levels that appear to be biologically relevant (i.e., log2 fold change >2.0 (q<0.05)). At passage 10, the number of up/down-regulated miRNAs fell to 63; this number increased to 93 at passage 40. Principal-component analysis grouped these miRNAs into 3 clusters; miRNAs in sub-clusters of these groups could be correlated with initiation, promotion, and progression, stages that have been described for neoplastic development. Thirty-four of the AGMK1-9T7 miRNAs have been associated with these stages in human cancer. Based on these data, we propose that the evolution of AGMK1-9T7 cells represents a detailed model of neoplasia in vitro.}, number={10}, journal={PLOS ONE}, author={Lewis, Andrew M., Jr. and Thomas, Rachael and Breen, Matthew and Peden, Keith and Teferedegne, Belete and Foseh, Gideon and Motsinger-Reif, Alison and Rotroff, Daniel and Lewis, Gladys}, year={2022}, month={Oct} }
 @article{fleming_marvel_supak_motsinger-reif_reif_2022, title={ToxPi*GIS Toolkit: creating, viewing, and sharing integrative visualizations for geospatial data using ArcGIS}, volume={4}, ISSN={["1559-064X"]}, DOI={10.1038/s41370-022-00433-w}, abstractNote={Abstract Background Presenting a comprehensive picture of geographic data comprising multiple factors is an inherently integrative undertaking. Visualizing such data in an interactive form is essential for public sharing and geographic information systems (GIS) analysis. The Toxicological Prioritization Index (ToxPi) framework offers a visual analytic integrating data that is compatible with geographic data. ArcGIS is a predominant geospatial software available for presenting and communicating geographic data, yet to our knowledge there is no methodology for integrating ToxPi profiles into ArcGIS maps. Objective We introduce an actively developed suite of software, the ToxPi*GIS Toolkit, for creating, viewing, sharing, and analyzing interactive ToxPi profiles in ArcGIS to allow for new GIS analysis and an avenue for providing geospatial results to the public. Methods The ToxPi*GIS Toolkit is a collection of methods for creating interactive feature layers that contain ToxPi profiles. It currently includes an ArcGIS Toolbox ( ToxPiToolbox.tbx ) for drawing location-specific ToxPi profiles in a single feature layer, a collection of modular Python scripts that create predesigned layer files containing ToxPi feature layers from the command line, and a collection of Python routines for useful data manipulation and preprocessing. We present workflows documenting ToxPi feature layer creation, sharing, and embedding for both novice and advanced users looking for additional customizability. Results Map visualizations created with the ToxPi*GIS Toolkit can be made freely available on public URLs, allowing users without ArcGIS Pro access or expertise to view and interact with them. Novice users with ArcGIS Pro access can create de novo custom maps, and advanced users can exploit additional customization options. The ArcGIS Toolbox provides a simple means for generating ToxPi feature layers. We illustrate its usage with current COVID-19 data to compare drivers of pandemic vulnerability in counties across the United States. Significance The integration of ToxPi profiles with ArcGIS provides new avenues for geospatial analysis, visualization, and public sharing of multi-factor data. This allows for comparison of data across a region, which can support decisions that help address issues such as disease prevention, environmental health, natural disaster prevention, chemical risk, and many others. Development of new features, which will advance the interests of the scientific community in many fields, is ongoing for the ToxPi*GIS Toolkit, which can be accessed from www.toxpi.org .}, journal={JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY}, author={Fleming, Jonathon and Marvel, Skylar W. and Supak, Stacy and Motsinger-Reif, Alison A. and Reif, David M.}, year={2022}, month={Apr} }
 @article{mcdonough_warren_jack_motsinger‐reif_armstrong_bis_house_singh_el rouby_gong_et al._2021, title={Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome‐Wide Interaction Meta‐Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies}, volume={110}, ISSN={0009-9236 1532-6535}, url={http://dx.doi.org/10.1002/cpt.2355}, DOI={10.1002/cpt.2355}, abstractNote={We sought to identify genome‐wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome‐wide antihypertensive drug‐single nucleotide polymorphism (SNP) interaction tests for four drug classes (β‐blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide‐like diuretics, n = 3,516; ACE‐inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta‐analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study ( n = 21,267), blood pressure (BP) response in independent ICAPS studies ( n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome‐wide significance in the β‐blocker‐SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10 −8 ). rs139945292 was validated through BP response to β‐blockers, with the T‐allele associated with less BP reduction (systolic BP response P = 6 × 10 −4 , Beta = 3.09, diastolic BP response P = 5 × 10 −3 , Beta = 1.53). The T‐allele was also associated with increased adverse cardiovascular risk within the β‐blocker treated patients’ subgroup ( P = 2.35 × 10 −4 , odds ratio = 1.57, 95% confidence interval = 1.23–1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β‐blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome‐wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE‐inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β‐blocker treated patients. Further investigation into this region is warranted.}, number={3}, journal={Clinical Pharmacology & Therapeutics}, publisher={Wiley}, author={McDonough, Caitrin W. and Warren, Helen R. and Jack, John R. and Motsinger‐Reif, Alison A. and Armstrong, Nicole D. and Bis, Joshua C. and House, John S. and Singh, Sonal and El Rouby, Nihal M. and Gong, Yan and et al.}, year={2021}, month={Aug}, pages={723–732} }
 @article{green_anchang_akhtari_reif_motsinger-reif_2021, title={Extending the lymphoblastoid cell line model for drug combination pharmacogenomics}, volume={22}, ISSN={["1744-8042"]}, url={https://doi.org/10.2217/pgs-2020-0160}, DOI={10.2217/pgs-2020-0160}, abstractNote={Combination drug therapies have become an integral part of precision oncology, and while evidence of clinical effectiveness continues to grow, the underlying mechanisms supporting synergy are poorly understood. Immortalized human lymphoblastoid cell lines (LCLs) have been proven as a particularly useful, scalable and low-cost model in pharmacogenetics research, and are suitable for elucidating the molecular mechanisms of synergistic combination therapies. In this review, we cover the advantages of LCLs in synergy pharmacogenomics and consider recent studies providing initial evidence of the utility of LCLs in synergy research. We also discuss several opportunities for LCL-based systems to address gaps in the research through the expansion of testing regimens, assessment of new drug classes and higher-order combinations, and utilization of integrated omics technologies.}, number={9}, journal={PHARMACOGENOMICS}, publisher={Future Medicine Ltd}, author={Green, Adrian J. and Anchang, Benedict and Akhtari, Farida S. and Reif, David M. and Motsinger-Reif, Alison}, year={2021}, month={May} }
 @article{akhtari_green_small_havener_house_roell_reif_mcleod_wiltshire_motsinger-reif_2021, title={High-throughput screening and genome-wide analyses of 44 anticancer drugs in the 1000 Genomes cell lines reveals an association of the NQO1 gene with the response of multiple anticancer drugs}, volume={17}, ISSN={["1553-7404"]}, url={https://doi.org/10.1371/journal.pgen.1009732}, DOI={10.1371/journal.pgen.1009732}, abstractNote={Cancer patients exhibit a broad range of inter-individual variability in response and toxicity to widely used anticancer drugs, and genetic variation is a major contributor to this variability. To identify new genes that influence the response of 44 FDA-approved anticancer drug treatments widely used to treat various types of cancer, we conducted high-throughput screening and genome-wide association mapping using 680 lymphoblastoid cell lines from the 1000 Genomes Project. The drug treatments considered in this study represent nine drug classes widely used in the treatment of cancer in addition to the paclitaxel + epirubicin combination therapy commonly used for breast cancer patients. Our genome-wide association study (GWAS) found several significant and suggestive associations. We prioritized consistent associations for functional follow-up using gene-expression analyses. The NAD(P)H quinone dehydrogenase 1 (NQO1) gene was found to be associated with the dose-response of arsenic trioxide, erlotinib, trametinib, and a combination treatment of paclitaxel + epirubicin. NQO1 has previously been shown as a biomarker of epirubicin response, but our results reveal novel associations with these additional treatments. Baseline gene expression of NQO1 was positively correlated with response for 43 of the 44 treatments surveyed. By interrogating the functional mechanisms of this association, the results demonstrate differences in both baseline and drug-exposed induction.}, number={8}, journal={PLOS GENETICS}, publisher={Public Library of Science (PLoS)}, author={Akhtari, Farida S. and Green, Adrian J. and Small, George W. and Havener, Tammy M. and House, John S. and Roell, Kyle R. and Reif, David M. and McLeod, Howard L. and Wiltshire, Timothy and Motsinger-Reif, Alison A.}, editor={Vazquez, FranciscaEditor}, year={2021}, month={Aug} }
 @article{weeks_motsinger-reif_reems_2021, title={In vitro iatrogenic hemolysis of canine packed red blood cells during various rapid transfusion techniques}, volume={31}, ISSN={["1476-4431"]}, DOI={10.1111/vec.13020}, abstractNote={Abstract Objective To evaluate which rapid blood administration technique causes the least iatrogenic hemolysis in canine packed red blood cells (pRBCs) as determined by plasma free hemoglobin (fHb) and percent hemolysis (% hemolysis). Design Prospective in vitro randomized study. Setting Private referral center. Animals None. Interventions Thirteen units of canine pRBCs were divided equally into 5 aliquots, resulting in 65 trials. The aliquots of each unit were subjected to the following administration techniques: gravity‐driven (control), an infusion pump at maximal rate, application of a pressure bag, manual compression, and syringe bolus. Plasma fHb and % hemolysis were recorded before and after each trial. Rate of administration (mL/s) was calculated for each method. Measurements and main results Compared to the control, there were no significant increases in % hemolysis or plasma fHb noted among any of the trial methods. The manual compression and syringe bolus methods resulted in the fastest transfusion rates, whereas the infusion pump was not faster than the gravity‐driven method. Despite a storage time of ≤14 days, 15% of pRBC units had unsuitable (>0.8%) hemolysis before even being subjected to the trials. Conclusions Commonly used rapid infusion techniques in small animal transfusion medicine do not cause significant iatrogenic hemolysis of canine pRBCs in vitro, although a significant risk is present in stored blood. This suggests that if an expedited transfusion is needed, any method described in this study could be considered, although stored pRBCs should be tested for unsuitable levels of hemolysis prior to transfusion.}, number={1}, journal={JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE}, author={Weeks, Jessica M. and Motsinger-Reif, Alison A. and Reems, Miryam M.}, year={2021}, month={Jan}, pages={25–31} }
 @article{jiang_li_motsinger-reif_2021, title={Knockoff boosted tree for model-free variable selection}, volume={37}, ISSN={["1460-2059"]}, DOI={10.1093/bioinformatics/btaa770}, abstractNote={Abstract Motivation The recently proposed knockoff filter is a general framework for controlling the false discovery rate (FDR) when performing variable selection. This powerful new approach generates a ‘knockoff’ of each variable tested for exact FDR control. Imitation variables that mimic the correlation structure found within the original variables serve as negative controls for statistical inference. Current applications of knockoff methods use linear regression models and conduct variable selection only for variables existing in model functions. Here, we extend the use of knockoffs for machine learning with boosted trees, which are successful and widely used in problems where no prior knowledge of model function is required. However, currently available importance scores in tree models are insufficient for variable selection with FDR control. Results We propose a novel strategy for conducting variable selection without prior model topology knowledge using the knockoff method with boosted tree models. We extend the current knockoff method to model-free variable selection through the use of tree-based models. Additionally, we propose and evaluate two new sampling methods for generating knockoffs, namely the sparse covariance and principal component knockoff methods. We test and compare these methods with the original knockoff method regarding their ability to control type I errors and power. In simulation tests, we compare the properties and performance of importance test statistics of tree models. The results include different combinations of knockoffs and importance test statistics. We consider scenarios that include main-effect, interaction, exponential and second-order models while assuming the true model structures are unknown. We apply our algorithm for tumor purity estimation and tumor classification using Cancer Genome Atlas (TCGA) gene expression data. Our results show improved discrimination between difficult-to-discriminate cancer types. Availability and implementation The proposed algorithm is included in the KOBT package, which is available at https://cran.r-project.org/web/packages/KOBT/index.html. Supplementary information Supplementary data are available at Bioinformatics online.}, number={7}, journal={BIOINFORMATICS}, author={Jiang, Tao and Li, Yuanyuan and Motsinger-Reif, Alison A.}, year={2021}, month={Apr}, pages={976–983} }
 @article{ma_motsinger-reif_2021, title={Prediction of synergistic drug combinations using PCA-initialized deep learning}, volume={14}, ISSN={["1756-0381"]}, DOI={10.1186/s13040-021-00278-3}, abstractNote={Cancer is one of the main causes of death worldwide. Combination drug therapy has been a mainstay of cancer treatment for decades and has been shown to reduce host toxicity and prevent the development of acquired drug resistance. However, the immense number of possible drug combinations and large synergistic space makes it infeasible to screen all effective drug pairs experimentally. Therefore, it is crucial to develop computational approaches to predict drug synergy and guide experimental design for the discovery of rational combinations for therapy.We present a new deep learning approach to predict synergistic drug combinations by integrating gene expression profiles from cell lines and chemical structure data. Specifically, we use principal component analysis (PCA) to reduce the dimensionality of the chemical descriptor data and gene expression data. We then propagate the low-dimensional data through a neural network to predict drug synergy values. We apply our method to O'Neil's high-throughput drug combination screening data as well as a dataset from the AstraZeneca-Sanger Drug Combination Prediction DREAM Challenge. We compare the neural network approach with and without dimension reduction. Additionally, we demonstrate the effectiveness of our deep learning approach and compare its performance with three state-of-the-art machine learning methods: Random Forests, XGBoost, and elastic net, with and without PCA-based dimensionality reduction.Our developed approach outperforms other machine learning methods, and the use of dimension reduction dramatically decreases the computation time without sacrificing accuracy.}, number={1}, journal={BIODATA MINING}, author={Ma, Jun and Motsinger-Reif, Alison}, year={2021}, month={Oct} }
 @article{akhtari_havener_hertz_ash_larson_carey_mcleod_motsinger-reif_2021, title={Race and smoking status associated with paclitaxel drug response in patient-derived lymphoblastoid cell lines}, volume={31}, ISSN={["1744-6880"]}, DOI={10.1097/FPC.0000000000000419}, abstractNote={The use of ex-vivo model systems to provide a level of forecasting for in-vivo characteristics remains an important need for cancer therapeutics. The use of lymphoblastoid cell lines (LCLs) is an attractive approach for pharmacogenomics and toxicogenomics, due to their scalability, efficiency, and cost-effectiveness. There is little data on the impact of demographic or clinical covariates on LCL response to chemotherapy. Paclitaxel sensitivity was determined in LCLs from 93 breast cancer patients from the University of North Carolina Lineberger Comprehensive Cancer Center Breast Cancer Database to test for potential associations and/or confounders in paclitaxel dose-response assays. Measures of paclitaxel cell viability were associated with patient data included treatment regimens, cancer status, demographic and environmental variables, and clinical outcomes. We used multivariate analysis of variance to identify the in-vivo variables associated with ex-vivo dose-response. In this unique dataset that includes both in-vivo and ex-vivo data from breast cancer patients, race (P = 0.0049) and smoking status (P = 0.0050) were found to be significantly associated with ex-vivo dose-response in LCLs. Racial differences in clinical dose-response have been previously described, but the smoking association has not been reported. Our results indicate that in-vivo smoking status can influence ex-vivo dose-response in LCLs, and more precise measures of covariates may allow for more precise forecasting of clinical effect. In addition, understanding the mechanism by which exposure to smoking in-vivo effects ex-vivo dose-response in LCLs may open up new avenues in the quest for better therapeutic prediction.}, number={2}, journal={PHARMACOGENETICS AND GENOMICS}, author={Akhtari, Farida S. and Havener, Tammy M. and Hertz, Daniel L. and Ash, Jeremy and Larson, Alexandra and Carey, Lisa A. and McLeod, Howard L. and Motsinger-Reif, Alison A.}, year={2021}, month={Feb}, pages={48–52} }
 @misc{marvel_house_wheeler_song_zhou_wright_chiu_rusyn_motsinger-reif_reif_2021, title={The COVID-19 Pandemic Vulnerability Index (PVI) Dashboard: Monitoring County-Level Vulnerability Using Visualization, Statistical Modeling, and Machine Learning}, volume={129}, ISSN={["1552-9924"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85099420902&partnerID=MN8TOARS}, DOI={10.1289/EHP8690}, abstractNote={Vol. 129, No. 1 Research LetterOpen AccessThe COVID-19 Pandemic Vulnerability Index (PVI) Dashboard: Monitoring County-Level Vulnerability Using Visualization, Statistical Modeling, and Machine Learning Skylar W. Marvel, John S. House, Matthew Wheeler, Kuncheng Song, Yi-Hui Zhou, Fred A. Wright, Weihsueh A. Chiu, Ivan Rusyn, Alison Motsinger-Reif, and David M. Reif Skylar W. Marvel Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA Search for more papers by this author , John S. House Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA Search for more papers by this author , Matthew Wheeler Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA Search for more papers by this author , Kuncheng Song Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA Search for more papers by this author , Yi-Hui Zhou Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA Search for more papers by this author , Fred A. Wright Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA Department of Statistics, NCSU, Raleigh, North Carolina, USA Search for more papers by this author , Weihsueh A. Chiu Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA Search for more papers by this author , Ivan Rusyn Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA Search for more papers by this author , Alison Motsinger-Reif Address correspondence to Alison Motsinger-Reif, 111 T.W. Alexander Dr., Rall Building, Research Triangle Park, NC 27709 USA. Email: E-mail Address: [email protected], or David M. Reif, Box 7566, 1 Lampe Dr., Raleigh NC 27695 USA. Email: E-mail Address: [email protected] Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA Search for more papers by this author , and David M. Reif Address correspondence to Alison Motsinger-Reif, 111 T.W. Alexander Dr., Rall Building, Research Triangle Park, NC 27709 USA. Email: E-mail Address: [email protected], or David M. Reif, Box 7566, 1 Lampe Dr., Raleigh NC 27695 USA. Email: E-mail Address: [email protected] Bioinformatics Research Center, Department of Biological Sciences, North Carolina State University (NCSU), Raleigh, North Carolina, USA Search for more papers by this author Published:5 January 2021CID: 017701https://doi.org/10.1289/EHP8690AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit IntroductionExpert groups have coalesced around a roadmap to address the current COVID-19 pandemic centered on social distancing, monitoring case counts and health care capacity, and, eventually, moving to pharmaceutical interventions. However, responsibility for navigating the pandemic response falls largely on state and local officials. To make equitable decisions on allocating resources, caring for vulnerable subpopulations, and implementing local- and state-level interventions, access to current pandemic data and key vulnerabilities at the community level are essential (National Academies of Sciences, Engineering, and Medicine 2020). Although numerous predictive models and interactive monitoring applications have been developed using pandemic-related data sets (Wynants et al. 2020), their capacity to aid in dynamic, community-level decision-making is limited. We developed the interactive COVID-19 Pandemic Vulnerability Index (PVI) Dashboard ( https://covid19pvi.niehs.nih.gov/) to address this need by presenting a visual synthesis of dynamic information at the county level to monitor disease trajectories, communicate local vulnerabilities, forecast key outcomes, and guide informed responses (Figure 1).Figure 1. COVID-19 PVI Dashboard. Dashboard screenshot displaying PVI profiles atop a choropleth map layer indicating overall COVID-19 PVI rank. The PVI Scorecard and associated data for Clarendon County, South Carolina, has been selected. The scorecard summarizes the overall PVI score and rank compared with all 3,142 U.S. counties on each indicator slice. The scrollable score distributions at left compare the selected county PVI to the distributions of overall and slice-wise scores across the United States. The panels below the map are populated with county-specific information on observed trends in cases and deaths, cumulative numbers for the county, historical timelines (for cumulative cases, cumulative deaths, PVI, and PVI rank), daily case and death counts for the most recent 14-d period, and a 14-d forecast of predicted cases and deaths. The information displayed for both observed COVID-19 data and PVI layers is scrollable back through March 2020. Documentation of additional features and usage, including advanced options (accessible via the collapsed menu at the upper left), is provided in a Quick Start Guide (linked at the upper right corner). Note: Pop, population; PVI, Pandemic Vulnerability Index.MethodsThe current PVI model integrates multiple data streams into an overall score derived from 12 key indicators—including well-established, general vulnerability factors for public health, plus emerging factors relevant to the pandemic—distributed across four domains: current infection rates, baseline population concentration, current interventions, and health and environmental vulnerabilities. The PVI profiles translate numerical results into visual representations, with each vulnerability factor represented as a component slice of a radar chart (Figure 2). The PVI profile for each county is calculated using the Toxicological Prioritization Index (ToxPi) framework for data integration within a geospatial context (Marvel et al. 2018; Bhandari et al. 2020). Data sources in the current model (version 11.2.1) include the Social Vulnerability Index (SVI) of the Centers for Disease Control and Prevention (CDC) for emergency response and hazard mitigation planning (Horney et al. 2017), testing rates from the COVID Tracking Project (Atlantic Monthly Group 2020), social distancing metrics from mobile device data ( https://www.unacast.com/covid19/social-distancing-scoreboard), and dynamic measures of disease spread and case numbers ( https://usafacts.org/issues/coronavirus/). Methodological details concerning the integration of data streams—plus the complete, daily time series of all source data since February 2020 and resultant PVI scores—are maintained on the public Github project page (COVID19PVI 2020). Over this period, the PVI has been strongly associated with key vulnerability-related outcome metrics (by rank-correlation), with updates of its performance assessment posted with model updates alongside data at the Github project page (COVID19PVI 2020).Figure 2. Translation of data into COVID-19 PVI profiles. Information from all 3,142 U.S. counties is translated into PVI slices. The illustration shows how air pollution data (average density of fine particulate matterPM2.5 per county) are compared for two example counties. The county with the higher relative measurement (County Y) has a longer air pollution slice than the county with a lower measurement (County X). This procedure is repeated for all slices, resulting in an integrated, overall PVI profile. Note: pop, population; PVI, Pandemic Vulnerability Index.In addition to the PVI itself—which is a summary, human-centric visualization of relative vulnerability drivers—the dashboard is supported by rigorous statistical modeling of the underlying data to enable quantitative analysis and provide short-term, local predictions of cases and deaths [complete methodological details are maintained at the Github project page (COVID19PVI 2020)]. Generalized linear models of cumulative outcome data indicated that, after population size, the most significant predictors were the proportion of Black residents, mean fine particulate matter [particulate matter less than or equal to 2.5 micrometers≤2.5μm in diameter (fine particulate matterPM2.5)], percentage of population with insurance coverage (which was positively associated), and proportion of Hispanic residents. The local predictions of cases and deaths (see the “Predictions” panel in Figure 1) are updated daily using a Bayesian spatiotemporal random-effects model to build forecasts up to 2 weeks out.DiscussionThe PVI Dashboard supports decision-making and dynamic monitoring in several ways. The display can be tailored to add or remove layers of information, filtered by region (e.g., all counties within a state) or clustered by profile shape similarity. The timelines for both PVI models and observed COVID-19 outcomes facilitate tracking the impact of interventions and directing local resource allocations. The “Predictions” panel (Figure 1) connects these historical numbers to local forecasts of cases and deaths. By communicating an integrated concept of vulnerability that considers both dynamic (infection rate and interventions) and static (community population and health care characteristics) drivers, the interactive dashboard can promote buy-in from diverse audiences, which is necessary for effective public health interventions. This messaging can assist in addressing known racial disparities in COVID-19 case and death rates (Tan et al. 2020) or populations, and the PVI Dashboard is part of the “Unique Populations” tab of the CDC’s COVID-19 Data Tracker ( https://covid.cdc.gov/covid-data-tracker). By filtering the display to highlight vulnerability drivers within an overall score context, the dashboard can inform targeted interventions for specific localities.Unfortunately, the pandemic endures across the United States, with broad disparities based on the local environment (Tan et al. 2020). We present the PVI Dashboard as a dynamic container for contextualizing these disparities. It is a modular tool that will evolve to incorporate new data sources and analytics as they emerge (e.g., concurrent flu infections, school and business reopening statistics, heterogeneous public health practices). This flexibility positions it well as a resource for integrated prioritization of eventual vaccine distribution and monitoring its local impact. The PVI Dashboard can empower local and state officials to take informed action to combat the pandemic by communicating interactive, visual profiles of vulnerability atop an underlying statistical framework that enables the comparison of counties and the evaluation of the PVI’s component data.AcknowledgmentsWe thank the information technology and web services staff at the National Institute of Environmental Health Sciences (NIEHS)/National Institutes of Health (NIH) for their help and support, as well as J.K. Cetina and D.J. Reif for their useful technical input and advice. This work was supported by NIEHS/NIH grants (P42 ES027704, P30 ES029067, P42 ES031009, and P30 ES025128) and NIEHS/NIH intramural funds (Z ES103352-01).ReferencesAtlantic Monthly Group.2020. The COVID Tracking Project. https://covidtracking.com/ [accessed 15 November 2020]. Google ScholarBhandari S, Lewis PGT, Craft E, Marvel SW, Reif DM, Chiu WA. 2020. HGBEnviroScreen: enabling community action through data integration in the Houston–Galveston–Brazoria region. Int J Environ Res Public Health 17(4):1130, PMID: 32053902, 10.3390/ijerph17041130. Crossref, Medline, Google ScholarCOVID19PVI.2020. COVID19PVI/data. https://github.com/COVID19PVI/data [accessed 15 November 2020]. Google ScholarHorney J, Nguyen M, Salvesen D, Dwyer C, Cooper J, Berke P. 2017. Assessing the quality of rural hazard mitigation plans in the southeastern United States. J Plan Educ Res 37(1):56–65, 10.1177/0739456X16628605. Crossref, Google ScholarMarvel SW, To K, Grimm FA, Wright FA, Rusyn I, Reif DM. 2018. ToxPi Graphical User Interface 2.0: dynamic exploration, visualization, and sharing of integrated data models. BMC Bioinformatics 19(1):80, PMID: 29506467, 10.1186/s12859-018-2089-2. Crossref, Medline, Google ScholarNational Academies of Sciences, Engineering, and Medicine.2020. Framework for Equitable Allocation of COVID-19 Vaccine. Gayle H, Foege W, Brown L, Kahn B, eds. Washington, DC: National Academies Press. Google ScholarTan TQ, Kullar R, Swartz TH, Mathew TA, Piggott DA, Berthaud V. 2020. Location matters: geographic disparities and impact of coronavirus disease 2019. J Infect Dis 222(12):1951–1954, PMID: 32942299, 10.1093/infdis/jiaa583. Crossref, Medline, Google ScholarWynants L, Van Calster B, Collins GS, Riley RD, Heinze G, Schuit E, et al.2020. Prediction models for diagnosis and prognosis of covid-19: systematic review and critical appraisal. BMJ 369:m1328, PMID: 32265220, 10.1136/bmj.m1328. Crossref, Medline, Google ScholarThe authors declare they have no actual or potential competing financial interests.FiguresReferencesRelatedDetails Vol. 129, No. 1 January 2021Metrics About Article Metrics Publication History Manuscript received20 November 2020Manuscript revised14 December 2020Manuscript accepted21 December 2020Originally published5 January 2021 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.}, number={1}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={Marvel, Skylar W. and House, John S. and Wheeler, Matthew and Song, Kuncheng and Zhou, Yi-Hui and Wright, Fred A. and Chiu, Weihsueh A. and Rusyn, Ivan and Motsinger-Reif, Alison and Reif, David M.}, year={2021}, month={Jan} }
 @article{wise_hammel_herkert_ma_motsinger-reif_stapleton_breen_2020, title={Comparative Exposure Assessment Using Silicone Passive Samplers Indicates That Domestic Dogs Are Sentinels To Support Human Health Research}, volume={54}, ISSN={["1520-5851"]}, DOI={10.1021/acs.est.9b06605}, abstractNote={Silicone wristbands are promising passive samplers to support epidemiological studies in characterizing exposure to organic contaminants; however, investigating associated health risks remains challenging because of the latency period for many chronic diseases that take years to manifest. Dogs provide valuable insights as sentinels for exposure-related human disease because they share similar exposures in the home, have shorter life spans, share many clinical/biological features, and have closely related genomes. Here, we evaluated exposures among pet dogs and their owners using silicone dog tags and wristbands to determine if contaminant levels were correlated with validated exposure biomarkers. Significant correlations between measures on dog tags and wristbands were observed (rs = 0.38–0.90; p < 0.05). Correlations with their respective urinary biomarkers were stronger in dog tags compared to that in human wristbands (rs = 0.50–0.71; p < 0.01) for several organophosphate esters. This supports the value of using silicone bands with dogs to investigate health impacts on humans from shared exposures.}, number={12}, journal={ENVIRONMENTAL SCIENCE & TECHNOLOGY}, author={Wise, Catherine F. and Hammel, Stephanie C. and Herkert, Nicholas and Ma, Jun and Motsinger-Reif, Alison and Stapleton, Heather M. and Breen, Matthew}, year={2020}, month={Jun}, pages={7409–7419} }
 @article{craun_ekena_sacco_jiang_motsinger-reif_trepanier_2020, title={Genetic and environmental risk for lymphoma in boxer dogs}, volume={34}, ISSN={["1939-1676"]}, DOI={10.1111/jvim.15849}, abstractNote={Background Non-Hodgkin lymphoma in humans is associated with environmental chemical exposures, and risk is enhanced by genetic variants in glutathione S-transferases (GST) enzymes. Objective We hypothesized that boxer dogs, a breed at risk for lymphoma, would have a higher prevalence of GST variants with predicted low activity, and greater accumulated DNA damage, compared to other breeds. We also hypothesized that lymphoma in boxers would be associated with specific environmental exposures and a higher prevalence of canine GST variants. Animals Fifty-four healthy boxers and 56 age-matched nonboxer controls; 63 boxers with lymphoma and 89 unaffected boxers ≥10 years old. Methods We resequenced variant loci in canine GSTT1, GSTT5, GSTM1, and GSTP1 and compared endogenous DNA damage in peripheral leukocytes of boxers and nonboxers using the comet assay. We also compared GST variants and questionnaire-based environmental exposures in boxers with and without lymphoma. Results Endogenous DNA damage did not differ between boxers and nonboxers. Boxers with lymphoma were more likely to live within 10 miles of a nuclear power plant and within 2 miles of a chemical supplier or crematorium. Lymphoma risk was not modulated by known canine GST variants. Conclusions and Clinical Importance Proximity to nuclear power plants, chemical suppliers, and crematoria were significant risk factors for lymphoma in this population of boxers. These results support the hypothesis that aggregate exposures to environmental chemicals and industrial waste may contribute to lymphoma risk in dogs.}, number={5}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Craun, Kaitlyn and Ekena, Joanne and Sacco, James and Jiang, Tao and Motsinger-Reif, Alison and Trepanier, Lauren A.}, year={2020}, month={Sep}, pages={2068–2077} }
 @article{house_bouzos_fahy_francisco_lloyd_wright_motsinger-reif_asuri_wheeler_2020, title={Low-Dose Silver Nanoparticle Surface Chemistry and Temporal Effects on Gene Expression in Human Liver Cells}, volume={16}, ISSN={["1613-6829"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85082473420&partnerID=MN8TOARS}, DOI={10.1002/smll.202000299}, abstractNote={Abstract Silver nanoparticles (AgNPs) are widely incorporated into consumer and biomedical products for their antimicrobial and plasmonic properties with limited risk assessment of low‐dose cumulative exposure in humans. To evaluate cellular responses to low‐dose AgNP exposures across time, human liver cells (HepG2) are exposed to AgNPs with three different surface charges (1.2 µg mL −1 ) and complete gene expression is monitored across a 24 h period. Time and AgNP surface chemistry mediate gene expression. In addition, since cells are fed, time has marked effects on gene expression that should be considered. Surface chemistry of AgNPs alters gene transcription in a time‐dependent manner, with the most dramatic effects in cationic AgNPs. Universal to all surface coatings, AgNP‐treated cells responded by inactivating proliferation and enabling cell cycle checkpoints. Further analysis of these universal features of AgNP cellular response, as well as more detailed analysis of specific AgNP treatments, time points, or specific genes, is facilitated with an accompanying application. Taken together, these results provide a foundation for understanding hepatic response to low‐dose AgNPs for future risk assessment.}, number={21}, journal={SMALL}, author={House, John S. and Bouzos, Evangelia and Fahy, Kira M. and Francisco, Victorino Miguel and Lloyd, Dillon T. and Wright, Fred A. and Motsinger-Reif, Alison A. and Asuri, Prashanth and Wheeler, Korin E.}, year={2020}, month={May} }
 @article{ma_bair_motsinger-reif_2020, title={Nonlinear Dose-Response Modeling of High-Throughput Screening Data Using an Evolutionary Algorithm}, volume={18}, ISSN={["1559-3258"]}, DOI={10.1177/1559325820926734}, abstractNote={Nonlinear dose–response relationships exist extensively in the cellular, biochemical, and physiologic processes that are affected by varying levels of biological, chemical, or radiation stress. Modeling such responses is a crucial component of toxicity testing and chemical screening. Traditional model fitting methods such as nonlinear least squares (NLS) are very sensitive to initial parameter values and often had convergence failure. The use of evolutionary algorithms (EAs) has been proposed to address many of the limitations of traditional approaches, but previous methods have been limited in the types of models they can fit. Therefore, we propose the use of an EA for dose–response modeling for a range of potential response model functional forms. This new method can not only fit the most commonly used nonlinear dose–response models (eg, exponential models and 3-, 4-, and 5-parameter logistic models) but also select the best model if no model assumption is made, which is especially useful in the case of high-throughput curve fitting. Compared with NLS, the new method provides stable and robust solutions without sensitivity to initial values.}, number={2}, journal={DOSE-RESPONSE}, author={Ma, Jun and Bair, Eric and Motsinger-Reif, Alison}, year={2020}, month={Apr} }
 @article{lynch_ruterbories_jack_motsinger-reif_hanel_2020, title={The influence of packed cell volume versus plasma proteins on thromboelastographic variables in canine blood}, volume={30}, ISSN={["1476-4431"]}, url={https://doi.org/10.1111/vec.12979}, DOI={10.1111/vec.12979}, abstractNote={Abstract Objective Determine the correlation between kaolin‐activated thromboelastography (TEG) variables (R, K, angle, and maximum amplitude [MA]) and PCV, fibrinogen concentration (FC), and total fibrinogen (TF) in an ex vivo model. Animals Two healthy adult mixed‐breed dogs. Procedures Citrated whole blood was obtained and separated into packed red cells, platelet rich plasma, and platelet poor plasma (PPP). An aliquot of PPP was heated to denature heat labile proteins (fibrinogen, factor V, factor VIII). Blood components were recombined for analyses of 6 physiological scenarios: anemia with low fibrinogen; anemia with moderate fibrinogen; anemia with normal fibrinogen; anemia with normal saline; normal PCV and normal fibrinogen; and normal PCV and low fibrinogen. A Kruskal–Wallis test, along with linear regressions on pairwise combinations of TEG variables, was used to determine the correlation between TEG variables and PCV, FC, and TF. Results Maximum amplitude correlated with FC ( R 2 0.60, P < 0.001) and TF ( R 2 0.57, P < 0.001) but not PCV ( R 2 0.003, P = 0.7). Angle and K time were moderately correlated with FC ([angle: R 2 0.53, P < 0.001]; [K: R 2 0.55, P < 0.001]) and TF ([alpha angle: R 2 0.52, P < 0.001]; [K: R 2 0.51, P < 0.001]) but not PCV. The R time was weakly correlated with PCV ( R 2 0.15, P < 0.009) but not FC or TF. Conclusions and clinical relevance In an ex vivo model, plasma proteins but not PCV impacted TEG variables. This suggests that TEG changes noted with anemia are imparted by changes in available fibrinogen in a fixed microenvironment rather than artifact of anemia.}, number={4}, journal={JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE}, author={Lynch, Alex M. and Ruterbories, Laura and Jack, John and Motsinger-Reif, Alison A. and Hanel, Rita}, year={2020}, month={Jul}, pages={418–425} }
 @article{crestani_harb_charbonnier_leirer_motsinger-reif_rachid_phipatanakul_kaddurah-daouk_chatila_2020, title={Untargeted metabolomic profiling identifies disease-specific signatures in food allergy and asthma}, volume={145}, ISSN={["1097-6825"]}, DOI={10.1016/j.jaci.2019.10.014}, abstractNote={Background Food allergy (FA) affects an increasing proportion of children for reasons that remain obscure. Novel disease biomarkers and curative treatment options are strongly needed. Objective We sought to apply untargeted metabolomic profiling to identify pathogenic mechanisms and candidate disease biomarkers in patients with FA. Methods Mass spectrometry–based untargeted metabolomic profiling was performed on serum samples of children with either FA alone, asthma alone, or both FA and asthma, as well as healthy pediatric control subjects. Results In this pilot study patients with FA exhibited a disease-specific metabolomic signature compared with both control subjects and asthmatic patients. In particular, FA was uniquely associated with a marked decrease in sphingolipid levels, as well as levels of a number of other lipid metabolites, in the face of normal frequencies of circulating natural killer T cells. Specific comparison of patients with FA and asthmatic patients revealed differences in the microbiota-sensitive aromatic amino acid and secondary bile acid metabolism. Children with both FA and asthma exhibited a metabolomic profile that aligned with that of FA alone but not asthma. Among children with FA, the history of severe systemic reactions and the presence of multiple FAs were associated with changes in levels of tryptophan metabolites, eicosanoids, plasmalogens, and fatty acids. Conclusions Children with FA have a disease-specific metabolomic profile that is informative of disease mechanisms and severity and that dominates in the presence of asthma. Lower levels of sphingolipids and ceramides and other metabolomic alterations observed in children with FA might reflect the interplay between an altered microbiota and immune cell subsets in the gut.}, number={3}, journal={JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY}, author={Crestani, Elena and Harb, Hani and Charbonnier, Louis-Marie and Leirer, Jonathan and Motsinger-Reif, Alison and Rachid, Rima and Phipatanakul, Wanda and Kaddurah-Daouk, Rima and Chatila, Talal A.}, year={2020}, month={Mar}, pages={897–906} }
 @article{tang_lenzini_pop-busui_ray_campbell_perkins_callaghan_wagner_motsinger-reif_buse_et al._2019, title={A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies}, volume={68}, ISSN={["1939-327X"]}, DOI={10.2337/db19-0109}, abstractNote={Genetic factors have been postulated to be involved in the etiology of diabetic peripheral neuropathy (DPN), but their identity remains mostly unknown. The aim of this study was to conduct a systematic search for genetic variants influencing DPN risk using two well-characterized cohorts. A genome-wide association study (GWAS) testing 6.8 million single nucleotide polymorphisms was conducted among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial. Included were 4,384 white case patients with type 2 diabetes (T2D) and prevalent or incident DPN (defined as a Michigan Neuropathy Screening Instrument clinical examination score >2.0) and 784 white control subjects with T2D and no evidence of DPN at baseline or during follow-up. Replication of significant loci was sought among white subjects with T2D (791 DPN-positive case subjects and 158 DPN-negative control subjects) from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial. Association between significant variants and gene expression in peripheral nerves was evaluated in the Genotype-Tissue Expression (GTEx) database. A cluster of 28 SNPs on chromosome 2q24 reached GWAS significance (P < 5 × 10−8) in ACCORD. The minor allele of the lead SNP (rs13417783, minor allele frequency = 0.14) decreased DPN odds by 36% (odds ratio [OR] 0.64, 95% CI 0.55–0.74, P = 1.9 × 10−9). This effect was not influenced by ACCORD treatment assignments (P for interaction = 0.6) or mediated by an association with known DPN risk factors. This locus was successfully validated in BARI 2D (OR 0.57, 95% CI 0.42–0.80, P = 9 × 10−4; summary P = 7.9 × 10−12). In GTEx, the minor, protective allele at this locus was associated with higher tibial nerve expression of an adjacent gene (SCN2A) coding for human voltage-gated sodium channel NaV1.2 (P = 9 × 10−4). To conclude, we have identified and successfully validated a previously unknown locus with a powerful protective effect on the development of DPN in T2D. These results may provide novel insights into DPN pathogenesis and point to a potential target for novel interventions.}, number={8}, journal={DIABETES}, author={Tang, Yaling and Lenzini, Petra A. and Pop-Busui, Rodica and Ray, Pradipta R. and Campbell, Hannah and Perkins, Bruce A. and Callaghan, Brian and Wagner, Michael J. and Motsinger-Reif, Alison A. and Buse, John B. and et al.}, year={2019}, month={Aug}, pages={1649–1662} }
 @article{mahmoudiandehkordi_arnold_nho_ahmad_jia_xie_louie_kueider-paisley_moseley_thompson_et al._2019, title={Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome}, volume={15}, ISSN={1552-5260}, url={http://dx.doi.org/10.1016/J.JALZ.2018.07.217}, DOI={10.1016/J.JALZ.2018.07.217}, abstractNote={Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD).Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing.In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles.We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.}, number={1}, journal={Alzheimer's & Dementia}, publisher={Elsevier BV}, author={MahmoudianDehkordi, Siamak and Arnold, Matthias and Nho, Kwangsik and Ahmad, Shahzad and Jia, Wei and Xie, Guoxiang and Louie, Gregory and Kueider-Paisley, Alexandra and Moseley, M. Arthur and Thompson, J. Will and et al.}, year={2019}, month={Jan}, pages={76–92} }
 @article{st john-williams_mahmoudiandehkordi_arnold_massaro_blach_kastenmueller_louie_kueider-paisley_han_baillie_et al._2019, title={Bile acids targeted metabolomics and medication classification data in the ADNI1 and ADNIGO/2 cohorts}, volume={6}, ISSN={["2052-4463"]}, DOI={10.1038/s41597-019-0181-8}, abstractNote={Abstract Alzheimer’s disease (AD) is the most common cause of dementia. The mechanism of disease development and progression is not well understood, but increasing evidence suggests multifactorial etiology, with a number of genetic, environmental, and aging-related factors. There is a growing body of evidence that metabolic defects may contribute to this complex disease. To interrogate the relationship between system level metabolites and disease susceptibility and progression, the AD Metabolomics Consortium (ADMC) in partnership with AD Neuroimaging Initiative (ADNI) is creating a comprehensive biochemical database for patients in the ADNI1 cohort. We used the Biocrates Bile Acids platform to evaluate the association of metabolic levels with disease risk and progression. We detail the quantitative metabolomics data generated on the baseline samples from ADNI1 and ADNIGO/2 (370 cognitively normal, 887 mild cognitive impairment, and 305 AD). Similar to our previous reports on ADNI1, we present the tools for data quality control and initial analysis. This data descriptor represents the third in a series of comprehensive metabolomics datasets from the ADMC on the ADNI.}, journal={SCIENTIFIC DATA}, author={St John-Williams, Lisa and Mahmoudiandehkordi, Siamak and Arnold, Matthias and Massaro, Tyler and Blach, Colette and Kastenmueller, Gabi and Louie, Gregory and Kueider-Paisley, Alexandra and Han, Xianlin and Baillie, Rebecca and et al.}, year={2019}, month={Oct} }
 @article{ash_kuenemann_rotroff_motsinger-reif_fourches_2019, title={Cheminformatics approach to exploring and modeling trait-associated metabolite profiles}, volume={11}, ISSN={["1758-2946"]}, DOI={10.1186/s13321-019-0366-3}, abstractNote={Developing predictive and transparent approaches to the analysis of metabolite profiles across patient cohorts is of critical importance for understanding the events that trigger or modulate traits of interest (e.g., disease progression, drug metabolism, chemical risk assessment). However, metabolites’ chemical structures are still rarely used in the statistical modeling workflows that establish these trait-metabolite relationships. Herein, we present a novel cheminformatics-based approach capable of identifying predictive, interpretable, and reproducible trait-metabolite relationships. As a proof-of-concept, we utilize a previously published case study consisting of metabolite profiles from non-small-cell lung cancer (NSCLC) adenocarcinoma patients and healthy controls. By characterizing each structurally annotated metabolite using both computed molecular descriptors and patient metabolite concentration profiles, we show that these complementary features enhance the identification and understanding of key metabolites associated with cancer. Ultimately, we built multi-metabolite classification models for assessing patients’ cancer status using specific groups of metabolites identified based on high structural similarity through chemical clustering. We subsequently performed a metabolic pathway enrichment analysis to identify potential mechanistic relationships between metabolites and NSCLC adenocarcinoma. This cheminformatics-inspired approach relies on the metabolites’ structural features and chemical properties to provide critical information about metabolite-trait associations. This method could ultimately facilitate biological understanding and advance research based on metabolomics data, especially with respect to the identification of novel biomarkers.}, journal={JOURNAL OF CHEMINFORMATICS}, author={Ash, Jeremy R. and Kuenemann, Melaine A. and Rotroff, Daniel and Motsinger-Reif, Alison and Fourches, Denis}, year={2019}, month={Jun} }
 @article{menden_wang_mason_szalai_bulusu_guan_yu_kang_jeon_wolfinger_et al._2019, title={Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen}, volume={10}, ISSN={["2041-1723"]}, DOI={10.1038/s41467-019-09799-2}, abstractNote={Abstract The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.}, journal={NATURE COMMUNICATIONS}, author={Menden, Michael P. and Wang, Dennis and Mason, Mike J. and Szalai, Bence and Bulusu, Krishna C. and Guan, Yuanfang and Yu, Thomas and Kang, Jaewoo and Jeon, Minji and Wolfinger, Russ and et al.}, year={2019}, month={Jun} }
 @article{sikdar_joehanes_joubert_xu_vives-usano_rezwan_felix_ward_guan_richmond_et al._2019, title={Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking}, volume={11}, ISSN={["1750-192X"]}, DOI={10.2217/epi-2019-0066}, abstractNote={Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.}, number={13}, journal={EPIGENOMICS}, author={Sikdar, Sinjini and Joehanes, Roby and Joubert, Bonnie R. and Xu, Cheng-Jian and Vives-Usano, Marta and Rezwan, Faisal I. and Felix, Janine F. and Ward, James M. and Guan, Weihua and Richmond, Rebecca C. and et al.}, year={2019}, month={Oct}, pages={1487–1500} }
 @article{kennedy_thomas_durrant_jiang_motsinger-reif_breen_2019, title={Genome-wide DNA copy number analysis and targeted transcriptional analysis of canine histiocytic malignancies identifies diagnostic signatures and highlights disruption of spindle assembly complex}, volume={27}, ISSN={["1573-6849"]}, DOI={10.1007/s10577-019-09606-0}, number={3}, journal={CHROMOSOME RESEARCH}, author={Kennedy, Katherine and Thomas, Rachael and Durrant, Jessica and Jiang, Tao and Motsinger-Reif, Alison and Breen, Matthew}, year={2019}, month={Sep}, pages={179–202} }
 @article{west_lu_rotroff_kuenemann_chang_wu_wagner_buse_motsinger-reif_fourches_et al._2019, title={Identifying individual risk rare variants using protein structure guided local tests (POINT)}, volume={15}, ISSN={["1553-7358"]}, DOI={10.1371/journal.pcbi.1006722}, abstractNote={Rare variants are of increasing interest to genetic association studies because of their etiological contributions to human complex diseases. Due to the rarity of the mutant events, rare variants are routinely analyzed on an aggregate level. While aggregation analyses improve the detection of global-level signal, they are not able to pinpoint causal variants within a variant set. To perform inference on a localized level, additional information, e.g., biological annotation, is often needed to boost the information content of a rare variant. Following the observation that important variants are likely to cluster together on functional domains, we propose a protein structure guided local test (POINT) to provide variant-specific association information using structure-guided aggregation of signal. Constructed under a kernel machine framework, POINT performs local association testing by borrowing information from neighboring variants in the 3-dimensional protein space in a data-adaptive fashion. Besides merely providing a list of promising variants, POINT assigns each variant a p-value to permit variant ranking and prioritization. We assess the selection performance of POINT using simulations and illustrate how it can be used to prioritize individual rare variants in PCSK9, ANGPTL4 and CETP in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data.}, number={2}, journal={PLOS COMPUTATIONAL BIOLOGY}, author={West, Rachel Marceau and Lu, Wenbin and Rotroff, Daniel M. and Kuenemann, Melaine A. and Chang, Sheng-Mao and Wu, Michael C. and Wagner, Michael J. and Buse, John B. and Motsinger-Reif, Alison A. and Fourches, Denis and et al.}, year={2019}, month={Feb} }
 @article{fox_keene_lamb_schober_chetboul_fuentes_payne_wess_hogan_abbott_et al._2019, title={Long-term incidence and risk of noncardiovascular and all-cause mortality in apparently healthy cats and cats with preclinical hypertrophic cardiomyopathy}, volume={33}, ISSN={["1939-1676"]}, DOI={10.1111/jvim.15609}, abstractNote={Background Epidemiologic knowledge regarding noncardiovascular and all-cause mortality in apparently healthy cats (AH) and cats with preclinical hypertrophic cardiomyopathy (pHCM) is limited, hindering development of evidence-based healthcare guidelines. Objectives To characterize/compare incidence rates, risk, and survival associated with noncardiovascular and all-cause mortality in AH and pHCM cats. Animals A total of 1730 client-owned cats (722 AH, 1008 pHCM) from 21 countries. Methods Retrospective, multicenter, longitudinal, cohort study. Long-term health data were extracted by medical record review and owner/referring veterinarian interviews. Results Noncardiovascular death occurred in 534 (30.9%) of 1730 cats observed up to 15.2 years. Proportion of noncardiovascular death did not differ significantly between cats that at study enrollment were AH or had pHCM (P = .48). Cancer, chronic kidney disease, and conditions characterized by chronic weight-loss-vomiting-diarrhea-anorexia were the most frequently recorded noncardiovascular causes of death. Incidence rates/risk of noncardiac death increased with age in AH and pHCM. All-cause death proportions were greater in pHCM than AH (65% versus 40%, respectively; P < .001) because of higher cardiovascular mortality in pHCM cats. Comparing AH with pHCM, median survival (study entry to noncardiovascular death) did not differ (AH, 9.8 years; pHCM, 8.6 years; P = .10), but all-cause survival was significantly shorter in pHCM (P = .0001). Conclusions and Clinical Importance All-cause mortality was significantly greater in pHCM cats due to disease burden contributed by increased cardiovascular death superimposed upon noncardiovascular death.}, number={6}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Fox, Philip R. and Keene, Bruce W. and Lamb, Kenneth and Schober, Karsten E. and Chetboul, Valerie and Fuentes, Virginia Luis and Payne, Jessie Rose and Wess, Gerhard and Hogan, Daniel F. and Abbott, Jonathan A. and et al.}, year={2019}, month={Nov}, pages={2572–2586} }
 @article{roell_havener_reif_jack_mcleod_wiltshire_motsinger-reif_2019, title={Synergistic Chemotherapy Drug Response Is a Genetic Trait in Lymphoblastoid Cell Lines}, volume={10}, ISSN={["1664-8021"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85074258240&partnerID=MN8TOARS}, DOI={10.3389/fgene.2019.00829}, abstractNote={Lymphoblastoid cell lines (LCLs) are a highly successful model for evaluating the genetic etiology of cancer drug response, but applications using this model have typically focused on single drugs. Combination therapy is quite common in modern chemotherapy treatment since drugs often work synergistically, and it is an important progression in the use of the LCL model to expand work for drug combinations. In the present work, we demonstrate that synergy occurs and can be quantified in LCLs across a range of clinically important drug combinations. Lymphoblastoid cell lines have been commonly employed in association mapping in cancer pharmacogenomics, but it is so far untested as to whether synergistic effects have a genetic etiology. Here we use cell lines from extended pedigrees to demonstrate that there is a substantial heritable component to synergistic drug response. Additionally, we perform linkage mapping in these pedigrees to identify putative regions linked to this important phenotype. This demonstration supports the premise of expanding the use of the LCL model to perform association mapping for combination therapies.}, journal={FRONTIERS IN GENETICS}, author={Roell, Kyle R. and Havener, Tammy M. and Reif, David M. and Jack, John and McLeod, Howard L. and Wiltshire, Tim and Motsinger-Reif, Alison A.}, year={2019}, month={Oct} }
 @article{crestani_leirer_motsinger-reif_phipatanakul_kaddurah-daouk_chatila_2019, title={Untargeted Metabolomic Profiling Identifies Disease-Specific Pathways in Food Allergy and Asthma}, volume={143}, ISSN={["1097-6825"]}, DOI={10.1016/j.jaci.2018.12.778}, abstractNote={Food allergy (FA) affects an increasing proportion of children in the US and other developed countries for reasons that remain largely unknown. A deeper understanding of pathogenic mechanisms active in FA may lead to much needed diagnostic and prognostic biomarkers of disease and improved treatment options. Children with asthma alone, children with FA alone, children with both FA and asthma as well as healthy pediatric controls were recruited in the Allergy clinic at Boston Children’s Hospital. Mass spectrometry-based untargeted metabolomic profiling was performed on serum samples (n=35 for FA or asthma alone and FA/asthma; n=20 for controls) looking at global metabolism. Untargeted metabolomic analysis revealed differential profiles of altered metabolites in patients’ groups. In comparison to both controls and children with asthma, FA was uniquely associated with a marked decrease in sphingolipids - in particular sphingomyelins and ceramides - as well as lysophospholipids. Among atopic children, differences in aromatic amino acid metabolism and metabolism of secondary bile acids were observed between food allergic and asthmatic children. Among children with FA, the metabolomic profile of those with asthma was indistinguishable from that of children without asthma. Both unique and shared metabolomic alterations were detected in children with FA, asthma, or both, likely reflecting overlapping but distinct mechanisms and environmental influences operative in these disorders. Lower levels of sphingolipids and ceramides observed in food allergic children may affect the interplay between microbiota and immune cell subsets in the gut, including iNKT cells.}, number={2}, journal={JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY}, author={Crestani, Elena and Leirer, Jonathan and Motsinger-Reif, Alison and Phipatanakul, Wanda and Kaddurah-Daouk, Rima and Chatila, Talal A.}, year={2019}, month={Feb}, pages={AB255–AB255} }
 @article{jack_small_brown_havener_mcleod_motsinger-reif_richards_2018, title={Gene expression and linkage analysis implicate as a mediator of rituximab resistance}, volume={18}, ISSN={["1473-1150"]}, DOI={10.1038/tpj.2017.41}, abstractNote={Elucidating resistance mechanisms for therapeutic monoclonal antibodies (MAbs) is challenging, because they are difficult to study in non-human models. We therefore developed a strategy to genetically map in vitro drug sensitivity, identifying genes that alter responsiveness to rituximab, a therapeutic anti-CD20 MAb that provides significant benefit to patients with B-cell malignancies. We discovered novel loci with genome-wide mapping analyses and functionally validated one of these genes, CBLB, which causes rituximab resistance when knocked down in lymphoma cells. This study demonstrates the utility of genome-wide mapping to discover novel biological mechanisms of potential clinical advantage.}, number={3}, journal={PHARMACOGENOMICS JOURNAL}, author={Jack, J. and Small, G. W. and Brown, C. C. and Havener, T. M. and McLeod, H. L. and Motsinger-Reif, A. A. and Richards, K. L.}, year={2018}, month={May}, pages={467–473} }
 @article{mathur_rotroff_ma_shojaie_motsinger-reif_2018, title={Gene set analysis methods: A systematic comparison}, volume={11}, journal={Biodata Mining}, author={Mathur, R. and Rotroff, D. and Ma, J. and Shojaie, A. and Motsinger-Reif, A.}, year={2018} }
 @article{morieri_gao_pigeyre_shah_sjaarda_mendonca_hastings_buranasupkajorn_motsinger-reif_rotroff_et al._2018, title={Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial}, volume={41}, ISSN={["1935-5548"]}, DOI={10.2337/dc18-0709}, abstractNote={OBJECTIVE We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk. RESEARCH DESIGN AND METHODS A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression. RESULTS The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18–1.37, P = 4 × 10−10, and HR per SD 1.35, 95% CI 1.16–1.58, P = 2 × 10−4, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 × 10−4). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years. CONCLUSIONS When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci.}, number={11}, journal={DIABETES CARE}, author={Morieri, Mario Luca and Gao, He and Pigeyre, Marie and Shah, Hetal S. and Sjaarda, Jennifer and Mendonca, Christine and Hastings, Timothy and Buranasupkajorn, Patinut and Motsinger-Reif, Alison A. and Rotroff, Daniel M. and et al.}, year={2018}, month={Nov}, pages={2404–2413} }
 @article{rotroff_yee_zhou_marvel_shah_jack_havener_hedderson_kubo_herman_et al._2018, title={Genetic variants in CPA6 and PRPF31 are associated with variation in response to metformin in individuals with type 2 diabetes}, volume={67}, number={7}, journal={Diabetes}, author={Rotroff, D. M. and Yee, S. W. and Zhou, K. X. and Marvel, S. W. and Shah, H. S. and Jack, J. R. and Havener, T. M. and Hedderson, M. M. and Kubo, M. and Herman, M. A. and et al.}, year={2018}, pages={1428–1440} }
 @article{fox_keene_lamb_schober_chetboul_fuentes_wess_payne_hogan_motsinger-reif_et al._2018, title={International collaborative study to assess cardiovascular risk and evaluate long-term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats: The REVEAL Study}, volume={32}, number={3}, journal={Journal of Veterinary Internal Medicine}, author={Fox, P. R. and Keene, B. W. and Lamb, K. and Schober, K. A. and Chetboul, V. and Fuentes, V. L. and Wess, G. and Payne, J. R. and Hogan, D. F. and Motsinger-Reif, A. and et al.}, year={2018}, pages={930–943} }
 @article{shah_morieri_marcovina_sigal_gerstein_wagner_motsinger-reif_buse_kraft_mychaleckyj_et al._2018, title={Modulation of GLP-1 Levels by a Genetic Variant That Regulates the Cardiovascular Effects of Intensive Glycemic Control in ACCORD}, volume={41}, ISSN={["1935-5548"]}, DOI={10.2337/dc17-1638}, abstractNote={OBJECTIVE A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants. RESEARCH DESIGN AND METHODS Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD-MIND) MRI substudy (n = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (Δ), among white subjects, with genotype data (n = 351) stratified by intervention arm. RESULTS A significant association was observed between GRS and ΔGLP-1 (glucagon-like peptide 1, active) in the intensive arm (P = 3 × 10−4). This effect was driven by rs57922 (P = 5 × 10−4). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between ΔGLP-1 and GRS or rs57922 was observed in the standard treatment arm. CONCLUSIONS Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor.}, number={2}, journal={DIABETES CARE}, author={Shah, Hetal S. and Morieri, Mario Luca and Marcovina, Santica M. and Sigal, Ronald J. and Gerstein, Hertzel C. and Wagner, Michael J. and Motsinger-Reif, Alison A. and Buse, John B. and Kraft, Peter and Mychaleckyj, Josyf C. and et al.}, year={2018}, month={Feb}, pages={348–355} }
 @article{chen_akhtari_wagner_suzuki_wiltshire_motsinger-reif_dumond_2018, title={Pharmacogenetic Analysis of the Model-Based Pharmacokinetics of Five Anti-HIV Drugs: How Does This Influence the Effect of Aging?}, volume={11}, ISSN={["1752-8062"]}, DOI={10.1111/cts.12525}, abstractNote={Analysis of aging and pharmacogenetics (PGx) on antiretroviral pharmacokinetics (PKs) could inform precision dosing for older human HIV-infected patients. Seventy-four participants receiving either atazanavir/ritonavir (ATV/RTV) or efavirenz (EFV) with tenofovir/emtricitabine (TFV/FTC) provided PK and PGx information. Aging-PGx-PK association and interaction analyses were conducted using one-way analysis of variance (ANOVA), multiple linear regression, and Random Forest ensemble methods. Our analyses associated unbound ATV disposition with multidrug resistance protein (MRP)4, RTV with P-glycoprotein (P-gp), and EFV with cytochrome P450 (CYP)2B6 and MRP4 genetic variants. The clearance and cellular distribution of TFV were associated with P-gp, MRP2, and concentrative nucleoside transporters (CNTs), and FTC parameters were associated with organic cation transporters (OCTs) and MRP2 genetic variants. Notably, p16INK4a expression, a cellular aging marker, predicted EFV and FTC PK when genetic factors were adjusted. Both age and p16INK4a expression interacted with PGx on ATV and TFV disposition, implying potential dose adjustment based on aging may depend on genetic background.}, number={2}, journal={CTS-CLINICAL AND TRANSLATIONAL SCIENCE}, author={Chen, Jingxian and Akhtari, Farida S. and Wagner, Michael J. and Suzuki, Oscar and Wiltshire, Tim and Motsinger-Reif, Alison A. and Dumond, Julie B.}, year={2018}, month={Mar}, pages={226–236} }
 @article{kaddurah-daouk_hankemeier_scholl_baillie_harms_stage_dalhoff_jurgens_taboureau_nzabonimpa_et al._2018, title={Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate}, volume={7}, DOI={10.1002/psp4.12309}, abstractNote={Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity as determined by PK parameters of methylphenidate including a ceramide (q value = 0.001) and a phosphatidylcholine (q value = 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value = 0.040) and several high polyunsaturated fatty acid lipids (PUFAs). The half‐maximal inhibitory concentration (IC 50 ) values of chenodeoxycholate and taurocholate were 13.55 and 19.51 μM, respectively, consistent with a physiological significance. In silico analysis suggested that bile acid inhibition of CES1 involved both binding to the active and superficial sites of the enzyme. We initiated identification of metabolites predicting PKs of drugs metabolized by CES1 and suggest lipids to regulate or be regulated by this enzyme.}, number={8}, journal={CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY}, author={Kaddurah-Daouk, Rima and Hankemeier, Thomas and Scholl, Elizabeth H. and Baillie, Rebecca and Harms, Amy and Stage, Claus and Dalhoff, Kim P. and Jurgens, Gesche and Taboureau, Olivier and Nzabonimpa, Grace S. and et al.}, year={2018}, pages={525–533} }
 @article{shahin_gong_frye_rotroff_beitelshees_baillie_chapman_gums_turner_boerwinkle_et al._2018, title={Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics}, volume={7}, ISSN={["2047-9980"]}, DOI={10.1161/jaha.117.006656}, abstractNote={Although hydrochlorothiazide (HCTZ) is a well-established first-line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure (BP) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response.First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway (P=5.8E-05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C-allele carriers had a better BP response to HCTZ versus noncarriers (∆SBP/∆DBP: -11.4/-6.9 versus -6.8/-3.5 mm Hg; ∆SBP P=6.7E-04; ∆DBP P=4.8E-04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC3 genomic region significantly associated with the BP response to HCTZ (P<0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP-response (r=-0.42; P=7E-03) and SBP-response (r=-0.36; P=2E-02).This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC3 is a potential determinant of the BP response to HCTZ.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519.}, number={1}, journal={JOURNAL OF THE AMERICAN HEART ASSOCIATION}, author={Shahin, Mohamed H. and Gong, Yan and Frye, Reginald F. and Rotroff, Daniel M. and Beitelshees, Amber L. and Baillie, Rebecca A. and Chapman, Arlene B. and Gums, John G. and Turner, Stephen T. and Boerwinkle, Eric and et al.}, year={2018}, month={Jan} }
 @article{akhtari_havener_fukudo_jack_mcleod_wiltshire_motsinger-reif_2018, title={The influence of Neanderthal alleles on cytotoxic response}, volume={6}, ISSN={["2167-8359"]}, DOI={10.7717/peerj.5691}, abstractNote={Various studies have shown that people of Eurasian origin contain traces of DNA inherited from interbreeding with Neanderthals. Recent studies have demonstrated that these Neanderthal variants influence a range of clinically important traits and diseases. Thus, understanding the genetic factors responsible for the variability in individual response to drug or chemical exposure is a key goal of pharmacogenomics and toxicogenomics, as dose responses are clinically and epidemiologically important traits. It is well established that ethnic and racial differences are important in dose response traits, but to our knowledge the influence of Neanderthal ancestry on response to xenobiotics is unknown. Towards this aim, we examined if Neanderthal ancestry plays a role in cytotoxic response to anti-cancer drugs and toxic environmental chemicals. We identified common Neanderthal variants in lymphoblastoid cell lines (LCLs) derived from the globally diverse 1000 Genomes Project and Caucasian cell lines from the Children’s Hospital of Oakland Research Institute. We analyzed the effects of these Neanderthal alleles on cytotoxic response to 29 anti-cancer drugs and 179 environmental chemicals at varying concentrations using genome-wide data. We identified and replicated single nucleotide polymorphisms (SNPs) from these association results, including a SNP in the SNORD-113 cluster. Our results also show that the Neanderthal alleles cumulatively lead to increased sensitivity to both the anti-cancer drugs and the environmental chemicals. Our results demonstrate the influence of Neanderthal ancestry-informative markers on cytotoxic response. These results could be important in identifying biomarkers for personalized medicine or in dissecting the underlying etiology of dose response traits.}, journal={PEERJ}, author={Akhtari, Farida S. and Havener, Tammy M. and Fukudo, Masahide and Jack, John R. and McLeod, Howard L. and Wiltshire, Tim and Motsinger-Reif, Alison A.}, year={2018}, month={Oct} }
 @misc{roell_reif_motsinger-reif_2017, title={An introduction to terminology and methodology of chemical synergy-perspectives from across disciplines}, volume={8}, journal={Frontiers in Pharmacology}, author={Roell, K. R. and Reif, D. M. and Motsinger-Reif, A. A.}, year={2017} }
 @article{teferedegne_rotroff_macauley_foseh_lewis_motsinger-rief_lewis_2017, title={Assessment of potential miRNA biomarkers of VERO-cell tumorigenicity in a new line (AGMK1-9T7) of African green monkey kidney cells}, volume={35}, ISSN={["1873-2518"]}, DOI={10.1016/j.vaccine.2017.04.004}, abstractNote={Patterns of microRNA expression appear to delineate the process of spontaneous neoplastic development-transformation (SPNDT) occurring in the African green monkey kidney (AGMK) VERO cell line (Teferedegne et al., 2010). Analysis of microarray data identified 6 microRNAs whose high-level of expression peaked when the World Health Organization 10-87 VERO cells became tumorigenic at passage (p) 190. Six miRNAs were identified as potential biomarkers for the expression of the VERO-cell tumorigenic phenotype (Teferedegne et al., 2014). However, the question remained whether these miRNA biomarkers are specific for VERO cells or can be generalizable to other cells originating from African green monkey kidneys. To examine miRNA expression patterns in AGMK cells at lower passage levels and to re-examine the identified miRNAs as biomarkers associated with tumorigenic phenotype of VERO cells in another independently-derived line, we established a new line of African green monkey kidney cells (AGMK1-9T7) by serially passaging kidney cells from another AGM. The AGMK1-9T7 cells became tumorigenic in nude mice at p40. Evaluation of miRNA expression at intervals from p1 to p40 revealed similarities between the evolution of miRNA expression during SPNDT in the AGMK1-9T7 cells and the 10-87 VERO cells. Four of the 6 potential biomarker miRNAs (miR-376a, miR-654-3p, miR-543, miR-134) in our earlier reports were detected by microarray in the AGMK1-9T7 cells; RT-qPCR analysis detected all 6 miRNAs. All 6 of these miRNAs have been associated with human tumors. Detection of the same miRNAs associated with the tumorigenic p40 AGMK1-9T7 cells and tumorigenic 10-87 VERO cells confirmed our proposal that these miRNA represent biomarkers for the tumor-forming ability of AGMK/VERO cells. The similarities of expression of miRNAs in different AGMK cell lines that were established 50years apart suggest that the process of SPNDT in these non-human primate cells in tissue culture is based upon similar genetic and epigenetic mechanisms.}, number={41}, journal={VACCINE}, author={Teferedegne, Belete and Rotroff, Daniel M. and Macauley, Juliete and Foseh, Gideon and Lewis, Gladys and Motsinger-Rief, Alison and Lewis, Andrew M., Jr.}, year={2017}, month={Oct}, pages={5503–5509} }
 @article{mochizuki_motsinger-reif_bettini_moroff_breen_2017, title={Association of breed and histopathological grade in canine mast cell tumours}, volume={15}, ISSN={["1476-5829"]}, url={http://europepmc.org/abstract/med/27198171}, DOI={10.1111/vco.12225}, abstractNote={Abstract The aim of this study was to evaluate the relationship between breed and the histopathological grade of canine mast cell tumours ( MCTs ). A retrospective survey of pathology data of 9375 histopathologically confirmed diagnoses of cutaneous MCTs in the US was evaluated in the context of breed prevalence in over two million registered purebred dogs. Association of histopathological grade with breed, age, sex and spay/neuter status was assessed. The data indicate that the proportion of high‐grade tumours increases with advancing age, and that male and intact dogs have increased odds of developing high‐grade tumours. A significant difference in the proportion of high‐grade tumours between breeds was detected. The Pug was at significantly increased risk of developing low/intermediate‐grade tumours, but not high‐grade tumours, resulting in preponderance of less aggressive MCTs in this breed. The results of this study suggest a genetic association for the development of high‐grade MCTs .}, number={3}, journal={VETERINARY AND COMPARATIVE ONCOLOGY}, author={Mochizuki, H. and Motsinger-Reif, A. and Bettini, C. and Moroff, S. and Breen, M.}, year={2017}, month={Sep}, pages={829–839} }
 @article{marvel_rotroff_wagner_buse_havener_mcleod_motsinger-reif_2017, title={Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial}, volume={5}, journal={PeerJ}, author={Marvel, S. W. and Rotroff, D. M. and Wagner, M. J. and Buse, J. B. and Havener, T. M. and McLeod, H. L. and Motsinger-Reif, A. A.}, year={2017} }
 @article{rotroff_marvel_jack_havener_doria_shah_mychaleckyi_mcleod_buse_wagner_et al._2017, title={Common genetic variants in neurobeachin (nbea) are associated with metformin drug response in individuals with type 2 diabetes in the accord clinical trial}, volume={101}, number={S1}, journal={Clinical Pharmacology & Therapeutics}, author={Rotroff, D. M. and Marvel, S. W. and Jack, J. R. and Havener, T. M. and Doria, A. and Shah, H. S. and Mychaleckyi, J. C. and McLeod, H. L. and Buse, J. B. and Wagner, M. J. and et al.}, year={2017}, pages={S9–9} }
 @article{st john-williams_blach_toledo_rotroff_kim_klavins_baillie_han_mahmoudiandehkordi_jack_et al._2017, title={Data descriptor: Targeted metabolomics and medication classification data from participants in the ADNI1 cohort}, volume={4}, journal={Scientific Data}, author={St John-Williams, L. and Blach, C. and Toledo, J. B. and Rotroff, D. M. and Kim, S. and Klavins, K. and Baillie, R. and Han, X. L. and Mahmoudiandehkordi, S. and Jack, J. and et al.}, year={2017} }
 @article{nho_dehkordi_motsinger-reif_baillie_bhattacharyya_tenenbaum_thompson_st. john williams_moseley_koal_et al._2017, title={GUT DERIVED BILE ACID METABOLITES CORRELATE WITH STRUCTURAL AND FUNCTIONAL NEUROIMAGING MEASURES IN ALZHEIMER’S DISEASE}, volume={13}, ISSN={1552-5260}, url={http://dx.doi.org/10.1016/J.JALZ.2017.07.131}, DOI={10.1016/J.JALZ.2017.07.131}, abstractNote={Primary and secondary bile acids and their glycine and taurine conjugated forms are end products of cholesterol metabolism produced by human and gut microbiome co metabolism. Mounting evidence suggests that they could play an endogenous role in the central nervous system as signaling molecules in the brain. Initial data suggested that their metabolism seems dysregulated in Alzheimer's disease (AD). Little work has been done to link peripheral metabolic changes to brain central changes. In studies of two large cohorts ADNI-1 and ADNI-GO-2, we performed a neuroimaging analysis to identify serum-based bile acid metabolites associated with AD-related structural and functional neuroimaging measures. 1,556 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (720 ADNI-1 and 836 ADNI-GO-2) with both neuroimaging scans and bile acid metabolite data (measured from fasting serum samples; 15 bile acids, 3 summations, and 10 ratios) were included in this analysis. We investigated the association of bile acid profiles with eleven AD-related structural MRI-based ROI (region of interest) mean values of volumes, cortical thicknesses, and grey matter densities. Significant associations were determined using FDR (false discovery rate) adjustment. Following this ROI-based analysis, we performed a detailed whole brain analysis using multivariate regression models to assess the effect of bile acid profiles on cortical thickness and glucose metabolism. Of 28 bile acid measures, 10 profiles were significantly associated with at least one imaging phenotype after controlling for multiple testing (FDR-corrected p<0.05) in the ADNI-1 cohort. For a ratio GCDCA:CDCA profile, higher levels were associated with more structural atrophy, especially associated with reduced cortical thickness predominantly in the bilateral frontal, parietal, and temporal lobes (Fig. 1). Of the 10 significantly associated bile acid profiles, 2 ratios (GCDCA:CDCA and GUDCA:UDCA) were replicated in the independent ADNI-GO-2 cohort. For the functional neuroimaging analysis, the ratio GCDCA:CDCA profile was significantly associated with decreased glucose metabolism (measured by FDG PET) in the bilateral temporal and parietal lobes. This is the first study to show that serum-based bile acid metabolites are associated with AD-related structural and functional neuroimaging phenotypes. Our results provide further support that bile acid signaling machinery is most likely implicated in neurodegenerative diseases. Association of a ratio GCDCA:CDCA profile with brain structure using whole brain surface-based analysis using two independent cohorts: (a) ADNI-1 (discovery sample) and (b) ADNI-GO-2 (replication sample). Whole-brain cortical thickness analysis demonstrated the identification and replication of brain regions, especially bilateral temporal lobes, significantly associated with bile acid levels. Higher levels were associated with more structural atrophy or reduced cortical thickness. Statistical maps computed using SurfStat were thresholded using random field theory (RFT) as a multiple testing correction at p-corrected < 0.05.}, number={7}, journal={Alzheimer's & Dementia}, publisher={Elsevier BV}, author={Nho, Kwangsik and Dehkordi, Siamak Mahmoudian and Motsinger-Reif, Alison and Baillie, Rebecca A. and Bhattacharyya, Sudeepa and Tenenbaum, Jessica D. and Thompson, J Will and St. John Williams, Lisa and Moseley, M Arthur and Koal, Therese and et al.}, year={2017}, month={Jul}, pages={P543–P544} }
 @article{rotroff_pijut_marvel_jack_havener_pujol_schluter_graf_ginsberg_shah_et al._2017, title={Genetic Variants in
            HSD17B3
            ,
            SMAD3
            , and
            IPO11
            Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes}, volume={103}, ISSN={0009-9236 1532-6535}, url={http://dx.doi.org/10.1002/CPT.798}, DOI={10.1002/CPT.798}, abstractNote={Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10-6 ). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor-beta (TGF-β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D.}, number={4}, journal={Clinical Pharmacology & Therapeutics}, publisher={Wiley}, author={Rotroff, Daniel M. and Pijut, Sonja S. and Marvel, Skylar W. and Jack, John R. and Havener, Tammy M. and Pujol, Aurora and Schluter, Agatha and Graf, Gregory A. and Ginsberg, Henry N. and Shah, Hetal S. and et al.}, year={2017}, month={Nov}, pages={712–721} }
 @article{toledo_arnold_kastenmuller_chang_baillie_han_thambisetty_tenenbaum_suhre_thompson_et al._2017, title={Metabolic network failures in Alzheimer's disease: A biochemical road map}, volume={13}, number={9}, journal={Alzheimers & Dementia}, author={Toledo, J. B. and Arnold, M. and Kastenmuller, G. and Chang, R. and Baillie, R. A. and Han, X. L. and Thambisetty, M. and Tenenbaum, J. D. and Suhre, K. and Thompson, J. W. and et al.}, year={2017}, pages={965–984} }
 @article{toledo_arnold_kastenmüller_chang_baillie_han_thambisetty_tenenbaum_suhre_thompson_et al._2017, title={Metabolic network failures in Alzheimer's disease: A biochemical road map}, volume={13}, ISSN={1552-5260}, url={http://dx.doi.org/10.1016/J.JALZ.2017.01.020}, DOI={10.1016/J.JALZ.2017.01.020}, abstractNote={The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.}, number={9}, journal={Alzheimer's & Dementia}, publisher={Elsevier BV}, author={Toledo, Jon B. and Arnold, Matthias and Kastenmüller, Gabi and Chang, Rui and Baillie, Rebecca A. and Han, Xianlin and Thambisetty, Madhav and Tenenbaum, Jessica D. and Suhre, Karsten and Thompson, J. Will and et al.}, year={2017}, month={Sep}, pages={965–984} }
 @article{st john-williams_blach_toledo_rotroff_kim_klavins_baillie_han_mahmoudiandehkordi_jack_et al._2017, title={Targeted metabolomics and medication classification data from participants in the ADNI1 cohort}, volume={4}, ISSN={2052-4463}, url={http://dx.doi.org/10.1038/SDATA.2017.140}, DOI={10.1038/SDATA.2017.140}, abstractNote={Alzheimer's disease (AD) is the most common neurodegenerative disease presenting major health and economic challenges that continue to grow. Mechanisms of disease are poorly understood but significant data point to metabolic defects that might contribute to disease pathogenesis. The Alzheimer Disease Metabolomics Consortium (ADMC) in partnership with Alzheimer Disease Neuroimaging Initiative (ADNI) is creating a comprehensive biochemical database for AD. Using targeted and non- targeted metabolomics and lipidomics platforms we are mapping metabolic pathway and network failures across the trajectory of disease. In this report we present quantitative metabolomics data generated on serum from 199 control, 356 mild cognitive impairment and 175 AD subjects enrolled in ADNI1 using AbsoluteIDQ-p180 platform, along with the pipeline for data preprocessing and medication classification for confound correction. The dataset presented here is the first of eight metabolomics datasets being generated for broad biochemical investigation of the AD metabolome. We expect that these collective metabolomics datasets will provide valuable resources for researchers to identify novel molecular mechanisms contributing to AD pathogenesis and disease phenotypes.}, number={1}, journal={Scientific Data}, publisher={Springer Science and Business Media LLC}, author={St John-Williams, Lisa and Blach, Colette and Toledo, Jon B. and Rotroff, Daniel M. and Kim, Sungeun and Klavins, Kristaps and Baillie, Rebecca and Han, Xianlin and Mahmoudiandehkordi, Siamak and Jack, John and et al.}, year={2017}, month={Oct} }
 @article{carter_motsinger-reif_krug_keene_2017, title={The Effect of Heart Disease on Anesthetic Complications During Routine Dental Procedures in Dogs}, volume={53}, ISSN={["1547-3317"]}, DOI={10.5326/jaaha-ms-6512}, abstractNote={Dental procedures are a common reason for general anesthesia, and there is widespread concern among veterinarians that heart disease increases the occurrence of anesthetic complications. Anxiety about anesthetizing dogs with heart disease is a common cause of referral to specialty centers. To begin to address the potential effect of heart disease on anesthetic complications in dogs undergoing anesthesia for routine dental procedures, we compared anesthetic complications in 100 dogs with heart disease severe enough to trigger referral to a specialty center (cases) to those found in 100 dogs without cardiac disease (controls) that underwent similar procedures at the same teaching hospital. Medical records were reviewed to evaluate the occurrence of anesthetic complications. No dogs died in either group, and no significant differences were found between the groups in any of the anesthetic complications evaluated, although dogs in the heart disease group were significantly older with higher American Society of Anesthesiologists scores. Midazolam and etomidate were used more frequently, and alpha-2 agonists used less frequently, in the heart disease group compared to controls. This study suggests dogs with heart disease, when anesthetized by trained personnel and carefully monitored during routine dental procedures, are not at significantly increased risk for anesthetic complications.}, number={4}, journal={JOURNAL OF THE AMERICAN ANIMAL HOSPITAL ASSOCIATION}, author={Carter, Jennifer E. and Motsinger-Reif, Alison A. and Krug, William V. and Keene, Bruce W.}, year={2017}, pages={206–213} }
 @article{nguyen_reuter_gaikwad_rotroff_kucera_motsinger-reif_smith_nieman_rubinow_kaddurah-daouk_et al._2017, title={The steroid metabolome in women with premenstrual dysphoric disorder during GnRH agonist-induced ovarian suppression: effects of estradiol and progesterone addback}, volume={7}, ISSN={2158-3188}, url={http://dx.doi.org/10.1038/TP.2017.146}, DOI={10.1038/TP.2017.146}, abstractNote={Clinical evidence suggests that symptoms in premenstrual dysphoric disorder (PMDD) reflect abnormal responsivity to ovarian steroids. This differential steroid sensitivity could be underpinned by abnormal processing of the steroid signal. We used a pharmacometabolomics approach in women with prospectively confirmed PMDD (n=15) and controls without menstrual cycle-related affective symptoms (n=15). All were medication-free with normal menstrual cycle lengths. Notably, women with PMDD were required to show hormone sensitivity in an ovarian suppression protocol. Ovarian suppression was induced for 6 months with gonadotropin-releasing hormone (GnRH)-agonist (Lupron); after 3 months all were randomized to 4 weeks of estradiol (E2) or progesterone (P4). After a 2-week washout, a crossover was performed. Liquid chromatography/tandem mass spectrometry measured 49 steroid metabolites in serum. Values were excluded if >40% were below the limit of detectability (n=21). Analyses were performed with Wilcoxon rank-sum tests using false-discovery rate (q<0.2) for multiple comparisons. PMDD and controls had similar basal levels of metabolites during Lupron and P4-derived neurosteroids during Lupron or E2/P4 conditions. Both groups had significant increases in several steroid metabolites compared with the Lupron alone condition after treatment with E2 (that is, estrone-SO4 (q=0.039 and q=0.002, respectively) and estradiol-3-SO4 (q=0.166 and q=0.001, respectively)) and after treatment with P4 (that is, allopregnanolone (q=0.001 for both PMDD and controls), pregnanediol (q=0.077 and q=0.030, respectively) and cortexone (q=0.118 and q=0.157, respectively). Only sulfated steroid metabolites showed significant diagnosis-related differences. During Lupron plus E2 treatment, women with PMDD had a significantly attenuated increase in E2-3-sulfate (q=0.035) compared with control women, and during Lupron plus P4 treatment a decrease in DHEA-sulfate (q=0.07) compared with an increase in controls. Significant effects of E2 addback compared with Lupron were observed in women with PMDD who had significant decreases in DHEA-sulfate (q=0.065) and pregnenolone sulfate (q=0.076), whereas controls had nonsignificant increases (however, these differences did not meet statistical significance for a between diagnosis effect). Alterations of sulfotransferase activity could contribute to the differential steroid sensitivity in PMDD. Importantly, no differences in the formation of P4-derived neurosteroids were observed in this otherwise highly selected sample of women studied under controlled hormone exposures.}, number={8}, journal={Translational Psychiatry}, publisher={Springer Science and Business Media LLC}, author={Nguyen, T V and Reuter, J M and Gaikwad, N W and Rotroff, D M and Kucera, H R and Motsinger-Reif, A and Smith, C P and Nieman, L K and Rubinow, D R and Kaddurah-Daouk, R and et al.}, year={2017}, month={Aug}, pages={e1193–e1193} }
 @article{mclaughlin_marks_dorman_motsinger-reif_hanel_2017, title={Thromboelastographic monitoring of the effect of unfractionated heparin in healthy dogs}, volume={27}, ISSN={["1476-4431"]}, DOI={10.1111/vec.12526}, abstractNote={Abstract Objective To characterize the correlation between thromboelastography (TEG) variables using strong activators and anti‐Xa (AXa) activity in healthy dogs administered subcutaneous unfractionated heparin (UFH). Design Prospective experimental study. Setting University research facility. Animals Eight adult random‐source male dogs. Intervention Dogs were randomized to receive subcutaneous UFH at 200, 250, or 300 IU/kg every 8 hours for a total of 10 injections. Blood samples were collected at time 0 (preheparin) and 3, 6, and 8 hours after the 1st (Day 1) and 10th (Day 4) UFH injection. After the 8‐hour blood sample was obtained on day 4, a 100 IU/kg IV bolus of UFH was administered and an additional blood sample was collected 1 hour later (hour 9). AXa activity, activated partial thromboplastin time (aPTT), and TEG (with up to 5 activators) were performed at each time point. Modes of activation for TEG included recalcified (Ca), Ca with heparinase (CaH), CaH and tissue factor 1:3600 (CTF3600H), Ca with tissue factor 1:100 (CTF100), and RapidTEG. Spearman rank correlations were calculated for each of the aforementioned parameters and the AXa activity. P ‐values were corrected for multiple comparisons with a Bonferroni correction. Measurements and Main Results Significant correlations were found between AXa activity and the TEG R values generated with CTF100 (R = 0.83, P ≤ 0.0001) and RapidTEG (R = 0.90, P < 0.0001), as well as both forms of aPTT measurement (R = 0.86 and 0.84, P < 0.0001). Conclusions This study demonstrates that TEG variables derived using robust activation correlate with AXa activity as well as aPTT and have the potential to be used for monitoring UFH therapy in healthy dogs. Future studies are warranted to evaluate its diagnostic utility in critically ill animals.}, number={1}, journal={JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE}, author={McLaughlin, Christopher M. and Marks, Steven L. and Dorman, David C. and Motsinger-Reif, Alison and Hanel, Rita M.}, year={2017}, pages={71–81} }
 @article{mizzi_dalabira_kumuthini_dzimiri_balogh_basak_bohm_borg_borgiani_bozina_et al._2016, title={A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics}, volume={11}, number={9}, journal={PLoS One}, author={Mizzi, C. and Dalabira, E. and Kumuthini, J. and Dzimiri, N. and Balogh, I. and Basak, N. and Bohm, R. and Borg, J. and Borgiani, P. and Bozina, N. and et al.}, year={2016} }
 @article{jackson_long_he_motsinger-reif_mcleod_jack_2016, title={A comparison of DMET Plus microarray and genome-wide technologies by assessing population substructure}, volume={26}, ISSN={["1744-6880"]}, DOI={10.1097/fpc.0000000000000200}, abstractNote={The capacity of the Affymetrix drug metabolism enzymes and transporters (DMET) Plus pharmacogenomics genotyping chip to estimate population substructure and cryptic relatedness was evaluated. The results were compared with estimates using genome-wide HapMap data for the same individuals.For 301 unrelated individuals, spanning three continental populations and one admixed population, genotypic data were collected using the Affymetrix DMET Plus microarray. Genome-wide data on these individuals were obtained from HapMap release 3. Population substructure was assessed using Eigenstrat and ADMIXTURE software for both platforms. Cryptic relatedness was explored by inbreeding coefficient estimation. Nonparametric tests were used to determine correlations of the analytical results of the two genotyping platforms.Principal components analysis identified population substructure for both datasets, with 15.8 and 16.6% of the total variance explained in the first two principal components for DMET Plus and HapMap data, respectively. ADMIXTURE results correctly identified four subpopulations within each dataset. Nonparametric rank correlations indicated significant associations between analyses with an average ρ=0.7272 (P<10) across the three continental populations and ρ=0.4888 for the admixed population. Concordance correlation coefficients (average ρc=0.9693 across all four subpopulations) strongly indicate concordance between ADMIXTURE results. Inbreeding coefficients were slightly inflated (16 individuals>0.15) using DMET Plus data and no cryptic relatedness was indicated using HapMap data. The inflated inbreeding estimation could be because of the limited number of markers provided by DMET as a random sample of 1832 markers from HapMap also yielded inflated estimates of cryptic relatedness (39 individuals>0.15). Furthermore, use of single nucleotide polymorphisms located in genes involved in metabolism and transport may have different allele frequencies in subpopulations than single nucleotide polymorphisms sampled from the whole genome.The DMET Plus pharmacogenomics genotyping chip is effective in quantifying population substructure across the three continental populations and inferring the presence of an admixed population. On the basis of our results, these microarrays offer sufficient depth for covariate adjustment of population substructure in genomic association studies.}, number={4}, journal={PHARMACOGENETICS AND GENOMICS}, author={Jackson, Jami N. and Long, Kevin M. and He, Yijing and Motsinger-Reif, Alison A. and McLeod, Howard L. and Jack, John}, year={2016}, month={Apr}, pages={147–153} }
 @article{shahin_gong_mcdonough_rotroff_beitelshees_garrett_gums_motsinger-reif_chapman_turner_et al._2016, title={A genetic response score for hydrochlorothiazide use insights from genomics and metabolomics integration}, volume={68}, number={3}, journal={Hypertension}, author={Shahin, M. H. and Gong, Y. and McDonough, C. W. and Rotroff, D. M. and Beitelshees, A. L. and Garrett, T. J. and Gums, J. G. and Motsinger-Reif, A. and Chapman, A. B. and Turner, S. T. and et al.}, year={2016}, pages={621-} }
 @article{irvin_rotroff_aslibekyan_zhi_hidalgo_motsinger-reif_marvel_srinivasasainagendra_claas_buse_et al._2016, title={A genome-wide study of lipid response to fenofibrate in Caucasians: A combined analysis of the GOLDN and ACCORD studies}, volume={26}, number={7}, journal={Pharmacogenetics and Genomics}, author={Irvin, M. R. and Rotroff, D. M. and Aslibekyan, S. and Zhi, D. G. and Hidalgo, B. and Motsinger-Reif, A. and Marvel, S. and Srinivasasainagendra, V. and Claas, S. A. and Buse, J. B. and et al.}, year={2016}, pages={324–333} }
 @article{he_winham_hoskins_glass_paul_brown_motsinger-reif_mcleod_2016, title={Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial}, volume={16}, ISSN={["1473-1150"]}, DOI={10.1038/tpj.2015.52}, abstractNote={Carboplatin/taxane combination is first-line therapy for ovarian cancer. However, patients can encounter treatment delays, impaired quality of life, even death because of chemotherapy-induced gastrointestinal (GI) toxicity. A candidate gene study was conducted to assess potential association of genetic variants with GI toxicity in 808 patients who received carboplatin/taxane in the Scottish Randomized Trial in Ovarian Cancer 1 (SCOTROC1). Patients were randomized into discovery and validation cohorts consisting of 404 patients each. Clinical covariates and genetic variants associated with grade III/IV GI toxicity in discovery cohort were evaluated in replication cohort. Chemotherapy-induced GI toxicity was significantly associated with seven single-nucleotide polymorphisms in the ATP7B, GSR, VEGFA and SCN10A genes. Patients with risk genotypes were at 1.53 to 18.01 higher odds to develop carboplatin/taxane-induced GI toxicity (P<0.01). Variants in the VEGF gene were marginally associated with survival time. Our data provide potential targets for modulation/inhibition of GI toxicity in ovarian cancer patients.}, number={3}, journal={PHARMACOGENOMICS JOURNAL}, author={He, Y. J. and Winham, S. J. and Hoskins, J. M. and Glass, S. and Paul, J. and Brown, R. and Motsinger-Reif, A. and McLeod, H. L.}, year={2016}, month={Jun}, pages={243–248} }
 @article{roode_rotroff_richards_moore_motsinger-reif_okamura_mizuno_tsujimoto_suter_breen_2016, title={Comprehensive genomic characterization of five canine lymphoid tumor cell lines}, volume={12}, journal={BMC Veterinary Research}, author={Roode, S. C. and Rotroff, D. and Richards, K. L. and Moore, P. and Motsinger-Reif, A. and Okamura, Y. and Mizuno, T. and Tsujimoto, H. and Suter, S. E. and Breen, M.}, year={2016} }
 @article{chialvo_che_reif_motsinger-reif_reed_2016, title={Eigenvector metabolite analysis reveals dietary effects on the association among metabolite correlation patterns, gene expression, and phenotypes}, volume={12}, ISSN={["1573-3890"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84988377963&partnerID=MN8TOARS}, DOI={10.1007/s11306-016-1117-3}, abstractNote={'Multi-omics' datasets obtained from an organism of interest reared under different environmental treatments are increasingly common. Identifying the links among metabolites and transcripts can help to elucidate our understanding of the impact of environment at different levels within the organism. However, many methods for characterizing physiological connections cannot address unidentified metabolites.Here, we use Eigenvector Metabolite Analysis (EvMA) to examine links between metabolomic, transcriptomic, and phenotypic variation data and to assess the impact of environmental factors on these associations. Unlike other methods, EvMA can be used to analyze datasets that include unidentified metabolites and unannotated transcripts.To demonstrate the utility of EvMA, we analyzed metabolomic, transcriptomic, and phenotypic datasets produced from 20 Drosophila melanogaster genotypes reared on four dietary treatments. We used a hierarchical distance-based method to cluster the metabolites. The links between metabolite clusters, gene expression, and overt phenotypes were characterized using the eigenmetabolite (first principal component) of each cluster.EvMA recovered chemically related groups of metabolites within the clusters. Using the eigenmetabolite, we identified genes and phenotypes that significantly correlated with each cluster. EvMA identifies new connections between the phenotypes, metabolites, and gene transcripts. Conclusion EvMA provides a simple method to identify correlations between metabolites, gene expression, and phenotypes, which can allow us to partition multivariate datasets into meaningful biological modules and identify under-studied metabolites and unannotated gene transcripts that may be central to important biological processes. This can be used to inform our understanding of the effect of environmental mechanisms underlying physiological states of interest.}, number={11}, journal={METABOLOMICS}, publisher={Springer Nature}, author={Chialvo, Clare H. Scott and Che, Ronglin and Reif, David and Motsinger-Reif, Alison and Reed, Laura K.}, year={2016}, month={Nov} }
 @misc{rotroff_motsinger-reif_2016, title={Embracing integrative multiomics approaches}, journal={International Journal of Genomics}, author={Rotroff, D. M. and Motsinger-Reif, A. A.}, year={2016} }
 @article{kim_toledo_nho_risacher_shen_thompson_st. john williams_tenenbaum_han_baillie_et al._2016, title={GENETIC INFLUENCE ON LEVELS OF TARGETED METABOLITES ASSOCIATED WITH ALZHEIMER’S DISEASE}, volume={12}, ISSN={1552-5260}, url={http://dx.doi.org/10.1016/J.JALZ.2016.06.276}, DOI={10.1016/J.JALZ.2016.06.276}, abstractNote={There is increasing evidence that levels of enzymes and metabolites from several metabolic pathways including glycerophospholipid and sphingolipid pathways are perturbed in Alzheimer’s disease (AD) brains, CSF, and/or plasma [1-3] and may be related to disease severity. In addition to environment, genetic variation plays an important role in levels of metabolites [4-5]. Therefore, we investigated the role of genetic variation on serum metabolites associated with key AD relevant phenotypes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Quality-controlled baseline serum metabolites and GWAS (Illumina Human610-Quad) were used in the study. Standard QC and imputation to 1000 Genome reference panel were performed for GWAS data. Metabolites were pre-adjusted for sex, age, and several medications if they were associated with levels of metabolites and selected when they were significantly associated with AD relevant phenotypes. Analysis was restricted to 673 non-Hispanic Caucasian ADNI participants (control=181, MCI=331, AD=161) after removing 69 participants with non-fasting serum samples. Analysis with 49 targeted metabolites was conducted using an additive genetic model including the first principal component to correct for potential population substructure. Five analytes were significantly associated with SNPs on chromosome 1 or 11 after Bonferroni correction (p<1.02x10-9) and four analytes showed nominal genome-wide significant associations (p<5x10-8) (Figure 1). Genes associated with medium-chain acylcarnitines and phosphatidylcholine species play important roles in fatty acid beta oxidation and unsaturation of fatty acids. Two out of nine metabolites showed novel genetic associations.}, number={7}, journal={Alzheimer's & Dementia}, publisher={Elsevier BV}, author={Kim, Sungeun and Toledo, Jon B. and Nho, Kwangsik and Risacher, Shannon L. and Shen, Li and Thompson, J. Will and St. John Williams, Lisa and Tenenbaum, Jessie and Han, Xianlin and Baillie, Rebecca A. and et al.}, year={2016}, month={Jul}, pages={P164–P165} }
 @article{shah_gao_morieri_skupien_marvel_pare_mannino_buranasupkajorn_mendonca_hastings_et al._2016, title={Genetic predictors of cardiovascular mortality during intensive glycemic control in type 2 diabetes: Findings from the ACCORD clinical trial}, volume={39}, number={11}, journal={Diabetes Care}, author={Shah, H. S. and Gao, H. and Morieri, M. L. and Skupien, J. and Marvel, S. and Pare, G. and Mannino, G. C. and Buranasupkajorn, P. and Mendonca, C. and Hastings, T. and et al.}, year={2016}, pages={1915–1924} }
 @article{reinhart_motsinger-reif_dickey_yale_trepanier_2016, title={Genome-wide association study in immunocompetent patients with delayed hypersensitivity to sulfonamide antimicrobials}, volume={11}, number={6}, journal={PLoS One}, author={Reinhart, J. M. and Motsinger-Reif, A. and Dickey, A. and Yale, S. and Trepanier, L. A.}, year={2016} }
 @article{kling_goodenowe_toledo_senanayake_baillie_lucas_tenenbaum_motsinger-reif_han_kaddurah-daouk_2016, title={INDICES OF PLASMALOGEN BIOSYNTHESIS IN ADNI-1 BASELINE SERUM SAMPLES: ASSOCIATION WITH PROGRESSION TO DEMENTIA IN SUBJECTS WITH MILD COGNITIVE IMPAIRMENT}, volume={12}, ISSN={1552-5260}, url={http://dx.doi.org/10.1016/J.JALZ.2016.06.1817}, DOI={10.1016/J.JALZ.2016.06.1817}, abstractNote={Altered lipid metabolism has been implicated epidemiologically in risk for sporadic Alzheimer’s disease (AD); the underlying mechanisms remain uncertain. Although cholesterol and circulating lipoproteins have been the most well-studied lipids in AD, recent data implicate other classes such as glycerophospholipids (GPL). Plasmalogens (Pls), a GPL subclass, are integral membrane components with functions relevant to AD pathophysiology, including promoting vesicle fusion necessary for synaptic neurotransmitter release; modulation of membrane fluidity, raft dynamics, and antioxidant functions; and neuroprotection. Plasmalogen-rich membrane regions favor amyloid precursor protein (APP) breakdown by α-secretase to non-amyloidogenic products, over amyloidogenic β-secretase-mediated products that promote AD plaque formation. The initial steps of endogenous Pls synthesis require peroxisomes, notably in the liver. Peroxisomal function is decreased in older individuals; previous studies have shown decreased Pls in AD serum and postmortem brain. We measured Pls biosynthesis indices in ADNI-1 baseline serum vs. progression from MCI to AD. We measured 4 ethanolamine plasmalogens (PlsEtn) and 4 related phosphatidylethanolamines (PtdEtn) by flow-injection tandem mass spectrometry (FIA-MS/MS) in serum from 736 Alzheimer’s Disease Neuroimaging Initiative (ADNI-1) subjects that included 20 blinded technical replicates. We calculated 5 key ratios of PlsEtn species to each other and to corresponding PtdEtn reflecting Pls biosynthesis and peroxisomal beta-oxidation. Quality control analyses showed strong correlation between replicates (r2>0.95, p<0.001) for all ratios. We then calculated an index of plasmalogen biosynthesis from the mean of 2 ratios (PlsEtn 22:6/PtdEtn 22:6, PlsEtn 20:5/PtdEtn 22:6), termed “PL/PE.” We examined the relationship between the PL/PE ratio and progression to AD in 358 patients with MCI at baseline, adjusting for age, gender, APOE genotype, body mass index, and concomitant medications. Higher baseline PL/PE was associated with a significantly (HR = 0.80, p<0.01) reduced risk of progression to AD in patients with MCI at baseline (Figure).}, number={7}, journal={Alzheimer's & Dementia}, publisher={Elsevier BV}, author={Kling, Mitchel A. and Goodenowe, Dayan B. and Toledo, Jon B. and Senanayake, Vijitha and Baillie, Rebecca A. and Lucas, Joseph E. and Tenenbaum, Jessica D. and Motsinger-Reif, Alison and Han, Xianlin and Kaddurah-Daouk, Rima F.}, year={2016}, month={Jul}, pages={P879–P880} }
 @article{graham_rotroff_marvel_buse_havener_wilson_wagner_motsinger-reif_2016, title={Incorporating concomitant medications into genome-wide analyses for the study of complex disease and drug response}, volume={7}, journal={Frontiers in Genetics}, author={Graham, H. T. and Rotroff, D. M. and Marvel, S. W. and Buse, J. B. and Havener, T. M. and Wilson, A. G. and Wagner, M. J. and Motsinger-Reif, A. A.}, year={2016} }
 @article{rotroff_joubert_marvel_haberg_wu_nilsen_ueland_nystad_london_motsinger-reif_2016, title={Maternal smoking impacts key biological pathways in newborns through epigenetic modification in Utero}, volume={17}, journal={BMC Genomics}, author={Rotroff, D. M. and Joubert, B. R. and Marvel, S. W. and Haberg, S. E. and Wu, M. C. and Nilsen, R. M. and Ueland, P. M. and Nystad, W. and London, S. J. and Motsinger-Reif, A.}, year={2016} }
 @article{rotroff_corum_motsinger-reif_fiehn_bottrel_drevets_singh_salvadore_kaddurah-daouk_2016, title={Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants}, volume={6}, ISSN={2158-3188}, url={http://dx.doi.org/10.1038/TP.2016.145}, DOI={10.1038/TP.2016.145}, abstractNote={Ketamine, at sub-anesthetic doses, is reported to rapidly decrease depression symptoms in patients with treatment-resistant major depressive disorder (MDD). Many patients do not respond to currently available antidepressants, (for example, serotonin reuptake inhibitors), making ketamine and its enantiomer, esketamine, potentially attractive options for treatment-resistant MDD. Although mechanisms by which ketamine/esketamine may produce antidepressant effects have been hypothesized on the basis of preclinical data, the neurobiological correlates of the rapid therapeutic response observed in patients receiving treatment have not been established. Here we use a pharmacometabolomics approach to map global metabolic effects of these compounds in treatment-refractory MDD patients upon 2 h from infusion with ketamine (n=33) or its S-enantiomer, esketamine (n=20). The effects of esketamine on metabolism were retested in the same subjects following a second exposure administered 4 days later. Two complementary metabolomics platforms were used to provide broad biochemical coverage. In addition, we investigated whether changes in particular metabolites correlated with treatment outcome. Both drugs altered metabolites related to tryptophan metabolism (for example, indole-3-acetate and methionine) and/or the urea cycle (for example, citrulline, arginine and ornithine) at 2 h post infusion (q<0.25). In addition, we observed changes in glutamate and circulating phospholipids that were significantly associated with decreases in depression severity. These data provide new insights into the mechanism underlying the rapid antidepressant effects of ketamine and esketamine, and constitute some of the first detailed metabolomics mapping for these promising therapies.}, number={9}, journal={Translational Psychiatry}, publisher={Springer Science and Business Media LLC}, author={Rotroff, D M and Corum, D G and Motsinger-Reif, A and Fiehn, O and Bottrel, N and Drevets, W C and Singh, J and Salvadore, G and Kaddurah-Daouk, R}, year={2016}, month={Sep}, pages={e894–e894} }
 @article{rotroff_oki_liang_yee_stocker_corum_meisner_fiehn_motsinger-reif_giacomini_et al._2016, title={Pharmacometabolomic assessment of metformin in non-diabetic, African Americans}, volume={7}, journal={Frontiers in Pharmacology}, author={Rotroff, D. M. and Oki, N. O. and Liang, X. M. and Yee, S. W. and Stocker, S. L. and Corum, D. G. and Meisner, M. and Fiehn, O. and Motsinger-Reif, A. A. and Giacomini, K. M. and et al.}, year={2016} }
 @article{toledo_thompson_st. john williams_tenenbaum_han_baillie_thambisetty_casanova_varma_legido-quigley_et al._2016, title={THE ALZHEIMER’S METABOLOME: RELATIONSHIP TO PATHOLOGICAL MARKERS AND COGNITIVE DECLINE IN THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI)}, volume={12}, ISSN={1552-5260}, url={http://dx.doi.org/10.1016/J.JALZ.2016.06.275}, DOI={10.1016/J.JALZ.2016.06.275}, abstractNote={Metabolomics provides powerful tools to investigate failures in biochemical pathways in Alzheimer’s disease (AD). Cohort studies with multi-modal biomarker profiling are needed to fully understand associations of metabolomics data given the heterogeneity of AD pathology, the protracted preclinical stages, and clinical misdiagnosis early in the disease course. We sought to interrogate the serum metabolome in the AD Neuroimaging Initiative (ADNI) and assess its relation to established AD biomarkers and clinical measures in preclinical, mild cognitive impairment (MCI) and dementia stages AD. Serum samples from 736 ADNI-1 subjects (203 controls, 358 MCI and 175 AD) were analyzed using a highly validated metabolomics platform (AbsoluteIDQ®-p180 kit), which measures close to 180 metabolites including amino acids, biogenic amines, acylcarnitines, sphingolipids and glycerophospolipids. Assay performance was validated in blinded replicates and metabolite values were adjusted for demographic variables and medications. The relation of metabolite values to clinical diagnosis, neuropsychological measures, cerebrospinal fluid (CSF) and neuroimaging biomarkers was assessed. A specific subset of phosphatidylcholines, lipids important for membrane structure and function, was already increased in preclinical AD stages. On the other hand, long chain acylcarnitines, which play a role in liver and peroxisomal lipid oxidation, were associated with baseline clinical diagnosis as well as biomarker measures of AD. In addition, these long chain acylcarnitines predicted cognitive decline and brain atrophy rates. Different blood metabolic processes relate to early cognitive changes and central changes in AD patients thereby supporting the concept of easily measurable peripheral markers for disease. Blood metabolic profiling pointed to an alteration in mitochondrial fatty acid oxidation and changes in mitochondrial energy utilization specifically in subjects with an AD-like CSF biomarker signature. Blood metabolite profiling offers additional tools for multi-modal AD biomarker assessment and risk profiling.}, number={7}, journal={Alzheimer's & Dementia}, publisher={Elsevier BV}, author={Toledo, Jon B. and Thompson, J. Will and St. John Williams, Lisa and Tenenbaum, Jessie and Han, Xianlin and Baillie, Rebecca A. and Thambisetty, Madhav and Casanova, Ramon and Varma, Sudhir and Legido-Quigley, Cristina and et al.}, year={2016}, month={Jul}, pages={P164} }
 @article{friedenberg_chdid_keene_sherry_motsinger-reif_meurs_2016, title={Use of RNA-seq to identify cardiac genes and gene pathways differentially expressed between dogs with and without dilated cardiomyopathy}, volume={77}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.77.7.693}, abstractNote={Abstract OBJECTIVE To identify cardiac tissue genes and gene pathways differentially expressed between dogs with and without dilated cardiomyopathy (DCM). ANIMALS 8 dogs with and 5 dogs without DCM. PROCEDURES Following euthanasia, samples of left ventricular myocardium were collected from each dog. Total RNA was extracted from tissue samples, and RNA sequencing was performed on each sample. Samples from dogs with and without DCM were grouped to identify genes that were differentially regulated between the 2 populations. Overrepresentation analysis was performed on upregulated and downregulated gene sets to identify altered molecular pathways in dogs with DCM. RESULTS Genes involved in cellular energy metabolism, especially metabolism of carbohydrates and fats, were significantly downregulated in dogs with DCM. Expression of cardiac structural proteins was also altered in affected dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that RNA sequencing may provide important insights into the pathogenesis of DCM in dogs and highlight pathways that should be explored to identify causative mutations and develop novel therapeutic interventions.}, number={7}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Friedenberg, Steven G. and Chdid, Lhoucine and Keene, Bruce and Sherry, Barbara and Motsinger-Reif, Alison and Meurs, Kathryn M.}, year={2016}, month={Jul}, pages={693–699} }
 @article{zhou_yee_seiser_van leeuwen_tavendale_bennett_groves_coleman_van der heijden_beulens_et al._2016, title={Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin}, volume={48}, ISSN={1061-4036 1546-1718}, url={http://dx.doi.org/10.1038/NG.3632}, DOI={10.1038/NG.3632}, abstractNote={Ewan Pearson, Kathleen Giacomini and the Metformin Genetics Consortium perform a genome-wide association study for glycemic response to the antidiabetic drug metformin. They find an intronic allele of the GLUT2 glucose transporter gene that associates with greater metformin action, an effect that is more pronounced in obese individuals. Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.}, number={9}, journal={Nature Genetics}, publisher={Springer Science and Business Media LLC}, author={Zhou, Kaixin and Yee, Sook Wah and Seiser, Eric L and van Leeuwen, Nienke and Tavendale, Roger and Bennett, Amanda J and Groves, Christopher J and Coleman, Ruth L and van der Heijden, Amber A and Beulens, Joline W and et al.}, year={2016}, month={Aug}, pages={1055–1059} }
 @article{zhou_yee_seiser_leeuwen_tavendalel_bennett_groves_coleman_heijden_beulens_et al._2016, title={Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin}, volume={48}, number={9}, journal={Nature Genetics}, author={Zhou, K. X. and Yee, S. W. and Seiser, E. L. and Leeuwen, N. and Tavendalel, R. and Bennett, A. J. and Groves, C. J. and Coleman, R. L. and Heijden, A. A. and Beulens, J. W. and et al.}, year={2016}, pages={1055-} }
 @article{cobb_eckhart_motsinger-reif_carr_groop_ferrannini_2016, title={alpha-Hydroxybutyric Acid Is a Selective Metabolite Biomarker of Impaired Glucose Tolerance}, volume={39}, ISSN={["1935-5548"]}, DOI={10.2337/dc15-2752}, abstractNote={OBJECTIVE Plasma metabolites that distinguish isolated impaired glucose tolerance (iIGT) from isolated impaired fasting glucose (iIFG) may be useful biomarkers to predict IGT, a high-risk state for the development of type 2 diabetes. RESEARCH DESIGN AND METHODS Targeted metabolomics with 23 metabolites previously associated with dysglycemia was performed with fasting plasma samples from subjects without diabetes at time 0 of an oral glucose tolerance test (OGTT) in two observational cohorts: RISC (Relationship Between Insulin Sensitivity and Cardiovascular Disease) and DMVhi (Diabetes Mellitus and Vascular Health Initiative). Odds ratios (ORs) for a one-SD change in the metabolite level were calculated using multiple logistic regression models controlling for age, sex, and BMI to test for associations with iIGT or iIFG versus normal. Selective biomarkers of iIGT were further validated in the Botnia study. RESULTS α-Hydroxybutyric acid (α-HB) was most strongly associated with iIGT in RISC (OR 2.54 [95% CI 1.86–3.48], P value 5E-9) and DMVhi (2.75 [1.81–4.19], 4E-5) while having no significant association with iIFG. In Botnia, α-HB was selectively associated with iIGT (2.03 [1.65–2.49], 3E-11) and had no significant association with iIFG. Linoleoyl-glycerophosphocholine (L-GPC) and oleic acid were also found to be selective biomarkers of iIGT. In multivariate IGT prediction models, addition of α-HB, L-GPC, and oleic acid to age, sex, BMI, and fasting glucose significantly improved area under the curve in all three cohorts. CONCLUSIONS α-HB, L-GPC, and oleic acid were shown to be selective biomarkers of iIGT, independent of age, sex, BMI, and fasting glucose, in 4,053 subjects without diabetes from three European cohorts. These biomarkers can be used in predictive models to identify subjects with IGT without performing an OGTT.}, number={6}, journal={DIABETES CARE}, author={Cobb, Jeff and Eckhart, Andrea and Motsinger-Reif, Alison and Carr, Bernadette and Groop, Leif and Ferrannini, Ele}, year={2016}, month={Jun}, pages={988–995} }
 @article{he_hoskins_clark_campbell_wagner_motsinger-reif_mcleod_2015, title={Accuracy of SNPs to predict risk of HLA alleles associated with drug-induced hypersensitivity events across racial groups}, volume={16}, ISSN={["1744-8042"]}, DOI={10.2217/pgs.15.41}, abstractNote={To evaluate the potential usefulness of selected SNPs to predict specific HLA alleles that are associated with drug-induced hypersensitivity reactions (HSR) in different ethnic groups.Five specific HLA alleles known to predict HSR were tagged by seven SNPs (rs1061235-HLA-A*31:01; rs2395029-HLA-B*57:01; rs3909184-HLA-B*15:02; rs9469003-HLA-B*58:01; rs3117583-HLA-B*58:01; rs9270986-HLA-DQA1*01:02 and rs3129900-HLA-DQA1*01:02). DNA from 24 African-Americans, 56 Asian, 44 Caucasians and 36 Hispanics of known high resolution HLA-A, B and DQA1 status were genotyped for tagSNPs using TaqMan. Sensitivity and specificity were considered the primary end points and were 100% across the four populations for rs2395029-HLA-B*57:01. SNP prediction of HLA-A*31:01 had 100% sensitivity and 84% specificity.This study demonstrates the utility of SNP tagging as a 'real time' approach to predict or exclude the presence of specific HLA alleles of known importance to HSR across diverse ethnic groups. Original submitted 24 April 2014; Revision submitted 2 April 2015.}, number={8}, journal={PHARMACOGENOMICS}, author={He, Yijing and Hoskins, Janelle M. and Clark, Scott and Campbell, Nathan H. and Wagner, Kim and Motsinger-Reif, Alison A. and McLeod, Howard L.}, year={2015}, pages={817–824} }
 @article{beam_motsinger-reif_doyle_2015, title={An investigation of gene-gene interactions in dose-response studies with Bayesian nonparametrics}, volume={8}, journal={Biodata Mining}, author={Beam, A. L. and Motsinger-Reif, A. A. and Doyle, J.}, year={2015} }
 @article{shapiro_raghunath_williams_motsinger-reif_cullen_liu_albertson_ruvolo_bergstrom lucas_jin_et al._2015, title={Canine urothelial carcinoma: genomically aberrant and comparatively relevant}, volume={23}, ISSN={0967-3849 1573-6849}, url={http://dx.doi.org/10.1007/S10577-015-9471-Y}, DOI={10.1007/s10577-015-9471-y}, abstractNote={Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97 % and 84 % of cases, respectively, and losses on CFA 19 were present in 77 % of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.}, number={2}, journal={Chromosome Research}, publisher={Springer Science and Business Media LLC}, author={Shapiro, S. G. and Raghunath, S. and Williams, C. and Motsinger-Reif, A. A. and Cullen, J. M. and Liu, T. and Albertson, D. and Ruvolo, M. and Bergstrom Lucas, A. and Jin, J. and et al.}, year={2015}, month={Mar}, pages={311–331} }
 @article{poorman_borst_moroff_roy_labelle_motsinger-reif_breen_2015, title={Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization}, volume={23}, ISSN={["1573-6849"]}, DOI={10.1007/s10577-014-9444-6}, abstractNote={Melanocytic lesions originating from the oral mucosa or cutaneous epithelium are common in the general dog population, with up to 100,000 diagnoses each year in the USA. Oral melanoma is the most frequent canine neoplasm of the oral cavity, exhibiting a highly aggressive course. Cutaneous melanocytomas occur frequently, but rarely develop into a malignant form. Despite the differential prognosis, it has been assumed that subtypes of melanocytic lesions represent the same disease. To address the relative paucity of information about their genomic status, molecular cytogenetic analysis was performed on the three recognized subtypes of canine melanocytic lesions. Using array comparative genomic hybridization (aCGH) analysis, highly aberrant distinct copy number status across the tumor genome for both of the malignant melanoma subtypes was revealed. The most frequent aberrations included gain of dog chromosome (CFA) 13 and 17 and loss of CFA 22. Melanocytomas possessed fewer genome wide aberrations, yet showed a recurrent gain of CFA 20q15.3–17. A distinctive copy number profile, evident only in oral melanomas, displayed a sigmoidal pattern of copy number loss followed immediately by a gain, around CFA 30q14. Moreover, when assessed by fluorescence in situ hybridization (FISH), copy number aberrations of targeted genes, such as gain of c-MYC (80 % of cases) and loss of CDKN2A (68 % of cases), were observed. This study suggests that in concordance with what is known for human melanomas, canine melanomas of the oral mucosa and cutaneous epithelium are discrete and initiated by different molecular pathways.}, number={2}, journal={CHROMOSOME RESEARCH}, author={Poorman, Kelsey and Borst, Luke and Moroff, Scott and Roy, Siddharth and Labelle, Philippe and Motsinger-Reif, Alison and Breen, Matthew}, year={2015}, month={Jun}, pages={171–186} }
 @article{jack_havener_mcleod_motsinger-reif_foster_2015, title={Evaluating the role of admixture in cancer therapy via in vitro drug response and multivariate genome-wide associations}, volume={16}, ISSN={["1744-8042"]}, DOI={10.2217/pgs.15.85}, abstractNote={We investigate the role of ethnicity and admixture in drug response across a broad group of chemotherapeutic drugs. Also, we generate hypotheses on the genetic variants driving differential drug response through multivariate genome-wide association studies.Immortalized lymphoblastoid cell lines from 589 individuals (Hispanic or non-Hispanic/Caucasian) were used to investigate dose-response for 28 chemotherapeutic compounds. Univariate and multivariate statistical models were used to elucidate associations between genetic variants and differential drug response as well as the role of ethnicity in drug potency and efficacy.For many drugs, the variability in drug response appears to correlate with self-reported race and estimates of genetic ancestry. Additionally, multivariate genome-wide association analyses offered interesting hypotheses governing these differential responses.}, number={13}, journal={PHARMACOGENOMICS}, author={Jack, John and Havener, Tammy M. and McLeod, Howard L. and Motsinger-Reif, Alison A. and Foster, Matthew}, year={2015}, pages={1451–1463} }
 @article{roode_rotroff_avery_suter_bienzle_schiffman_motsinger-reif_breen_2015, title={Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation}, volume={23}, ISSN={0967-3849 1573-6849}, url={http://dx.doi.org/10.1007/s10577-015-9475-7}, DOI={10.1007/s10577-015-9475-7}, number={4}, journal={Chromosome Research}, publisher={Springer Science and Business Media LLC}, author={Roode, Sarah C. and Rotroff, Daniel and Avery, Anne C. and Suter, Steven E. and Bienzle, Dorothee and Schiffman, Joshua D. and Motsinger-Reif, Alison and Breen, Matthew}, year={2015}, month={Jun}, pages={681–708} }
 @article{knazovicky_tomas_motsinger-reif_lascelles_2015, title={Initial evaluation of nighttime restlessness in a naturally occurring canine model of osteoarthritis pain}, volume={3}, journal={PeerJ}, author={Knazovicky, D. and Tomas, A. and Motsinger-Reif, A. and Lascelles, B. D. X.}, year={2015} }
 @article{rotroff_shahin_gurley_zhu_motsinger-reif_meisner_beitelshees_fiehn_johnson_elbadawi-sidhu_et al._2015, title={Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes}, volume={4}, ISSN={2163-8306}, url={http://dx.doi.org/10.1002/PSP4.12017}, DOI={10.1002/PSP4.12017}, abstractNote={Achieving hypertension (HTN) control and mitigating the adverse health effects associated with HTN continues to be a global challenge. Some individuals respond poorly to current HTN therapies, and mechanisms for response variation remain poorly understood. We used a nontargeted metabolomics approach (gas chromatography time-of-flight/mass spectrometry gas chromatography time-of-flight/mass spectrometry) measuring 489 metabolites to characterize metabolite signatures associated with treatment response to anti-HTN drugs, atenolol (ATEN), and hydrochlorothiazide (HCTZ), in white and black participants with uncomplicated HTN enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses study. Metabolite profiles were significantly different between races, and metabolite responses associated with home diastolic blood pressure (HDBP) response were identified. Metabolite pathway analyses identified gluconeogenesis, plasmalogen synthesis, and tryptophan metabolism increases in white participants treated with HCTZ (P < 0.05). Furthermore, we developed predictive models from metabolite signatures of HDBP treatment response (P < 1 × 10−5). As part of a quantitative systems pharmacology approach, the metabolites identified herein may serve as biomarkers for improving treatment decisions and elucidating mechanisms driving HTN treatment responses.}, number={11}, journal={CPT: Pharmacometrics & Systems Pharmacology}, publisher={Wiley}, author={Rotroff, DM and Shahin, MH and Gurley, SB and Zhu, H and Motsinger-Reif, A and Meisner, M and Beitelshees, AL and Fiehn, O and Johnson, JA and Elbadawi-Sidhu, M and et al.}, year={2015}, month={Oct}, pages={669–679} }
 @article{abdo_xia_brown_kosyk_huang_sakamuru_zhou_jack_gallins_xia_et al._2015, title={Population-Based in Vitro Hazard and Concentration-Response Assessment of Chemicals: The 1000 Genomes High-Throughput Screening Study}, volume={123}, ISSN={["1552-9924"]}, DOI={10.1289/ehp.1408775}, abstractNote={Understanding of human variation in toxicity to environmental chemicals remains limited, so human health risk assessments still largely rely on a generic 10-fold factor (10½ each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations.We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for interindividual toxicodynamic variability.We used 1,086 lymphoblastoid cell lines from the 1000 Genomes Project, representing nine populations from five continents, to assess variation in cytotoxic response to 179 chemicals. Analysis included assessments of population variation and heritability, and genome-wide association mapping, with attention to phenotypic relevance to human exposures.For about half the tested compounds, cytotoxic response in the 1% most "sensitive" individual occurred at concentrations within a factor of 10½ (i.e., approximately 3) of that in the median individual; however, for some compounds, this factor was > 10. Genetic mapping suggested important roles for variation in membrane and transmembrane genes, with a number of chemicals showing association with SNP rs13120371 in the solute carrier SLC7A11, previously implicated in chemoresistance.This experimental approach fills critical gaps unaddressed by recent large-scale toxicity testing programs, providing quantitative, experimentally based estimates of human toxicodynamic variability, and also testable hypotheses about mechanisms contributing to interindividual variation.}, number={5}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={Abdo, Nour and Xia, Menghang and Brown, Chad C. and Kosyk, Oksana and Huang, Ruili and Sakamuru, Srilatha and Zhou, Yi-Hui and Jack, John R. and Gallins, Paul and Xia, Kai and et al.}, year={2015}, month={May}, pages={458–466} }
 @article{hecht_scholl_walker_taylor_cliby_motsinger-reif_muddiman_2015, title={Relative Quantification and Higher-Order Modeling of the Plasma Glycan Cancer Burden Ratio in Ovarian Cancer Case-Control Samples}, volume={14}, ISSN={["1535-3907"]}, DOI={10.1021/acs.jproteome.5b00703}, abstractNote={An early-stage, population-wide biomarker for ovarian cancer (OVC) is essential to reverse its high mortality rate. Aberrant glycosylation by OVC has been reported, but studies have yet to identify an N-glycan with sufficiently high specificity. We curated a human biorepository of 82 case-control plasma samples, with 27%, 12%, 46%, and 15% falling across stages I-IV, respectively. For relative quantitation, glycans were analyzed by the individuality normalization when labeling with glycan hydrazide tags (INLIGHT) strategy for enhanced electrospray ionization, MS/MS analysis. Sixty-three glycan cancer burden ratios (GBRs), defined as the log10 ratio of the case-control extracted ion chromatogram abundances, were calculated above the limit of detection. The final GBR models, built using stepwise forward regression, included three significant terms: OVC stage, normalized mean GBR, and tag chemical purity; glycan class, fucosylation, or sialylation were not significant variables. After Bonferroni correction, seven N-glycans were identified as significant (p < 0.05), and after false discovery rate correction, an additional four glycans were determined to be significant (p < 0.05), with one borderline (p = 0.05). For all N-glycans, the vectors of the effects from stages II-IV were sequentially reversed, suggesting potential biological changes in OVC morphology or in host response.}, number={10}, journal={JOURNAL OF PROTEOME RESEARCH}, author={Hecht, Elizabeth S. and Scholl, Elizabeth H. and Walker, S. Hunter and Taylor, Amber D. and Cliby, William A. and Motsinger-Reif, Alison A. and Muddiman, David C.}, year={2015}, month={Oct}, pages={4394–4401} }
 @article{levine_birkenheuer_brooks_nordone_bellinger_jones_fischer_oglesbee_frey_brinson_et al._2014, title={A novel canine model of immune thrombocytopenia: has immune thrombocytopenia (ITP) gone to the dogs?}, volume={167}, ISSN={0007-1048}, url={http://dx.doi.org/10.1111/bjh.13005}, DOI={10.1111/bjh.13005}, abstractNote={Summary Canine immune thrombocytopenia ( ITP ) is analogous to human ITP , with similar platelet counts and heterogeneity in bleeding phenotype among affected individuals. With a goal of ultimately investigating this bleeding heterogeneity, a canine model of antibody‐mediated ITP was developed. Infusion of healthy dogs with 2 F 9, a murine I g G 2a monoclonal antibody to the canine platelet glycoprotein GPII b (a common target of autoantibodies in ITP ) resulted in profound, dose‐dependent thrombocytopenia. Model dogs developed variable bleeding phenotypes, e.g. petechiae and haematuria, despite similar degrees of thrombocytopenia. 2 F 9 infusion was not associated with systemic inflammation, consumptive coagulopathy, or impairment of platelet function. Unexpectedly however, evaluation of cytokine profiles led to the identification of platelets as a potential source of serum interleukin‐8 ( IL 8) in dogs. This finding was confirmed in humans with ITP , suggesting that platelet IL 8 may be a previously unrecognized modulator of platelet‐neutrophil crosstalk. The utility of this model will allow future study of bleeding phenotypic heterogeneity including the role of neutrophils and endothelial cells in ITP .}, number={1}, journal={British Journal of Haematology}, publisher={Wiley}, author={LeVine, Dana N. and Birkenheuer, Adam J. and Brooks, Marjory B. and Nordone, Shila K. and Bellinger, Dwight A. and Jones, Sam L. and Fischer, Thomas H. and Oglesbee, Stephen E. and Frey, Kahlina and Brinson, Nicole S. and et al.}, year={2014}, month={Jul}, pages={110–120} }
 @article{che_jack_motsinger-reif_brown_2014, title={An adaptive permutation approach for genome-wide association study: Evaluation and recommendations for use}, volume={7}, journal={Biodata Mining}, author={Che, R. L. and Jack, J. R. and Motsinger-Reif, A. A. and Brown, C. C.}, year={2014} }
 @article{beam_motsinger-reif_doyle_2014, title={Bayesian neural networks for detecting epistasis in genetic association studies}, volume={15}, journal={BMC Bioinformatics}, author={Beam, A. L. and Motsinger-Reif, A. and Doyle, J.}, year={2014} }
 @article{agler_nielsen_urkasemsin_singleton_tonomura_sigurdsson_tang_linder_arepalli_hernandez_et al._2014, title={Canine hereditary ataxia in Old English Sheepdogs and Gordon Setters is associated with a defect in the autophagy gene encoding RAB24}, volume={10}, number={2}, journal={PLoS Genetics}, author={Agler, C. and Nielsen, D. M. and Urkasemsin, G. and Singleton, A. and Tonomura, N. and Sigurdsson, S. and Tang, R. Q. and Linder, K. and Arepalli, S. and Hernandez, D. and et al.}, year={2014} }
 @article{bucknoff_hanel_marks_motsinger-reif_suter_2014, title={Evaluation of thromboelastography for prediction of clinical bleeding in thrombocytopenic dogs after total body irradiation and hematopoietic cell transplantation}, volume={75}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.75.5.425}, abstractNote={To determine whether thromboelastography is more accurate than conventional methods of evaluating hemostasis for the prediction of clinical bleeding in thrombocytopenic dogs following total body irradiation (TBI) and bone marrow transplantation (BMT).10 client-owned thrombocytopenic dogs with multicentric lymphoma.Results of a kaolin-activated thromboelastography assay, platelet count, and buccal mucosal bleeding time were evaluated for correlation to clinical bleeding.Maximum amplitude, derived via thromboelastography, was the only hemostatic variable with significant correlation to clinical bleeding. Buccal mucosal bleeding time had a high sensitivity but poor specificity for identifying dogs with clinical bleeding.Compared with buccal mucosal bleeding time and platelet count, thromboelastography was more reliable at identifying thrombocytopenic dogs with a low risk of bleeding and could be considered to help guide the use of transfusion products in dogs undergoing TBI and BMT.}, number={5}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Bucknoff, Melissa C. and Hanel, Rita M. and Marks, Steven L. and Motsinger-Reif, Alison A. and Suter, Steven E.}, year={2014}, month={May}, pages={425–432} }
 @article{hertz_roy_jack_motsinger-reif_drobish_clark_carey_dees_mcleod_2014, title={Genetic heterogeneity beyond CYP2C8*3 does not explain differential sensitivity to paclitaxel-induced neuropathy}, volume={145}, ISSN={["1573-7217"]}, DOI={10.1007/s10549-014-2910-1}, abstractNote={The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by drug exposure and patient genetics. The purpose of this analysis was to expand on a previous reported association of CYP2C8*3 and PIPN risk by investigating additional polymorphisms in CYP2C8 and in hundreds of other genes potentially relevant to paclitaxel pharmacokinetics. Clinical data was collected prospectively in an observational registry of newly diagnosed breast cancer patients. Patients treated with paclitaxel-containing regimens were genotyped using the Affymetrix DMET™ Plus chip. Patients who carried the CYP2C8*2, *3, or *4 variant were collapsed into a low-metabolizer CYP2C8 phenotype for association with PIPN. Separately, all SNPs that surpassed quality control were assessed individually and as a composite of genetic ancestry for associations with PIPN. 412 paclitaxel-treated patients and 564 genetic markers were included in the analysis. The risk of PIPN was significantly greater in the CYP2C8 low-metabolizer group (HR = 1.722, p = 0.018); however, the influences of the *2 and *4 SNPs were not independently significant (*2: p = 0.847, *4: p = 0.408). One intronic SNP in ABCG1 (rs492338) surpassed the exploratory significance threshold for an association with PIPN in the Caucasian cohort (p = 0.0008) but not in the non-Caucasian replication group (p = 0.54). Substantial genetic variability was observed within self-reported racial groups but this genetic variability was not associated with risk of grade 2+ PIPN. The pharmacogenetic heterogeneity within a cohort of breast cancer patients is dramatic, though we did not find evidence that this heterogeneity directly influences the risk of PIPN beyond the contribution of CYP2C8*3.}, number={1}, journal={BREAST CANCER RESEARCH AND TREATMENT}, author={Hertz, Daniel L. and Roy, Siddharth and Jack, John and Motsinger-Reif, Alison A. and Drobish, Amy and Clark, L. Scott and Carey, Lisa A. and Dees, E. Claire and McLeod, Howard L.}, year={2014}, month={May}, pages={245–254} }
 @article{brown_havener_medina_jack_krauss_mcleod_motsinger-reif_2014, title={Genome-wide association and pharmacological profiling of 29 anticancer agents using lymphoblastoid cell lines}, volume={15}, ISSN={["1744-8042"]}, DOI={10.2217/pgs.13.213}, abstractNote={Aim: Association mapping with lymphoblastoid cell lines (LCLs) is a promising approach in pharmacogenomics research, and in the current study we utilized LCLs to perform association mapping for 29 chemotherapy drugs. Materials & methods: Currently, we use LCLs to perform genome-wide association mapping of the cytotoxic response of 520 European–Americans to 29 different anticancer drugs; the largest LCL study to date. A novel association approach using a multivariate analysis of covariance design was employed with the software program MAGWAS, testing for differences in the dose–response profiles between genotypes without making assumptions about the response curve or the biologic mode of association. Additionally, by classifying 25 of the 29 drugs into eight families according to structural and mechanistic relationships, MAGWAS was used to test for associations that were shared across each drug family. Finally, a unique algorithm using multivariate responses and multiple linear regressions across pairs of response curves was used for unsupervised clustering of drugs. Results: Among the single-drug studies, suggestive associations were obtained for 18 loci, 12 within/near genes. Three of these, MED12L, CHN2 and MGMT, have been previously implicated in cancer pharmacogenomics. The drug family associations resulted in four additional suggestive loci (three contained within/near genes). One of these genes, HDAC4, associated with the DNA alkylating agents, shows possible clinical interactions with temozolomide. For the drug clustering analysis, 18 of 25 drugs clustered into the appropriate family. Conclusion: This study demonstrates the utility of LCLs in identifying genes that have clinical importance in drug response and for assigning unclassified agents to specific drug families, and proposes new candidate genes for follow-up in a large number of chemotherapy drugs. Original submitted 16 August 2013; Revision submitted 16 October 2013}, number={2}, journal={PHARMACOGENOMICS}, author={Brown, Chad C. and Havener, Tammy M. and Medina, Marisa W. and Jack, John R. and Krauss, Ronald M. and McLeod, Howard L. and Motsinger-Reif, Alison A.}, year={2014}, month={Feb}, pages={137–146} }
 @article{thomas_borst_rotroff_motsinger-reif_lindblad-toh_modiano_breen_2014, title={Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma}, volume={22}, ISSN={["1573-6849"]}, DOI={10.1007/s10577-014-9406-z}, abstractNote={Canine hemangiosarcoma is a highly aggressive vascular neoplasm associated with extensive clinical and anatomical heterogeneity and a grave prognosis. Comprehensive molecular characterization of hemangiosarcoma may identify novel therapeutic targets and advanced clinical management strategies, but there are no published reports of tumor-associated genome instability and disrupted gene dosage in this cancer. We performed genome-wide microarray-based somatic DNA copy number profiling of 75 primary intra-abdominal hemangiosarcomas from five popular dog breeds that are highly predisposed to this disease. The cohort exhibited limited global genomic instability, compared to other canine sarcomas studied to date, and DNA copy number aberrations (CNAs) were predominantly of low amplitude. Recurrent imbalances of several key cancer-associated genes were evident; however, the global penetrance of any single CNA was low and no distinct hallmark aberrations were evident. Copy number gains of dog chromosomes 13, 24, and 31, and loss of chromosome 16, were the most recurrent CNAs involving large chromosome regions, but their relative distribution within and between cases suggests they most likely represent passenger aberrations. CNAs involving CDKN2A, VEGFA, and the SKI oncogene were identified as potential driver aberrations of hemangiosarcoma development, highlighting potential targets for therapeutic modulation. CNA profiles were broadly conserved between the five breeds, although subregional variation was evident, including a near twofold lower incidence of VEGFA gain in Golden Retrievers versus other breeds (22 versus 40 %). These observations support prior transcriptional studies suggesting that the clinical heterogeneity of this cancer may reflect the existence of multiple, molecularly distinct subtypes of canine hemangiosarcoma.}, number={3}, journal={CHROMOSOME RESEARCH}, author={Thomas, Rachael and Borst, Luke and Rotroff, Daniel and Motsinger-Reif, Alison and Lindblad-Toh, Kerstin and Modiano, Jaime F. and Breen, Matthew}, year={2014}, month={Sep}, pages={305–319} }
 @article{jack_rotroff_motsinger-reif_2014, title={Lymphoblastoid Cell Lines Models of Drug Response: Successes and Lessons from this Pharmacogenomic Model}, volume={14}, ISSN={["1875-5666"]}, DOI={10.2174/1566524014666140811113946}, abstractNote={A new standard for medicine is emerging that aims to improve individual drug responses through studying associations with genetic variations. This field, pharmacogenomics, is undergoing a rapid expansion due to a variety of technological advancements that are enabling higher throughput with reductions in cost. Here we review the advantages, limitations, and opportunities for using lymphoblastoid cell lines (LCL) as a model system for human pharmacogenomic studies. There are a wide range of publicly available resources with genome-wide data available for LCLs from both related and unrelated populations, removing the cost of genotyping the data for drug response studies. Furthermore, in contrast to human clinical trials or in vivo model systems, with high-throughput in vitro screening technologies, pharmacogenomics studies can easily be scaled to accommodate large sample sizes. An important component to leveraging genome-wide data in LCL models is association mapping. Several methods are discussed herein, and include multivariate concentration response modeling, issues with multiple testing, and successful examples of the ‘triangle model’ to identify candidate variants. Once candidate gene variants have been determined, their biological roles can be elucidated using pathway analyses and functionally confirmed using siRNA knockdown experiments. The wealth of genomics data being produced using related and unrelated populations is creating many exciting opportunities leading to new insights into the genetic contribution and heritability of drug response. Keywords: Cytotoxics, genetic association mapping, genome wide association analysis, lymphoplastoid cell lines, pharmacogenomics.}, number={7}, journal={CURRENT MOLECULAR MEDICINE}, author={Jack, J. and Rotroff, D. and Motsinger-Reif, A.}, year={2014}, pages={833–840} }
 @article{gonzalez_fogle_baker_hughes_law_motsinger-reif_blikslager_2014, title={Operative factors associated with short-term outcome in horses with large colon volvulus: 47 cases from 2006 to 2013}, volume={47}, ISSN={0425-1644}, url={http://dx.doi.org/10.1111/evj.12273}, DOI={10.1111/evj.12273}, abstractNote={There is an important need for objective parameters that accurately predict the outcome of horses with large colon volvulus.To evaluate the predictive value of a series of histomorphometric parameters on short-term outcome, as well as the impact of colonic resection on horses with large colon volvulus.Retrospective cohort study.Adult horses admitted to the Equine and Farm Animal Veterinary Center at North Carolina State University, Peterson and Smith and Chino Valley Equine Hospitals between 2006 and 2013 that underwent an exploratory coeliotomy, diagnosed with large colon volvulus of ≥360 degrees, where a pelvic flexure biopsy was obtained, and that recovered from general anaesthesia, were selected for inclusion in the study. Logistic regression was used to determine associations between signalment, histomorphometric measurements of interstitium-to-crypt ratio, degree of haemorrhage, percentage loss of luminal and glandular epithelium, as well as colonic resection with short-term outcome (discharge from the hospital).Pelvic flexure biopsies from 47 horses with large colon volvulus were evaluated. Factors that were significantly associated with short-term outcome on univariate logistic regression were Thoroughbred breed (P = 0.04), interstitium-to-crypt ratio >1 (P = 0.02) and haemorrhage score ≥3 (P = 0.005). Resection (P = 0.92) was not found to be associated significantly with short-term outcome. No combined factors increased the likelihood of death in forward stepwise logistic regression modelling. A digitally quantified measurement of haemorrhage area strengthened the association of haemorrhage with nonsurvival in cases of large colon volvulus.Histomorphometric measurements of interstitium-to-crypt ratio and degree of haemorrhage predict short-term outcome in cases of large colon volvulus. Resection was not associated with short-term outcome in horses selected for this study. Accurate quantification of mucosal haemorrhage at the time of surgery may improve veterinary surgeons' prognostic capabilities in horses with large colon volvulus.}, number={3}, journal={Equine Veterinary Journal}, publisher={Wiley}, author={Gonzalez, L. M. and Fogle, C. A. and Baker, W. T. and Hughes, F. E. and Law, J. M. and Motsinger-Reif, A. A. and Blikslager, A. T.}, year={2014}, month={May}, pages={279–284} }
 @article{rotroff_jack_campbell_clark_motsinger-reif_2014, title={PGxClean: a quality control GUI for the Affymetrix DMET chip and other candidate gene studies with non-biallelic alleles}, volume={7}, journal={Biodata Mining}, author={Rotroff, D. and Jack, J. and Campbell, N. and Clark, S. and Motsinger-Reif, A. A.}, year={2014} }
 @article{ginn_sacco_wong_motsinger-reif_chun_trepanier_2014, title={Positive association between a glutathione-S-transferase polymorphism and lymphoma in dogs}, volume={12}, ISSN={["1476-5829"]}, DOI={10.1111/vco.12000}, abstractNote={Abstract Glutathione‐ S ‐transferase enzymes ( GSTs ) play an important role in the detoxification of environmental carcinogens. Defective GST genotypes are over‐represented in human cancers; in particular, low activity GSTT1 genotypes are risk factors for non‐Hodgkin lymphoma. We hypothesized that defective GSTT1 genotypes would be associated with lymphoma risk in dogs. To address this, we resequenced the exons, splice junctions, and 3′‐ UTR of canine GSTT1 in dogs with lymphoma ( n = 93) and age‐matched unaffected dogs ( n = 86). Of 27 canine GSTT1 variants identified, the I2 +28 G>A was significantly associated with lymphoma [odds ratio ( OR ) 6.26, 95% confidence interval ( CI ), 1.77–22.2], with the AA genotype found in 18.3% of affected dogs but only 3.5% of controls ( P = 0.002). This intronic variant was predicted to perturb GSTT1 mRNA splicing, and may increase lymphoma risk by impairing detoxification of environmental chemicals. Confirmation of this finding in a larger population of dogs may support the inclusion of GSTT1 genotyping in epidemiologic studies of canine lymphoma risk.}, number={3}, journal={VETERINARY AND COMPARATIVE ONCOLOGY}, author={Ginn, J. and Sacco, J. and Wong, Y. Y. and Motsinger-Reif, A. and Chun, R. and Trepanier, L. A.}, year={2014}, month={Sep}, pages={227–236} }
 @article{lockhart_motsinger-reif_simpson_posner_2014, title={Prevalence of onychectomy in cats presented for veterinary care near Raleigh, NC and educational attitudes toward the procedure}, volume={41}, ISSN={1467-2987}, url={http://dx.doi.org/10.1111/vaa.12077}, DOI={10.1111/vaa.12077}, abstractNote={Objective The current prevalence of onychectomy (declawing) in cats is unknown, and education regarding the procedure appears to vary greatly among veterinary schools. The purpose of this project was to determine the prevalence of onychectomized cats near Raleigh, NC and to document the frequency and style (laboratory or lecture) with which the procedure is taught in USA veterinary schools. Animals One thousand seven hundred ninety four cats ranging in age from 8 days to 21 years, of which 938 (52.3%) were female and 1719 (95.8%) were sterilized. Methods Data were collected over a 10-week period regarding cats seen for appointments in five veterinary facilities (two cat-only, two general, and one tertiary). Data collection included signalment and onychectomy status. During this time, 28 veterinary schools were polled regarding education of veterinary students in onychectomy. Results Three hundred and seventy four (20.8%) cats had undergone onychectomy. A significantly higher percentage of declawed cats were seen in the general practices compared with the other practice types (p < 0.030). Younger cats had a higher rate of onychectomy (p < 0.001). Twenty-six veterinary schools responded to the survey (93%). Fourteen (54%) of the responding schools did not include in their core curriculum a lecture or surgical laboratory providing instruction in the onychectomy procedure. Conclusions and clinical relevance Almost 21% of cats seen in veterinary hospitals near Raleigh, NC were declawed. Less than 50% of veterinary schools in the USA include a mandatory lecture or laboratory to teach the procedure. There appears to be a discrepancy between the popularity of the onychectomy procedure and the emphasis placed on relevant instruction in veterinary schools in the USA.}, number={1}, journal={Veterinary Anaesthesia and Analgesia}, publisher={Elsevier BV}, author={Lockhart, Laura E and Motsinger-Reif, Alison A and Simpson, Wendy M and Posner, Lysa P}, year={2014}, month={Jan}, pages={48–53} }
 @article{tomas_marcellin-little_roe_motsinger-reif_lascelles_2014, title={Relationship Between Mechanical Thresholds and Limb Use in Dogs With Coxofemoral Joint OA-Associated Pain and the Modulating Effects of Pain Alleviation From Total Hip Replacement on Mechanical Thresholds}, volume={43}, ISSN={["1532-950X"]}, url={https://dx.doi.org/10.1111/j.1532-950x.2014.12160.x}, DOI={10.1111/j.1532-950x.2014.12160.x}, abstractNote={Objectives To compare von Frey mechanical quantitative sensory thresholds (mQSTvF) between pelvic limbs in dogs before unilateral total hip replacement (THR) surgery; to correlate ground reaction forces (GRF) with mQSTvF; to assess changes in mQSTvF after THR surgery. Study Design Prospective clinical study. Animals Dogs (n = 44). Methods mQSTvF and GRF measured using a pressure sensitive walkway were evaluated before, and 3, 6, and 12 months after, unilateral THR. Measurements were recorded from the affected (operated) pelvic limb (APL) and the non-operated pelvic limb (NPL). Random effects analysis and forwards stepwise linear regression models were used to evaluate the influence of time since surgery and patient factors on mQSTvF thresholds. Results There were no significant correlations between mQSTvF data and age, bodyweight or the GRF variables. Preoperative mQSTvF measured at the APL and NPL did not differ (P = .909). mQSTvF thresholds increased significantly after 12 months in NPL (P = .047) and APL (P = .001). In addition to time, APL mQSTvF values were significantly affected by sex (higher in males, P = .010) and body condition score (higher in leaner dogs, P = .035) and NPL mQSTvF values by sex (P = .038). Conclusion Successful unilateral THR results in decreased central sensitization after 12 months.}, number={5}, journal={VETERINARY SURGERY}, author={Tomas, Andrea and Marcellin-Little, Denis J. and Roe, Simon C. and Motsinger-Reif, Alison and Lascelles, B. Duncan X.}, year={2014}, month={Jul}, pages={542–548} }
 @article{jack_motsinger-reif_koutros_alavanja_beane freeman_hoppin_2014, title={Single-Nucleotide Polymorphism Data Support the General Unrelatedness of the Males in the Agricultural Health Study}, volume={23}, ISSN={1055-9965 1538-7755}, url={http://dx.doi.org/10.1158/1055-9965.EPI-14-0276}, DOI={10.1158/1055-9965.epi-14-0276}, abstractNote={Farming is often a family and multigenerational business. Relatedness among farmers could bias gene-environment interaction analysis. To evaluate the potential relatedness of farmers, we used data from a nested case-control study of prostate cancer conducted in the Agricultural Health Study (AHS), a prospective study of farmers in Iowa and North Carolina.We analyzed the genetic data for 25,009 SNPs (single-nucleotide polymorphisms) from 2,220 White participants to test for cryptic relatedness among these farmers. We used two software packages: (i) PLINK, to calculate inbreeding coefficients and identity-by-descent (IBD) statistics and (ii) EIGENSOFT, to perform a principal component analysis on the genetic data.Inbreeding coefficients estimates and IBD statistics show that the subjects are overwhelmingly unrelated, with little potential for cryptic relatedness in these data.Our analysis rejects the hypothesis that individuals in the case-control study exhibit cryptic relatedness.These findings are important for all subsequent analyses of gene-environment interactions in the AHS.}, number={10}, journal={Cancer Epidemiology Biomarkers & Prevention}, publisher={American Association for Cancer Research (AACR)}, author={Jack, J. R. and Motsinger-Reif, A. A. and Koutros, S. and Alavanja, M. C. and Beane Freeman, L. E. and Hoppin, J. A.}, year={2014}, month={Jul}, pages={2192–2195} }
 @article{chen_small_motsinger-reif_suter_richards_2014, title={VH1-44 gene usage defines a subset of canine B-cell lymphomas associated with better patient survival}, volume={157}, ISSN={0165-2427}, url={http://dx.doi.org/10.1016/j.vetimm.2013.10.020}, DOI={10.1016/j.vetimm.2013.10.020}, abstractNote={The use of specific immunoglobulin heavy chain variable region (VH) genes has been associated with increased patient survival in human B-cell lymphomas (hBCL). Given the similarity of human and canine BCL (cBCL) in morphology and clinical treatment, we examined the choice of VH in cBCL and determined whether VH gene selection was a distinct feature associated with survival time in dogs. VH gene selection and mutational status in 52 cBCL, including 29 diffuse large B-cell lymphomas (cDLBCL, the most common subtype of cBCL), were analyzed by comparison with the 80 published canine germline VH gene sequences. We further examined the prognostic impact of the subgroups defined by these features on canine survival. We found that VH1-44 was preferentially expressed in the majority of the 52 cBCLs (60%) as well as in the majority of the cDLBCL subset (59%). VH1-44 gene expression was associated with a statistically better overall survival (p = 0.039) in cBCL patients, as well as in the cDLBCL subset of patients (p = 0.038). These findings suggest that VH gene selection in cBCL is not random and may therefore have functional implications for cBCL lymphomagenesis, in addition to being a useful prognostic biomarker.}, number={3-4}, journal={Veterinary Immunology and Immunopathology}, publisher={Elsevier BV}, author={Chen, Hsiao-Wei and Small, George W. and Motsinger-Reif, Alison and Suter, Steven E. and Richards, Kristy L.}, year={2014}, month={Feb}, pages={125–130} }
 @article{posner_bailey_richardson_motsinger-reif_harms_2013, title={Alfaxalone anesthesia in bullfrogs (Lithobates catesbeiana) by injection or immersion}, volume={44}, ISSN={1042-7260 1937-2825}, url={http://dx.doi.org/10.1638/2013-0090R.1}, DOI={10.1638/2013-0090r.1}, abstractNote={This project evaluated alfaxalone, a neurosteroid, as an anesthetic in bullfrogs. Eight adult bullfrogs (Lithobates catesbeiana), averaging 593 g (411–780 g) each, were used in a crossover design. Frogs were administered alfaxalone i.m. at 10, 12, 15, or 17.5 mg/kg with a 1-wk washout. Following injection, time to recumbency, first limb movement following induction, and recovery were recorded. Respiratory rate was recorded following injection and then every 15 min following induction. Heart rate was assessed via Doppler every 15 min following induction. At 20 and 40 min, a 25-ga needle was inserted in a thigh muscle to assess response to noxious stimuli. Frogs were also immersed in 2 g/L of alfaxalone for up to 30 min and similarly assessed. At dosages of 10, 12, 15, and 17.5 mg/kg, the median time to recumbency was 15.4, 12.6, 12.3, and 6.6 min, respectively. At dosages of 10, 12, 15, and 17.5 mg/kg, median time to first limb movement was 68.5, 77.5, 89.0, and 115 min, respectively. At dosages of 10, 12, 15, and 17.5 mg/kg, median time to recovery was 90, 68.5, 124.5, 115 min, respectively. Following induction, at 10, 12, 15, and 17.5 mg/kg, median heart rate was 42, 40, 40, and 42, respectively; and median respiratory rate was 44, 36, 29, and 35, respectively. Following administration of 10, 12, 15, and 17.5 mg/kg, 8/8, 6/8, 7/8, and 8/8 frogs, respectively, responded to needle insertion. None of the frogs dosed by immersion became anesthetized. Intramuscular alfaxalone produced immobilization in frogs but did not provide sufficient anesthesia to prevent response to noxious stimuli. Alfaxalone immersion at 2 g/L for 30 min did not produce immobilization or anesthesia.}, number={4}, journal={Journal of Zoo and Wildlife Medicine}, publisher={American Association of Zoo Veterinarians}, author={Posner, Lysa Pam and Bailey, Kate M. and Richardson, Erika Y. and Motsinger-Reif, Alison A. and Harms, Craig A.}, year={2013}, month={Dec}, pages={965–971} }
 @article{kaddurah-daouk_zhu_sharma_bogdanov_rozen_matson_oki_motsinger-reif_churchill_lei_et al._2013, title={Alterations in metabolic pathways and networks in Alzheimer’s disease}, volume={3}, ISSN={2158-3188}, url={http://dx.doi.org/10.1038/TP.2013.18}, DOI={10.1038/TP.2013.18}, abstractNote={The pathogenic mechanisms of Alzheimer's disease (AD) remain largely unknown and clinical trials have not demonstrated significant benefit. Biochemical characterization of AD and its prodromal phase may provide new diagnostic and therapeutic insights. We used targeted metabolomics platform to profile cerebrospinal fluid (CSF) from AD (n=40), mild cognitive impairment (MCI, n=36) and control (n=38) subjects; univariate and multivariate analyses to define between-group differences; and partial least square-discriminant analysis models to classify diagnostic groups using CSF metabolomic profiles. A partial correlation network was built to link metabolic markers, protein markers and disease severity. AD subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine and glutathione versus controls. MCI subjects had elevated 5-HIAA, MET, hypoxanthine and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET. These findings indicate that MCI and AD are associated with an overlapping pattern of perturbations in tryptophan, tyrosine, MET and purine pathways, and suggest that profound biochemical alterations are linked to abnormal Ab42 and tau metabolism. Metabolomics provides powerful tools to map interlinked biochemical pathway perturbations and study AD as a disease of network failure.}, number={4}, journal={Translational Psychiatry}, publisher={Springer Science and Business Media LLC}, author={Kaddurah-Daouk, R and Zhu, H and Sharma, S and Bogdanov, M and Rozen, S G and Matson, W and Oki, N O and Motsinger-Reif, A A and Churchill, E and Lei, Z and et al.}, year={2013}, month={Apr}, pages={e244–e244} }
 @article{hertz_roy_motsinger-reif_drobish_clark_mcleod_carey_dees_2013, title={CYP2C8*3 increases risk of neuropathy in breast cancer patients treated with paclitaxel}, volume={24}, ISSN={["0923-7534"]}, DOI={10.1093/annonc/mdt018}, abstractNote={Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased neuropathy risk and CYP2C8*3 genotype.Demographic, treatment, and toxicity data were collected for paclitaxel-treated breast cancer patients who were genotyped for the CYP2C8*3 K399R (rs10509681) variant. A log-rank test was used in the primary analysis of European-American patients. An additional independent replication was then attempted in a cohort of African-American patients, followed by modeling of the entire patient cohort with relevant covariates.In the primary analysis of 209 European patients, there was an increased risk of paclitaxel-induced neuropathy related to CYP2C8*3 status [HR (per allele) = 1.93 (95% CI: 1.05-3.55), overall log-rank P = 0.006]. The association was replicated in direction and magnitude of effect in 107 African-American patients (P = 0.043). In the Cox model using the entire mixed-race cohort (n = 411), each CYP2C8*3 allele approximately doubled the patient's risk of grade 2+ neuropathy (P = 0.004), and non-Europeans were at higher neuropathy risk than Europeans of similar genotype (P = 0.030).The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts.}, number={6}, journal={ANNALS OF ONCOLOGY}, author={Hertz, D. L. and Roy, S. and Motsinger-Reif, A. A. and Drobish, A. and Clark, L. S. and McLeod, H. L. and Carey, L. A. and Dees, E. C.}, year={2013}, month={Jun}, pages={1472–1478} }
 @article{guo_tsai_hardison_james_motsinger-reif_thames_stone_deng_piedrahita_2013, title={Differentially expressed microRNAs and affected biological pathways revealed by modulated modularity clustering (MMC) analysis of human preeclamptic and IUGR placentas}, volume={34}, ISSN={0143-4004}, url={http://dx.doi.org/10.1016/j.placenta.2013.04.007}, DOI={10.1016/j.placenta.2013.04.007}, abstractNote={This study focuses on the implementation of modulated modularity clustering (MMC) a new cluster algorithm for the identification of molecular signatures of preeclampsia and intrauterine growth restriction (IUGR), and the identification of affected microRNAs Eighty-six human placentas from normal (40), growth-restricted (27), and preeclamptic (19) term pregnancies were profiled using Illumina Human-6 Beadarrays. MMC was utilized to generate modules based on similarities in placental transcriptome. Gene Set Enrichment Analysis (GSEA) was used to predict affected microRNAs. Expression levels of these candidate microRNAs were investigated in seventy-one human term placentas as follows: control (29); IUGR (26); and preeclampsia (16). MMC identified two modules, one representing IUGR placentas and one representing preeclamptic placentas. 326 differentially expressed genes in the module representing IUGR and 889 differentially expressed genes in a module representing preeclampsia were identified. Functional analysis of molecular signatures associated with IUGR identified P13K/AKT, mTOR, p70S6K, apoptosis and IGF-1 signaling as being affected. Analysis of variance of GSEA-predicted microRNAs indicated that miR-194 was significantly down-regulated both in preeclampsia (p = 0.0001) and IUGR (p = 0.0304), and miR-149 was significantly down-regulated in preeclampsia (p = 0.0168). Implementation of MMC, allowed identification of genes disregulated in IUGR and preeclampsia. The reliability of MMC was validated by comparing to previous linear modeling analysis of preeclamptic placentas. MMC allowed the elucidation of a molecular signature associated with preeclampsia and a subset of IUGR samples. This allowed the identification of genes, pathways, and microRNAs affected in these diseases.}, number={7}, journal={Placenta}, publisher={Elsevier BV}, author={Guo, L. and Tsai, S.Q. and Hardison, N.E. and James, A.H. and Motsinger-Reif, A.A. and Thames, B. and Stone, E.A. and Deng, C. and Piedrahita, J.A.}, year={2013}, month={Jul}, pages={599–605} }
 @article{richards_motsinger-reif_chen_fedoriw_fan_nielsen_small_thomas_smith_dave_et al._2013, title={Gene Profiling of Canine B-Cell Lymphoma Reveals Germinal Center and Postgerminal Center Subtypes with Different Survival Times, Modeling Human DLBCL}, volume={73}, ISSN={0008-5472 1538-7445}, url={http://dx.doi.org/10.1158/0008-5472.CAN-12-3546}, DOI={10.1158/0008-5472.can-12-3546}, abstractNote={Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, and fewer than half of patients are cured with standard first-line therapy. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL, one of the most common cancers in veterinary oncology, is morphologically similar to hDLBCL and is treated using similar chemotherapeutic protocols. With genomic technologies, it is now possible to molecularly evaluate dogs as a potential large-animal model for hDLBCL. We evaluated canine B-cell lymphomas (cBCL) using immunohistochemistry (IHC) and gene expression profiling. cBCL expression profiles were similar in many ways to hDLBCLs. For instance, a subset had increased expression of NF-κB pathway genes, mirroring human activated B-cell (ABC)–type DLBCL. Furthermore, immunoglobulin heavy chain ongoing mutation status, which is correlated with ABC/germinal center B-cell cell of origin in hDLBCL, separated cBCL into two groups with statistically different progression-free and overall survival times. In contrast with hDLBCL, cBCL rarely expressed BCL6 and MUM1/IRF4 by IHC. Collectively, these studies identify molecular similarities to hDLBCL that introduce pet dogs as a representative model of hDLBCL for future studies, including therapeutic clinical trials. Cancer Res; 73(16); 5029–39. ©2013 AACR.}, number={16}, journal={Cancer Research}, publisher={American Association for Cancer Research (AACR)}, author={Richards, K. L. and Motsinger-Reif, A. A. and Chen, H.-W. and Fedoriw, Y. and Fan, C. and Nielsen, D. M. and Small, G. W. and Thomas, R. and Smith, C. and Dave, S. S. and et al.}, year={2013}, month={Jun}, pages={5029–5039} }
 @article{su_nielsen_zhu_richards_suter_breen_motsinger-reif_osborne_2013, title={Gene selection and cancer type classification of diffuse large-B-cell lymphoma using a bivariate mixture model for two-species data}, volume={7}, journal={Human Genomics}, author={Su, Y. H. and Nielsen, D. and Zhu, L. and Richards, K. and Suter, S. and Breen, M. and Motsinger-Reif, A. and Osborne, J.}, year={2013} }
 @article{motsinger-reif_jorgenson_relling_kroetz_weinshilboum_cox_roden_2013, title={Genome-wide association studies in pharmacogenomics: Successes and lessons}, volume={23}, number={8}, journal={Pharmacogenetics and Genomics}, author={Motsinger-Reif, A. A. and Jorgenson, E. and Relling, M. V. and Kroetz, D. L. and Weinshilboum, R. and Cox, N. J. and Roden, D. M.}, year={2013}, pages={383–394} }
 @article{jones_motsinger-reif_2013, title={Interview A discussion on genome-wide associations in pharmacogenomics}, volume={14}, number={4}, journal={Pharmacogenomics}, author={Jones, S. and Motsinger-Reif, A.}, year={2013}, pages={361–363} }
 @article{rotroff_thomas_breen_motsinger-reif_2013, title={Naturally occuring canine cancers: powerful models for stimulating pharmacogenomic advancement in human medicine}, volume={14}, ISSN={["1744-8042"]}, DOI={10.2217/pgs.13.178}, abstractNote={PharmacogenomicsVol. 14, No. 16 EditorialFree AccessNaturally occuring canine cancers: powerful models for stimulating pharmacogenomic advancement in human medicineDaniel M Rotroff, Rachael Thomas, Matthew Breen & Alison A Motsinger-ReifDaniel M RotroffBioinformatics Research Center, Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27695, USA.Search for more papers by this author, Rachael ThomasDepartment of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA and Center for Comparative Medicine & Translational Research, North Carolina State University, Raleigh, NC, USA.Search for more papers by this author, Matthew BreenDepartment of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA and Center for Comparative Medicine & Translational Research, North Carolina State University, Raleigh, NC, USA and Cancer Genetics Program, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.Search for more papers by this author & Alison A Motsinger-Reif* Author for correspondenceBioinformatics Research Center, Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27695, USA. Search for more papers by this authorEmail the corresponding author at motsinger@stat.ncsu.eduPublished Online:26 Nov 2013https://doi.org/10.2217/pgs.13.178AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: cancercanine modelchemotherapyclinical trialsAn estimated 1.6 million new cases of cancer were diagnosed in the USA in 2012 [101]. The pharmaceutical industry is working furiously to develop new efficacious chemotherapeutics; however, the vast majority of compounds that show anticancer activity in preclinical studies fail during subsequent human clinical trials, hindering progress in patient care and further increasing costs for drug development [1–3]. Modern cancer research places a heavy emphasis on murine models for investigating cancer etiology and for driving the development of new therapies. Mice represent excellent models for studying cancer due to their short lifespans, ease of maintenance and opportunities for genetic manipulation [4]. While their attributes have led to numerous fundamental advances in identifying novel therapies, several important limitations exist. Murine models of cancer are generally induced by genetic engineering, or by subcutaneous xenografts. The limitations and advantages of various methods of inducing neoplasms in mice are well reviewed elsewhere [4,5]. Induced murine neoplasms are developed in a short period of time and they lack heterogeneity in the tumor cell population, the microenvironment and the stroma, all of which are inconsistent with most human cancers. Furthermore, human cancers typically display increased genomic instability compared with their induced murine counterparts, which limits their utility as tools for pharmacogenomics [6]. Many of these limitations may be addressed by using the domestic dog as a complementary model system. Canines share our environment and develop many age-related diseases with similar pathologies to humans. Perhaps most importantly, dogs exhibit a wide variety of spontaneous cancers that share extensive clinicopathologic features with those of human patients, offering a unique opportunity for comparative analysis of naturally occurring cancers towards advancing treatment strategies in both species.Why canines make promising models of human cancerA survey conducted from 2011–2012 indicates that approximately 78 million domestic dogs currently reside in the USA [102]. The domestic dog suffers from more than 450 spontaneous diseases, approximately 360 of which have a human analog [7]. Cancer is the leading cause of death in several of the most popular dog breeds, such as golden retrievers, Labrador retrievers and boxers, which succumb to cancer with frequencies of 50, 34 and 44%, respectively [8]. When evaluated by breed, there are clear differences in predispositions for a variety of cancers. In turn, several canine cancers exhibit breed-associated profiles of tumor-associated genomic aberrations, including lymphoma, osteosarcoma (OS) and intracranial malignancies. Moreover, comparative studies have revealed conserved genomic signatures in canine and human counterparts of the same cancer [9–12]. Based on the large population of dogs that develop cancer and the clinical and pathological similarity between many dog and human cancers, research into canine cancer may offer a wealth of insight into driver mechanisms of human carcinogenesis and provide a more representative model for testing new therapies.Canine pharmacogenomicsThe availability of a high-quality canine genome sequence assembly [13] has opened the door for identifying key drivers of disease that may also impact human patients. In an effort to identify putative drivers of OS, Angstadt et al. combined bioinformatics and experimental methods to conduct a genome-wide assessment of tumor-associated DNA copy number aberrations in spontaneous canine and human OS [10]. OS in both species exhibits extensive genomic instability and a similar pathophysiological profile. Critically, however, human OS represents <1000 new diagnoses per year in the USA compared with >10,000/year in canines, thus providing tremendous sources of clinical materials [10]. Comparative analysis of recurrent copy number aberrations in human and canine OS revealed discrete gene sets that were common to both species, disrupting fundamental cellular functions such as osteoblast fate commitment, regulation of organ growth, telomerase activity and homophilic cell adhesion, among others [10]. These results shed new light on gene candidates that may play a role in OS development and progression in both species [10], reinforcing the enormous potential for advancement through cross-species approaches.Clinical potential of caninesIn addition to using tumor-bearing canines as preclinical models, methods for incorporating dogs into the existing clinical testing framework have been proposed, and a logical integrated approach has been well described by Paoloni and Khanna [6]. Since canine clinical management strategies utilize similar diagnostic and therapeutic modalities to those in human medicine, the diagnostic nomenclature of canine cancers broadly follows that of their human counterparts. Canine chemotherapy protocols focus on more palliative approaches and are therefore prescribed at lower doses than the equivalent human protocols [6]. For example, the standard protocol for canine B-cell non-Hodgkin’s lymphoma (NHL) is cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), which, until recently, was also the first-line treatment for humans with B-cell NHL. In human patients, the recent addition of the monoclonal antibody rituximab to the CHOP regimen (i.e., R-CHOP) has become the first-line treatment for humans with B-cell NHL.In the search for targeted lymphoma and autoimmune-related therapies, activation of the B-cell antigen receptor signaling pathway has become a high priority since being identified as critical for the survival of B-cell NHL cells [14]. Btk represents a key component for B-cell antigen receptor activation, making the recent discovery of ibrutinib, the small-molecule irreversible inhibitor of Btk, a promising advance in the search for new and effective therapies for NHL [14,15]. In a recent study by Honigberg et al., murine models were used to demonstrate ibrutinib’s efficacy for treating lupus and arthritis, and dogs with spontaneous B-cell NHL were enrolled in a trial to test whether ibrutinib would affect disease progression [15]. At the time the study was published, eight dogs had been treated, with three partial responses (one dog with a 77% reduction in tumor burden) and three incidences of stable disease [15]. Upon these findings, a human clinical trial was promptly conducted on patients with refractory and relapsed B-cell NHL. Promising results were achieved, with a complete response in 16% of patients, while 60% of patients reached the objective response rate, and the median progression-free survival at the end of the trial for all patients was 13.6 months [16]. The US FDA has granted ibrutinib three ‘breakthrough’ designations and it is currently pending FDA approval. Hopes are high that it will see approval by the end of the year.Ethics of the canine modelWhile the use of companion animals has enormous potential for comparative medicine, it is important to recognize that these canine patients are presenting with naturally occurring disorders and are receiving medical care for their own well-being with informed owner consent. Any time that research is performed in a clinical setting (rather than a laboratory setting), there are a number of additional factors that must be considered. These include the patient environment, owners of animals and the perspective of the general public.Many of the ethical concerns regarding involving companion animals in clinical research studies are shared with basic principles of human subjects, including autonomy (informed consent, in this case of the owners) and non-malfeasance (an absence of any sort of fraud or harmful deceit, as well as avoiding harm to the animal). Research conducted in this setting requires rigorous protection of confidential patient/owner data and must be performed to a high ethical standard. As such, companion animal studies are subject to strict regulatory oversight that is highly comparable to that enforced for human patients. These principles will inevitably impact the design of canine studies, but are also critical for assuaging concerns.ConclusionThe murine model will continue to be an indispensable resource for cancer research and is deserving of enormous credit for the advancements in cancer therapy over previous decades. We believe that the large numbers of available canine patients with spontaneous cancers can offer an unequalled opportunity for stimulating advancement in the clinical management of human and companion animal cancers. We propose that, for applicable diseases, the canine model should be integrated into existing preclinical and clinical frameworks (including pharmacogenomics studies) in a way that not only benefits human drug development and disease understanding, but also improves the quality of treatment for our four-legged friends. Although we have focused primarily on cancer, it should also be noted that dogs are successfully used to study and develop treatments for many other diseases and disorders, such as wound healing, blindness and other vision disorders, heart disease, epilepsy, autoimmune diseases and narcolepsy [17,18]. It is our hope that with continued integration in these areas, we can expedite both the identification of druggable targets and improve the efficiency of the drug development system, for the benefit of both humans and canines.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 DiMasi JA, Grabowski HG. Economics of new oncology drug development. J. Clin. Oncol.25(2),209–216 (2007).Crossref, Medline, Google Scholar2 Arrowsmith J. Trial watch: Phase II failures: 2008–2010. Nat. Rev. Drug Discov.10(5),328–329 (2011).Crossref, Medline, CAS, Google Scholar3 Bates SE, Amiri-Kordestani L, Giaccone G. Drug development: portals of discovery. Clin. Cancer Res.18(1),23–32 (2012).Crossref, Medline, CAS, Google Scholar4 Sharpless NE, DePinho RA. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov.5(9),741–754 (2006).Crossref, Medline, CAS, Google Scholar5 Cheon DJ, Orsulic S. Mouse models of cancer. Annu. Rev. Pathol. Mech. Dis.6(1),95–119 (2011).Crossref, CAS, Google Scholar6 Paoloni M, Khanna C. Translation of new cancer treatments from pet dogs to humans. Nat. Rev. Cancer8(2),147–156 (2008).Crossref, Medline, CAS, Google Scholar7 Shearin AL, Ostrander EA. Leading the way: canine models of genomics and disease. Dis. Model. Mech.3(1–2),27–34 (2010).Crossref, Medline, CAS, Google Scholar8 Fleming JM, Creevy KE, Promislow DE. Mortality in North American dogs from 1984 to 2004: an investigation into age-, size-, and breed-related causes of death. J. Vet. Intern. Med.25(2),187–198 (2011).Crossref, Medline, CAS, Google Scholar9 Thomas R, Seiser EL, Motsinger-Reif A et al. Refining tumor-associated aneuploidy through ‘genomic recoding’ of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas. Leuk. Lymphoma52(7),1321–1335 (2011).Crossref, Medline, Google Scholar10 Angstadt AY, Thayanithy V, Subramanian S, Modiano JF, Breen M. A genome-wide approach to comparative oncology: high-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations. Cancer Genet.205(11),572–587 (2012).Crossref, Medline, CAS, Google Scholar11 Modiano JF, Breen M. Shared pathogenesis of human and canine tumors – an inextricable link between cancer and evolution. Cancer Ther.6,239–246 (2008).CAS, Google Scholar12 Thomas R, Duke SE, Wang HJ et al. ‘Putting our heads together’: insights into genomic conservation between human and canine intracranial tumors. J. Neurooncol.94(3),333–349 (2009).Crossref, Medline, CAS, Google Scholar13 Lindblad-Toh K, Wade CM, Mikkelsen TS et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature438(7069),803–819 (2005).Crossref, Medline, CAS, Google Scholar14 Davis RE, Ngo VN, Lenz G et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature463(7277),88–92 (2010).Crossref, Medline, CAS, Google Scholar15 Honigberg LA, Smith AM, Sirisawad M et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl Acad. Sci. USA107(29),13075–13080 (2010).Crossref, Medline, CAS, Google Scholar16 Advani RH, Buggy JJ, Sharman JP et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J. Clin. Oncol.31(1),88–94 (2013).Crossref, Medline, CAS, Google Scholar17 Sutter NB, Ostrander EA. Dog star rising: the canine genetic system. Nat. Rev. Genet.5(12),900–910 (2004).Crossref, Medline, CAS, Google Scholar18 Volk SW, Bohling MW. Comparative wound healing – are the small animal veterinarian’s clinical patients an improved translational model for human wound healing research? Wound Repair Regen.21(3),372–381 (2013).Crossref, Medline, Google Scholar101 American Cancer Society. Cancer treatment and survivorship facts and figures 2012–2013 (2012). www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-033876.pdfGoogle Scholar102 2011–2012 APPA National Pet Owners Survey. www.humaneresearch.org/content/2011-2012-appa-national-pet-owners-surveyGoogle ScholarFiguresReferencesRelatedDetailsCited ByDNA methylation and targeted sequencing of methyltransferases family genes in canine acute myeloid leukaemia, modelling human myeloid leukaemia21 April 2016 | Veterinary and Comparative Oncology, Vol. 15, No. 3Embracing Integrative Multiomics ApproachesInternational Journal of Genomics, Vol. 2016Canine Spontaneous Head and Neck Squamous Cell Carcinomas Represent Their Human Counterparts at the Molecular Level1 June 2015 | PLOS Genetics, Vol. 11, No. 6 Vol. 14, No. 16 Follow us on social media for the latest updates Metrics History Published online 26 November 2013 Published in print December 2013 Information© Future Medicine LtdKeywordscancercanine modelchemotherapyclinical trialsFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download}, number={16}, journal={PHARMACOGENOMICS}, author={Rotroff, Daniel M. and Thomas, Rachael and Breen, Matthew and Motsinger-Reif, Alison A.}, year={2013}, month={Dec}, pages={1929–1931} }
 @article{dai_charnigo_becker_leeder_motsinger-reif_2013, title={Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction}, volume={6}, journal={Biodata Mining}, author={Dai, H. Y. and Charnigo, R. J. and Becker, M. L. and Leeder, J. S. and Motsinger-Reif, A. A.}, year={2013} }
 @article{brown_havener_medina_auman_mangravite_krauss_mcleod_motsinger-reif_2012, title={A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT}, volume={22}, ISSN={["1744-6872"]}, DOI={10.1097/fpc.0b013e3283589c50}, abstractNote={Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.Genome-wide association analysis using ∼2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P<10(-8)) with SNPs in the O(6)-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P<10(-26)) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas.The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations.}, number={11}, journal={PHARMACOGENETICS AND GENOMICS}, author={Brown, Chad C. and Havener, Tammy M. and Medina, Marisa W. and Auman, J. Todd and Mangravite, Lara M. and Krauss, Ronald M. and McLeod, Howard L. and Motsinger-Reif, Alison A.}, year={2012}, month={Nov}, pages={796–802} }
 @article{brown_oki_hariani_motsinger-reif_2012, title={A predictive model for Efavirenz dosing}, volume={13}, number={2}, journal={Pharmacogenomics}, author={Brown, C. and Oki, N. O. and Hariani, G. and Motsinger-Reif, A. A.}, year={2012}, pages={137–138} }
 @article{he_misher_irvin_motsinger-reif_mcleod_hoskins_2012, title={Assessing the utility of whole genome amplified DNA as a template for DMET Plus array}, volume={50}, number={8}, journal={Clinical Chemistry and Laboratory Medicine}, author={He, Y. J. and Misher, A. D. and Irvin, W. and Motsinger-Reif, A. and McLeod, H. L. and Hoskins, J. M.}, year={2012}, pages={1329–1334} }
 @article{hertz_motsinger-reif_drobish_winham_mcleod_carey_dees_2012, title={CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel}, volume={134}, ISSN={["1573-7217"]}, DOI={10.1007/s10549-012-2054-0}, abstractNote={Paclitaxel is one of the most frequently used chemotherapeutic agents for the treatment of breast cancer patients. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Patient and tumor characteristics and treatment outcomes were collected prospectively for breast cancer patients treated with paclitaxel-containing regimens in the neoadjuvant setting. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria, while toxicity data were collected from physician notes. The primary endpoint was achievement of clinical complete response (cCR) and secondary endpoints included clinical response rate (complete response+partial response) and grade 3+ peripheral neuropathy. The genotypes and haplotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1B/CYP3A5*3C, and ABCB1*2. A total of 111 patients were included in this study. Overall, cCR was 30.1% to the paclitaxel component. CYP2C8*3 carriers (23/111, 20.7%) had higher rates of cCR (55% vs. 23%; OR=3.92 [95% CI: 1.46-10.48], corrected p=0.046). In the secondary toxicity analysis, we observed a trend toward greater risk of severe neuropathy (22% vs. 8%; OR=3.13 [95% CI: 0.89-11.01], uncorrected p=0.075) in subjects carrying the CYP2C8*3 variant. Other polymorphisms interrogated were not significantly associated with response or toxicity. Patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity.}, number={1}, journal={BREAST CANCER RESEARCH AND TREATMENT}, author={Hertz, Daniel L. and Motsinger-Reif, Alison A. and Drobish, Amy and Winham, Stacey J. and McLeod, Howard L. and Carey, Lisa A. and Dees, E. Claire}, year={2012}, month={Jul}, pages={401–410} }
 @article{walker_hanel_hansen_motsinger-reif_2012, title={Comparison of venous sampling methods for thromboelastography in clinically normal dogs}, volume={73}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.73.12.1864}, abstractNote={Abstract Objective —To evaluate effects of blood collection method and site on results of thromboelastography in healthy dogs. Animals —8 clinically normal purpose-bred dogs. Procedures —Blood was collected from the external jugular vein by syringe aspiration via direct venipuncture with a 20-gauge needle, through a central venous catheter, or into an evacuated tube with a 21-gauge winged needle catheter. Blood was collected from the lateral saphenous vein by syringe aspiration via direct venipuncture with a 20-gauge needle or into an evacuated tube with a 21-gauge winged needle catheter. Kaolin-activated thromboelastographic analyses were performed, and R (reaction time), K (clot formation time), α angle, maximal amplitude, and G (global clot strength) were analyzed. Results —No significant differences were observed with regard to sampling site. Sample collection method had no effect on thromboelastographic results for saphenous vein samples. Blood samples collected from the jugular vein by syringe aspiration had a lower R and K and higher α angle than did blood samples collected from the jugular vein by evacuated tube collection. Significant differences were observed between blood samples collected from the jugular vein by syringe aspiration and samples collected from the saphenous vein by evacuated tube collection and between samples collected from the saphenous vein by evacuated tube collection and samples collected from the jugular vein through a central venous catheter. Conclusions and Clinical Relevance —Different sampling methods resulted in small but significant differences in thromboelastographic values. Results justify the use of standardized techniques for research purposes, but all of these sampling methods were acceptable for 1-time clinical use.}, number={12}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Walker, Julie M. and Hanel, Rita M. and Hansen, Bernard D. and Motsinger-Reif, Alison A.}, year={2012}, month={Dec}, pages={1864–1870} }
 @article{conner_hanel_hansen_motsinger-reif_asakawa_swanson_2012, title={Effects of acepromazine maleate on platelet function assessed by use of adenosine diphosphate activated- and arachidonic acid-activated modified thromboelastography in healthy dogs}, volume={73}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.73.5.595}, abstractNote={Abstract Objective —To evaluate the effect of acepromazine maleate administered IV on platelet function assessed in healthy dogs by use of a modified thromboelastography assay. Animals —6 healthy adult mixed-breed dogs. Procedures —Dogs received each of 3 treatments (saline [0.9% NaCl] solution [1 to 2 mL, IV] and acepromazine maleate [0.05 and 0.1 mg/kg, IV]) in a randomized crossover study with a minimum 3-day washout period between treatments. From each dog, blood samples were collected via jugular venipuncture immediately before and 30 and 240 minutes after administration of each treatment. A modified thromboelastography assay, consisting of citrated kaolin–activated (baseline assessment), reptilase-ADP–activated (ADP-activated), and reptilase-arachidonic acid (AA)–activated (AA-activated) thromboelastography, was performed for each sample. Platelet inhibition was evaluated by assessing the percentage change in maximum amplitude for ADP-activated or AA-activated samples, compared with baseline values. Percentage change in maximum amplitude was analyzed by use of Skillings-Mack tests with significance accepted at a family-wise error rate of P < 0.05 by use of Bonferroni corrections for multiple comparisons. Results —No significant differences were found in the percentage change of maximum amplitude from baseline for ADP-activated or AA-activated samples among treatments at any time. Conclusions and Clinical Relevance —Platelet function in dogs, as assessed by use of a modified thromboelastography assay, was not inhibited by acepromazine at doses of 0.05 or 0.1 mg/kg, IV. This was in contrast to previous reports in which it was suggested that acepromazine may alter platelet function via inhibition of ADP and AA.}, number={5}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Conner, Bobbi J. and Hanel, Rita M. and Hansen, Bernard D. and Motsinger-Reif, Alison A. and Asakawa, Makoto and Swanson, Clifford R.}, year={2012}, month={May}, pages={595–601} }
 @article{funk-keenan_sacco_wong_rasmussen_motsinger-reif_trepanier_2012, title={Evaluation of Polymorphisms in the Sulfonamide Detoxification Genes CYB5A and CYB5R3 in Dogs with Sulfonamide Hypersensitivity}, volume={26}, ISSN={["1939-1676"]}, DOI={10.1111/j.1939-1676.2012.00965.x}, abstractNote={Background Delayed hypersensitivity ( HS ) reactions to potentiated sulfonamide antimicrobials occur in both dogs and humans, and involve an intermediate hydroxylamine metabolite that is detoxified by cytochrome b 5 and NADH cytochrome b 5 reductase. Hypothesis/Objectives We hypothesized that polymorphisms in the genes ( CYB 5A and CYB 5R3) encoding these 2 enzymes would be associated with risk of sulfonamide HS in dogs. Animals A total of 18 dogs with delayed HS to potentiated sulfonamide antimicrobials and 16 dogs that tolerated ( TOL ) a therapeutic course of these drugs without adverse effect. Methods CYB 5A and CYB 5R3 were sequenced from canine liver, and the promoter, exons, and 3′ untranslated regions of both genes were resequenced from genomic DNA obtained from all dogs. Results Multiple polymorphisms were found in both genes. When controlled for multiple comparisons, the 729 GG variant in CYB 5R3 was significantly overrepresented in dogs with sulfonamide HS (78% of dogs), compared to TOL dogs (31%; P = .003). Conclusions and Clinical Importance The CYB 5R3 729 GG variant may contribute to the risk of sulfonamide HS in dogs. Functional characterization of this polymorphism, as well as genotyping in a larger number of HS and TOL dogs, is warranted.}, number={5}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Funk-Keenan, J. and Sacco, J. and Wong, Y. Y. and Rasmussen, S. and Motsinger-Reif, A. and Trepanier, L. A.}, year={2012}, pages={1126–1133} }
 @article{sacco_abouraya_motsinger-reif_yale_mccarty_trepanier_2012, title={Evaluation of polymorphisms in the sulfonamide detoxification genes NAT2, CYB5A, and CYB5R3 in patients with sulfonamide hypersensitivity}, volume={22}, ISSN={["1744-6872"]}, DOI={10.1097/fpc.0b013e328357a735}, abstractNote={Objective To determine whether polymorphisms in the sulfonamide detoxification genes, CYB5A (encoding cytochrome b5), CYB5R3 (encoding cytochrome b5 reductase), or NAT2 (encoding N-acetyltransferase 2) were over-represented in patients with delayed sulfonamide drug hypersensitivity, compared with control patients who tolerated a therapeutic course of trimethoprim–sulfamethoxazole without adverse event. Methods DNA from 99 nonimmunocompromised patients with sulfonamide hypersensitivity who were identified from the Personalized Medicine Research Project at the Marshfield Clinic, and from 99 age-matched, race-matched, and sex-matched drug-tolerant controls, were genotyped for four CYB5A and five CYB5R3 polymorphisms, and for all coding NAT2 SNPs. Results CYB5A and CYB5R3 SNPs were found at low allele frequencies (<3–4%), which did not differ between hypersensitive and tolerant patients. NAT2 allele and haplotype frequencies, as well as inferred NAT2 phenotypes, also did not differ between groups (60 vs. 59% slow acetylators). Finally, no difference in NAT2 status was found in a subset of patients with more severe hypersensitivity signs (drug reaction with eosinophilia and systemic symptoms) compared with tolerant patients. Conclusion We found no evidence of a substantial involvement of these nine CYB5A or CYB5R3 polymorphisms in sulfonamide hypersensitivity risk, although minor effects cannot be completely ruled out. Despite careful medical record review and full resequencing of the NAT2 coding region, we found no association of NAT2 coding alleles with sulfonamide hypersensitivity (predominantly cutaneous eruptions) in this adult Caucasian population.}, number={10}, journal={PHARMACOGENETICS AND GENOMICS}, author={Sacco, James C. and Abouraya, Mahmoud and Motsinger-Reif, Alison and Yale, Steven H. and McCarty, Catherine A. and Trepanier, Lauren A.}, year={2012}, month={Oct}, pages={733–740} }
 @article{che_motsinger-reif_brown_2012, title={Loss of Power in Two-Stage Residual-Outcome Regression Analysis in Genetic Association Studies}, ISSN={0741-0395}, url={http://dx.doi.org/10.1002/gepi.21671}, DOI={10.1002/gepi.21671}, abstractNote={Disclaimer: Supplementary materials have been peer-reviewed but not copyedited. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.}, journal={Genetic Epidemiology}, publisher={Wiley}, author={Che, Ronglin and Motsinger-Reif, Alison A. and Brown, Chad C.}, year={2012}, month={Aug}, pages={n/a-n/a} }
 @misc{che_motsinger-reif_brown_2012, title={Loss of power in two-stage residual-outcome regression analysis in genetic association studies}, volume={36}, number={8}, journal={Genetic Epidemiology}, author={Che, R. L. and Motsinger-Reif, A. A. and Brown, C. C.}, year={2012}, pages={890–894} }
 @article{brown_havener_medina_krauss_mcleod_motsinger-reif_2012, title={Multivariate methods and software for association mapping in dose-response genome-wide association studies}, volume={5}, journal={Biodata Mining}, author={Brown, C. C. and Havener, T. M. and Medina, M. W. and Krauss, R. M. and McLeod, H. L. and Motsinger-Reif, A. A.}, year={2012} }
 @article{ravel_gajer_fu_mauck_koenig_sakamoto_motsinger-reif_doncel_zeichner_2012, title={Twice-Daily Application of HIV Microbicides Alters the Vaginal Microbiota}, volume={3}, ISSN={["2150-7511"]}, DOI={10.1128/mbio.00370-12}, abstractNote={Vaginal HIV microbicides offer great promise in preventing HIV transmission, but failures of phase 3 clinical trials, in which microbicide-treated subjects had an increased risk of HIV transmission, raised concerns about endpoints used to evaluate microbicide safety. A possible explanation for the increased transmission risk is that the agents shifted the vaginal bacterial community, resulting in loss of natural protection and enhanced HIV transmission susceptibility. We characterized vaginal microbiota, using pyrosequencing of bar-coded 16S rRNA gene fragments, in samples from 35 healthy, sexually abstinent female volunteer subjects (ages 18 to 50 years) with regular menses in a repeat phase 1 study of twice-daily application over 13.5 days of 1 of 3 gel products: a hydroxyethylcellulose (HEC)-based "universal" placebo (10 subjects), 6% cellulose sulfate (CS; 13 subjects), and 4% nonoxynol-9 (N-9; 12 subjects). We used mixed effects models inferred using Bayesian Markov chain Monte Carlo methods, which showed that treatment with active agents shifted the microbiota toward a community type lacking significant numbers of Lactobacillus spp. and dominated by strict anaerobes. This state of the vaginal microbiota was associated with a low or intermediate Nugent score and was not identical to bacterial vaginosis, an HIV transmission risk factor. The placebo arm contained a higher proportion of communities dominated by Lactobacillus spp., particularly L. crispatus, throughout treatment. The data suggest that molecular evaluation of microbicide effects on vaginal microbiota may be a critical endpoint that should be incorporated in early clinical assessment of microbicide candidates.Despite large prevention efforts, HIV transmission and acquisition rates remain unacceptably high. In developing countries, transmission mainly occurs through heterosexual intercourse, where women are significantly more vulnerable to infection than men. Vaginal microbicides are considered to be one of the most promising female-controlled products, in that women themselves insert the microbicides into the vagina to prevent HIV transmission during sexual intercourse. The failure of several microbicides in clinical trials has raised questions concerning the low in vivo efficacy of such anti-HIV molecules. This study was designed to gain insights into the failures of two microbicides by testing the hypothesis that the microbicides negatively affect a critical line of defense against HIV, the vaginal microbiota. The results suggest that in the early assessment of candidate microbicides, culture-independent evaluation of their effect on the vaginal microbiota should be considered and may constitute a critical endpoint.}, number={6}, journal={MBIO}, author={Ravel, Jacques and Gajer, Pawel and Fu, Li and Mauck, Christine K. and Koenig, Sara S. K. and Sakamoto, Joyce and Motsinger-Reif, Alison A. and Doncel, Gustavo F. and Zeichner, Steven L.}, year={2012} }
 @article{winham_wang_motsinger-reif_2011, title={A Comparison of Multifactor Dimensionality Reduction and L-1-Penalized Regression to Identify Gene-Gene Interactions in Genetic Association Studies}, volume={10}, ISSN={["1544-6115"]}, DOI={10.2202/1544-6115.1613}, abstractNote={Recently, the amount of high-dimensional data has exploded, creating new analytical challenges for human genetics. Furthermore, much evidence suggests that common complex diseases may be due to complex etiologies such as gene-gene interactions, which are difficult to identify in high-dimensional data using traditional statistical approaches. Data-mining approaches are gaining popularity for variable selection in association studies, and one of the most commonly used methods to evaluate potential gene-gene interactions is Multifactor Dimensionality Reduction (MDR). Additionally, a number of penalized regression techniques, such as Lasso, are gaining popularity within the statistical community and are now being applied to association studies, including extensions for interactions. In this study, we compare the performance of MDR, the traditional lasso with L1 penalty (TL1), and the group lasso for categorical data with group-wise L1 penalty (GL1) to detect gene-gene interactions through a broad range of simulations. We find that each method has both advantages and disadvantages, and relative performance is context dependent. TL1 frequently over-fits, identifying false positive as well as true positive loci. MDR has higher power for epistatic models that exhibit independent main effects; for both Lasso methods, main effects tend to dominate. For purely epistatic models, GL1 has the best performance for lower minor allele frequencies, but MDR performs best for higher frequencies. These results provide guidance of when each approach might be best suited for detecting and characterizing interactions with different mechanisms.}, number={1}, journal={STATISTICAL APPLICATIONS IN GENETICS AND MOLECULAR BIOLOGY}, author={Winham, Stacey and Wang, Chong and Motsinger-Reif, Alison A.}, year={2011} }
 @article{angstadt_motsinger-reif_thomas_kisseberth_couto_duval_nielsen_modiano_breen_2011, title={Characterization of Canine Osteosarcoma by Array Comparative Genomic Hybridization and RT-qPCR: Signatures of Genomic Imbalance in Canine Osteosarcoma Parallel the Human Counterpart}, volume={50}, ISSN={["1098-2264"]}, DOI={10.1002/gcc.20908}, abstractNote={Osteosarcoma (OS) is the most commonly diagnosed malignant bone tumor in humans and dogs, characterized in both species by extremely complex karyotypes exhibiting high frequencies of genomic imbalance. Evaluation of genomic signatures in human OS using array comparative genomic hybridization (aCGH) has assisted in uncovering genetic mechanisms that result in disease phenotype. Previous low-resolution (10–20 Mb) aCGH analysis of canine OS identified a wide range of recurrent DNA copy number aberrations, indicating extensive genomic instability. In this study, we profiled 123 canine OS tumors by 1 Mb-resolution aCGH to generate a dataset for direct comparison with current data for human OS, concluding that several high frequency aberrations in canine and human OS are orthologous. To ensure complete coverage of gene annotation, we identified the human refseq genes that map to these orthologous aberrant dog regions and found several candidate genes warranting evaluation for OS involvement. Specifically, subsequenct FISH and qRT-PCR analysis of RUNX2, TUSC3, and PTEN indicated that expression levels correlated with genomic copy number status, showcasing RUNX2 as an OS associated gene and TUSC3 as a possible tumor suppressor candidate. Together these data demonstrate the ability of genomic comparative oncology to identify genetic abberations which may be important for OS progression. Large scale screening of genomic imbalance in canine OS further validates the use of the dog as a suitable model for human cancers, supporting the idea that dysregulation discovered in canine cancers will provide an avenue for complementary study in human counterparts. © 2011 Wiley-Liss, Inc.}, number={11}, journal={GENES CHROMOSOMES & CANCER}, author={Angstadt, Andrea Y. and Motsinger-Reif, Alison and Thomas, Rachael and Kisseberth, William C. and Couto, C. Guillermo and Duval, Dawn L. and Nielsen, Dahlia M. and Modiano, Jaime F. and Breen, Matthew}, year={2011}, month={Nov}, pages={859–874} }
 @article{watson_hardison_harris_motsinger-reif_mcleod_2011, title={Genomic Profiling in CEPH Cell Lines Distinguishes between the Camptothecins and Indenoisoquinolines}, volume={10}, ISSN={["1535-7163"]}, DOI={10.1158/1535-7163.mct-10-0872}, abstractNote={We have attempted to use a familial genetics strategy to study mechanisms of topoisomerase 1 (Top1) inhibition. Investigations have steadily been chipping away at the pathways involved in cellular response following Top1 inhibition for more than 20 years. Our system-wide approach, which phenotypes a collection of genotyped human cell lines for sensitivity to compounds and interrogates all genes and molecular pathways simultaneously. Previously, we characterized the in vitro sensitivity of 15 families of Centre d'Etude Polymorphisme Humain (CEPH) cell lines (n = 142) to 9 camptothecin analogues. Linkage analysis revealed a pattern of 7 quantitative trait loci (QTL) shared by all of the camptothecins. To identify which, if any, QTLs are related to the general mechanism of Top1 inhibition or should be considered camptothecin specific, we characterized the in vitro sensitivity of the same panel of CEPH cell lines to the indenisoquinolones, a structurally distinct class of Top1 inhibitors. Four QTLs on chromosomes 1, 5, 11, and 16 were shared by both the camptothecins and the indenoisoquinolines and are considered associated with the general mechanism of Top1 inhibition. The remaining 3 QTLs (chromosomes 6 and 20) are considered specific to camptothecin-induced cytotoxicity. Finally, 8 QTLs were identified, which were unique to the indenoisoquinolines.}, number={10}, journal={MOLECULAR CANCER THERAPEUTICS}, author={Watson, Venita Gresham and Hardison, Nicholas E. and Harris, Tyndall and Motsinger-Reif, Alison and McLeod, Howard L.}, year={2011}, month={Oct}, pages={1839–1845} }
 @article{watson_motsinger-reif_hardison_peters_havener_everitt_auman_comins_mcleod_2011, title={Identification and replication of loci involved in camptothecin-induced cytotoxicity using CEPH pedigrees}, volume={6}, number={5}, journal={PLoS One}, author={Watson, V. G. and Motsinger-Reif, A. and Hardison, N. E. and Peters, E. J. and Havener, T. M. and Everitt, L. and Auman, J. T. and Comins, D. L. and McLeod, H. L.}, year={2011} }
 @article{cohen_rossi_garbarino_bowling_motsinger-reif_schuler_dupont_gabriel_2011, title={Insights into the inhibition of platelet activation by omega-3 polyunsaturated fatty acids: Beyond aspirin and clopidogrel}, volume={128}, ISSN={["0049-3848"]}, DOI={10.1016/j.thromres.2011.04.023}, abstractNote={We sought to examine the effects of escalating doses of omega-3 polyunsaturated fatty acid (PUFA) supplements on platelet function using light transmission aggregometry (LTA) and electrophoretic quasi-elastic light scattering technology (EQELS).PUFA may inhibit platelet function through fatty acid substitution in the platelet membrane by changing the surface charge density and causing decreased production of thromboxane A2. EQELS can measure platelet surface charge density and determine whether the platelet is in resting or activated state.A total of 30 volunteers were divided in 3 groups of 10 as follows: Group A, no antiplatelet agent; Group B, daily aspirin only, and Group C, daily aspirin and clopidogrel. All patients received escalating doses of omega-3PUFA from 1 to 8 g daily over 24 weeks. Platelet function was measured by template bleeding time, LTA, and EQELS at baseline and at 6, 12, 18 and 24 weeks.Mean bleeding time increased in a dose-dependent manner with escalating omega-3 PUFA doses. LTA confirmed expected antiplatelet effects of aspirin and clopidogrel, but did not detect any additional antiplatelet effects of omega-3 PUFA. EQELS showed a significant increase in the negative resting platelet charge compared to baseline and an attenuated response to arachidonic acid mediated platelet activation. No bleeding events were observed.In this pilot study we were able to successfully measure platelet surface charge variation as a measure of omega-3 PUFA effect on platelets. Our results suggest that omega-3 PUFA increase the total platelet surface charge and, therefore, attenuate platelet activation, even among patients taking aspirin or aspirin plus clopidogrel. Further studies are needed to determine the clinical significance of these measured effects and EQELS results.}, number={4}, journal={THROMBOSIS RESEARCH}, author={Cohen, Mauricio G. and Rossi, Joseph S. and Garbarino, Jennifer and Bowling, Regina and Motsinger-Reif, Alison A. and Schuler, Carl and Dupont, Allison G. and Gabriel, Don}, year={2011}, month={Oct}, pages={335–340} }
 @article{thomas_motsinger-reif_hoskins_dvorak_roy_alyasiri_myerson_fleshman_tan_mcleod_2011, title={Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer}, volume={105}, ISSN={0007-0920 1532-1827}, url={http://dx.doi.org/10.1038/BJC.2011.442}, DOI={10.1038/BJC.2011.442}, abstractNote={There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study. The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed. MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C–1298C) and diplotypes (CA–TA and TA–TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response. MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.}, number={11}, journal={British Journal of Cancer}, publisher={Springer Science and Business Media LLC}, author={Thomas, F and Motsinger-Reif, A A and Hoskins, J M and Dvorak, A and Roy, S and Alyasiri, A and Myerson, R J and Fleshman, J W and Tan, B R and McLeod, H L}, year={2011}, month={Nov}, pages={1654–1662} }
 @article{hedan_thomas_motsinger-reif_abadie_andre_cullen_breen_2011, title={Molecular cytogenetic characterization of canine histiocytic sarcoma: A spontaneous model for human histiocytic cancer identifies deletion of tumor suppressor genes and highlights influence of genetic background on tumor behavior}, volume={11}, journal={BMC Cancer}, author={Hedan, B. and Thomas, R. and Motsinger-Reif, A. and Abadie, J. and Andre, C. and Cullen, J. and Breen, M.}, year={2011} }
 @article{beam_motsinger-reif_2011, title={Optimization of nonlinear dose- and concentration-response models utilizing evolutionary computation}, volume={9}, number={3}, journal={Dose-response}, author={Beam, A. L. and Motsinger-Reif, A. A.}, year={2011}, pages={387–409} }
 @article{peters_motsinger-reif_havener_everitt_hardison_watson_wagner_richards_province_mcleod_2011, title={Pharmacogenomic characterization of US FDA-approved cytotoxic drugs}, volume={12}, ISSN={["1462-2416"]}, DOI={10.2217/pgs.11.92}, abstractNote={Individualization of cancer chemotherapy based on the patient's genetic makeup holds promise for reducing side effects and improving efficacy. However, the relative contribution of genetics to drug response is unknown.In this study, we investigated the cytotoxic effect of 29 commonly prescribed chemotherapeutic agents from diverse drug classes on 125 lymphoblastoid cell lines derived from 14 extended families.The results of this systematic study highlight the variable role that genetics plays in response to cytotoxic drugs, ranging from a heritability of <0.15 for gemcitabine to >0.60 for epirubicin.Putative quantitative trait loci for cytotoxic response were identified, as well as drug class-specific signatures, which could indicate possible shared genetic mechanisms. In addition to the identification of putative quantitative trait locis, the results of this study inform the prioritization of chemotherapeutic drugs with a sizable genetic response component for future investigation.}, number={10}, journal={PHARMACOGENOMICS}, author={Peters, Eric J. and Motsinger-Reif, Alison and Havener, Tammy M. and Everitt, Lorraine and Hardison, Nicholas E. and Watson, Venita G. and Wagner, Michael and Richards, Kristy L. and Province, Mike A. and McLeod, Howard L.}, year={2011}, month={Oct}, pages={1407–1415} }
 @article{asher_motsinger-reif_jonas_viera_2011, title={Quality of reporting on randomised controlled trials of auriculotherapy for pain}, volume={29}, ISSN={["1759-9873"]}, DOI={10.1136/aim.2010.003475}, abstractNote={The authors investigated the quality of reporting for randomised controlled trials of auriculotherapy for pain before and after the implementation of the Consolidated Standards of Reporting Trials (CONSORT) and Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) guidelines.The authors identified randomised controlled trials of auriculotherapy that measured pain or pain medication use as a primary outcome and were published in English in peer-reviewed journals. Proportions of studies that reported STRICTA and CONSORT items were compared for the years before and after implementation of STRICTA (2001) using Fisher's exact tests. Global differences across all study factors were investigated using hierarchical clustering and principle component analysis (PCA).15 studies met our inclusion criteria. On average, 11 studies (74%) reported STRICTA items and eight studies (54%) reported CONSORT items. Differences in reporting between pre and post-STRICTA studies were found for two CONSORT items (randomised sequence and treatment provider) but no STRICTA items. However, the results of cluster analysis and PCA detected global differences over time for both STRICTA and CONSORT items.Quality of reporting for studies of auriculotherapy for pain appears to have generally improved since the implementation of STRICTA and CONSORT guidelines.}, number={2}, journal={ACUPUNCTURE IN MEDICINE}, author={Asher, Gary N. and Motsinger-Reif, Alison A. and Jonas, Daniel E. and Viera, Anthony J.}, year={2011}, month={Jun}, pages={122–126} }
 @article{thomas_seiser_motsinger-reif_borst_valli_kelley_suter_argyle_burgess_bell_et al._2011, title={Refining tumor-associated aneuploidy through ‘genomic recoding’ of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas}, volume={52}, ISSN={1042-8194 1029-2403}, url={http://dx.doi.org/10.3109/10428194.2011.559802}, DOI={10.3109/10428194.2011.559802}, abstractNote={Identification of the genomic regions most intimately associated with non-Hodgkin lymphoma (NHL) pathogenesis is confounded by the genetic heterogeneity of human populations. We hypothesize that the restricted genetic variation of purebred dogs, combined with the contrasting architecture of the human and canine karyotypes, will increase the penetrance of fundamental NHL-associated chromosomal aberrations in both species. We surveyed non-random aneuploidy in 150 canine NHL cases, revealing limited genomic instability compared to their human counterparts and no evidence for CDKN2A/B deletion in canine B-cell NHL. 'Genomic recoding' of canine NHL data into a 'virtual human' chromosome format showed remarkably few regions of copy number aberration (CNA) shared between both species, restricted to regions of dog chromosomes 13 and 31, and human chromosomes 8 and 21. Our data suggest that gene discovery in NHL may be enhanced through comparative studies exploiting the less complex association between CNAs and tumor pathogenesis in canine patients.}, number={7}, journal={Leukemia & Lymphoma}, publisher={Informa UK Limited}, author={Thomas, Rachael and Seiser, Eric L. and Motsinger-Reif, Alison and Borst, Luke and Valli, Victor E. and Kelley, Kathryn and Suter, Steven E. and Argyle, David and Burgess, Kristine and Bell, Jerold and et al.}, year={2011}, month={Mar}, pages={1321–1335} }
 @article{gamble_motsinger-reif_hida_borsetti_servick_ciarleglio_robbins_hicks_carver_hamilton_et al._2011, title={Shift work in nurses: Contribution of phenotypes and genotypes to adaptation}, volume={6}, number={4}, journal={PLoS One}, author={Gamble, K. L. and Motsinger-Reif, A. A. and Hida, A. and Borsetti, H. M. and Servick, S. V. and Ciarleglio, C. M. and Robbins, S. and Hicks, J. and Carver, K. and Hamilton, N. and et al.}, year={2011} }
 @article{winham_motsinger-reif_2011, title={The Effect of Retrospective Sampling on Estimates of Prediction Error for Multifactor Dimensionality Reduction}, volume={75}, journal={Annals of Human Genetics}, author={Winham, S. J. and Motsinger-Reif, A. A.}, year={2011}, pages={46–61} }
 @article{tsai_hardison_james_motsinger-reif_bischoff_thames_piedrahita_2011, title={Transcriptional profiling of human placentas from pregnancies complicated by preeclampsia reveals disregulation of sialic acid acetylesterase and immune signalling pathways}, volume={32}, ISSN={["1532-3102"]}, DOI={10.1016/j.placenta.2010.11.014}, abstractNote={The placenta plays an important role as a regulator of fetal nutrition and growth throughout development and placental factors contribute to gestational abnormalities such as preeclampsia. This study describes the genome-wide gene expression profiles of a large (n = 60) set of human placentas in order to uncover gene expression patterns associated with preeclampsia. In addition to confirming changes in expression of soluble factors associated with preeclampsia such as sFLT1 (soluble fms-like tyrosine kinase-1), sENG (soluble endoglin), and INHA (inhibin alpha), we also find changes in immune-associated signaling pathways, offering a potential upstream explanation for the shallow trophoblast invasion and inadequate uterine remodeling typically observed in pathogenesis of preeclampsia. Notably, we also find evidence of preeclampsia-associated placental upregulation of sialic acid acetylesterase (SIAE), a gene functionally associated with autoimmune diseases.}, number={2}, journal={PLACENTA}, author={Tsai, S. and Hardison, N. E. and James, A. H. and Motsinger-Reif, A. A. and Bischoff, S. R. and Thames, B. H. and Piedrahita, J. A.}, year={2011}, month={Feb}, pages={175–182} }
 @article{winham_slater_motsinger-reif_2010, title={A comparison of internal validation techniques for multifactor dimensionality reduction}, volume={11}, journal={BMC Bioinformatics}, author={Winham, S. J. and Slater, A. J. and Motsinger-Reif, A. A.}, year={2010} }
 @misc{asher_jonas_coeytaux_reilly_loh_motsinger-reif_winham_2010, title={Auriculotherapy for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials}, volume={16}, ISSN={["1557-7708"]}, DOI={10.1089/acm.2009.0451}, abstractNote={Objectives: Side-effects of standard pain medications can limit their use. Therefore, nonpharmacologic pain relief techniques such as auriculotherapy may play an important role in pain management. Our aim was to conduct a systematic review and meta-analysis of studies evaluating auriculotherapy for pain management. Design: MEDLINE,® ISI Web of Science, CINAHL, AMED, and Cochrane Library were searched through December 2008. Randomized trials comparing auriculotherapy to sham, placebo, or standard-of-care control were included that measured outcomes of pain or medication use and were published in English. Two (2) reviewers independently assessed trial eligibility, quality, and abstracted data to a standardized form. Standardized mean differences (SMD) were calculated for studies using a pain score or analgesic requirement as a primary outcome. Results: Seventeen (17) studies met inclusion criteria (8 perioperative, 4 acute, and 5 chronic pain). Auriculotherapy was superior to controls for studies evaluating pain intensity (SMD, 1.56 [95% confidence interval (CI): 0.85, 2.26]; 8 studies). For perioperative pain, auriculotherapy reduced analgesic use (SMD, 0.54 [95% CI: 0.30, 0.77]; 5 studies). For acute pain and chronic pain, auriculotherapy reduced pain intensity (SMD for acute pain, 1.35 [95% CI: 0.08, 2.64], 2 studies; SMD for chronic pain, 1.84 [95% CI: 0.60, 3.07], 5 studies). Removal of poor quality studies did not alter the conclusions. Significant heterogeneity existed among studies of acute and chronic pain, but not perioperative pain. Conclusions: Auriculotherapy may be effective for the treatment of a variety of types of pain, especially postoperative pain. However, a more accurate estimate of the effect will require further large, well-designed trials.}, number={10}, journal={JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE}, author={Asher, Gary N. and Jonas, Daniel E. and Coeytaux, Remy R. and Reilly, Aimee C. and Loh, Yen L. and Motsinger-Reif, Alison A. and Winham, Stacey J.}, year={2010}, month={Oct}, pages={1097–1108} }
 @article{motsinger-reif_2010, title={Discussion of a Genome-Wide Association Approach to Determine HIV-1 Set Point in African Americans}, volume={201}, ISSN={["0022-1899"]}, DOI={10.1086/651383}, number={8}, journal={JOURNAL OF INFECTIOUS DISEASES}, author={Motsinger-Reif, Alison A.}, year={2010}, month={Apr}, pages={1118–1120} }
 @article{ribaudo_liu_schwab_schaeffeler_eichelbaum_motsinger-reif_ritchie_zanger_acosta_morse_et al._2010, title={Effect of CYP2B6, ABCB1, and CYP3A5 Polymorphisms on Efavirenz Pharmacokinetics and Treatment Response: An AIDS Clinical Trials Group Study}, volume={202}, ISSN={["0022-1899"]}, DOI={10.1086/655470}, abstractNote={In AIDS Clinical Trials Group protocols 384, A5095, and A5097s, we characterized relationships between 22 polymorphisms in CYP2B6, ABCB1, and CYP3A5; plasma efavirenz exposure; and/or treatment responses. A stepwise logistic regression procedure selected polymorphisms associated with reduced drug clearance adjusted for body mass index and the composite CYP2B6 516/983 genotype. Relationships between selected polymorphisms and treatment responses were characterized by competing risk methodology. Association analyses involved 821 individuals (317 for pharmacokinetics and 643 for treatment response). Models that included CYP2B6 516/983 genotype best predicted pharmacokinetics. Slow-metabolizer genotypes were associated with increased central nervous system events among white participants and decreased virologic failure among black participants.}, number={5}, journal={JOURNAL OF INFECTIOUS DISEASES}, author={Ribaudo, Heather J. and Liu, Huan and Schwab, Matthias and Schaeffeler, Elke and Eichelbaum, Michel and Motsinger-Reif, Alison A. and Ritchie, Marylyn D. and Zanger, Ulrich M. and Acosta, Edward P. and Morse, Gene D. and et al.}, year={2010}, month={Sep}, pages={717–722} }
 @inbook{deodhar_motsinger-reif_2010, title={Grammatical Evolution Decision Trees for Detecting Gene-Gene Interactions}, ISBN={9783642122101 9783642122118}, ISSN={0302-9743 1611-3349}, url={http://dx.doi.org/10.1007/978-3-642-12211-8_9}, DOI={10.1007/978-3-642-12211-8_9}, booktitle={Evolutionary Computation, Machine Learning and Data Mining in Bioinformatics}, publisher={Springer Berlin Heidelberg}, author={Deodhar, Sushamna and Motsinger-Reif, Alison}, year={2010}, pages={98–109} }
 @inproceedings{deodhar_motsinger-reif_2010, title={Grammatical evolution decision trees for detecting gene-gene interactions}, volume={6023}, booktitle={Evolutionary computation, machine learning and data mining in bioinformatics, proceedings}, author={Deodhar, S. and Motsinger-Reif, A.}, year={2010}, pages={98–109} }
 @article{motsinger-reif_antas_oki_levy_holland_sterling_2010, title={Polymorphisms in IL-1 beta, vitamin D receptor Fok1, and Toll-like receptor 2 are associated with extrapulmonary tuberculosis}, volume={11}, journal={BMC Medical Genetics}, author={Motsinger-Reif, A. A. and Antas, P. R. Z. and Oki, N. O. and Levy, S. and Holland, S. M. and Sterling, T. R.}, year={2010} }
 @article{limdi_wadelius_cavallari_eriksson_crawford_lee_chen_motsinger-reif_sagreiya_liu_et al._2010, title={Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups}, volume={115}, ISSN={["0006-4971"]}, DOI={10.1182/blood-2009-12-255992}, abstractNote={Abstract Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 −1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 −1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 −1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the −1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.}, number={18}, journal={BLOOD}, author={Limdi, Nita A. and Wadelius, Mia and Cavallari, Larisa and Eriksson, Niclas and Crawford, Dana C. and Lee, Ming-Ta M. and Chen, Chien-Hsiun and Motsinger-Reif, Alison and Sagreiya, Hersh and Liu, Nianjun and et al.}, year={2010}, month={May}, pages={3827–3834} }
 @article{motsinger-reif_reif_fanelli_ritchie_2009, title={A Comparison of Analytical Methods for Genetic Association Studies (vol 32, pg 767, 2008)}, volume={33}, ISSN={["0741-0395"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-71249125696&partnerID=MN8TOARS}, DOI={10.1002/gepi.20420}, abstractNote={Genetic EpidemiologyVolume 33, Issue 8 p. 751-751 ErratumFree Access A comparison of analytical methods for genetic association studies Alison A. Motsinger-Reif, Alison A. Motsinger-Reif Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, North CarolinaSearch for more papers by this authorDavid M. Reif, David M. Reif National Center for Computational Toxicology, US Environmental Protection Agency, Research Triangle Park, North CarolinaSearch for more papers by this authorTheresa J. Fanelli, Theresa J. Fanelli Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TennesseeSearch for more papers by this authorMarylyn D. Ritchie, Marylyn D. Ritchie Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TennesseeSearch for more papers by this author Alison A. Motsinger-Reif, Alison A. Motsinger-Reif Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, North CarolinaSearch for more papers by this authorDavid M. Reif, David M. Reif National Center for Computational Toxicology, US Environmental Protection Agency, Research Triangle Park, North CarolinaSearch for more papers by this authorTheresa J. Fanelli, Theresa J. Fanelli Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TennesseeSearch for more papers by this authorMarylyn D. Ritchie, Marylyn D. Ritchie Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TennesseeSearch for more papers by this author First published: 17 March 2009 https://doi.org/10.1002/gepi.20420AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume33, Issue8December 2009Pages 751-751 RelatedInformation}, number={8}, journal={GENETIC EPIDEMIOLOGY}, publisher={Wiley-Blackwell}, author={Motsinger-Reif, Alison A. and Reif, David M. and Fanelli, Theresa J. and Ritchie, Marylyn D.}, year={2009}, month={Dec}, pages={751–751} }
 @article{bischoff_tsai_hardison_motsinger-reif_freking_nonneman_rohrer_piedrahita_2009, title={Characterization of Conserved and Nonconserved Imprinted Genes in Swine}, volume={81}, ISSN={["1529-7268"]}, DOI={10.1095/biolreprod.109.078139}, abstractNote={To increase our understanding of imprinted genes in swine, we carried out a comprehensive analysis of this gene family using two complementary approaches: expression and phenotypic profiling of parthenogenetic fetuses, and analysis of imprinting by pyrosequencing. The parthenote placenta and fetus were smaller than those of controls but had no obvious morphological differences at Day 28 of gestation. By Day 30, however, the parthenote placentas had decreased chorioallantoic folding, decreased chorionic ruggae, and reduction of fetal-maternal interface surface in comparison with stage-matched control fetuses. Using Affymetrix Porcine GeneChip microarrays and/or semiquantitative PCR, brain, fibroblast, liver, and placenta of Day 30 fetuses were profiled, and 25 imprinted genes were identified as differentially expressed in at least one of the four tissue types: AMPD3, CDKN1C, COPG2, DHCR7, DIRAS3, IGF2 (isoform specific), IGF2AS, IGF2R, MEG3, MEST, NAP1L5, NDN, NNAT, OSBPL1A, PEG3, APEG3, PEG10, PLAGL1, PON2, PPP1R9A, SGCE, SLC38A4, SNORD107, SNRPN, and TFPI2. For DIRAS3, PLAGL1, SGCE, and SLC38A4, tissue-specific differences were detected. In addition, we examined the imprinting status of candidate genes by quantitative allelic pyrosequencing. Samples were collected from Day 30 pregnancies generated from reciprocal crosses of Meishan and White Composite breeds, and single-nucleotide polymorphisms were identified in candidate genes. Imprinting was confirmed for DIRAS3, DLK1, H19, IGF2AS, NNAT, MEST, PEG10, PHLDA2, PLAGL1, SGCE, and SNORD107. We also found no evidence of imprinting in ASB4, ASCL2, CD81, COMMD1, DCN, DLX5, and H13. Combined, these results represent the most comprehensive survey of imprinted genes in swine to date.}, number={5}, journal={BIOLOGY OF REPRODUCTION}, author={Bischoff, Steve R. and Tsai, Shengdar and Hardison, Nicholas and Motsinger-Reif, Alison A. and Freking, Brad A. and Nonneman, Dan and Rohrer, Gary and Piedrahita, Jorge A.}, year={2009}, month={Nov}, pages={906–920} }
 @article{reif_motsinger-reif_mckinney_rock_crowe_moore_2009, title={Integrated analysis of genetic and proteomic data identifies biomarkers associated with adverse events following smallpox vaccination}, volume={10}, ISSN={["1476-5470"]}, url={http://europepmc.org/abstract/med/18923431}, DOI={10.1038/gene.2008.80}, abstractNote={Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying the development of adverse events (AEs) in patients after smallpox vaccination. As vaccination was successful in all of the patients under study, the AE outcomes reported likely represent the result of interactions among immune system components that result in excessive or prolonged immune stimulation. In this study, we examined 1442 genetic variables (single nucleotide polymorphisms) and 108 proteomic variables (serum cytokine concentrations) to model AE risk. To accomplish this daunting analytical task, we employed the Random Forests (RF) method to filter the most important attributes, then we used the selected attributes to build a final decision tree model. This strategy is well suited to integrated analysis, as relevant attributes may be selected from categorical or continuous data. Importantly, RF is a natural approach for studying the type of gene-gene, gene-protein and protein-protein interactions we hypothesize to be involved in the development of clinical AEs. RF importance scores for particular attributes take interactions into account, and there may be interactions across data types. Combining information from previous studies on AEs related to smallpox vaccination with the genetic and proteomic attributes identified by RF, we built a comprehensive model of AE development that includes the cytokines intercellular adhesion molecule-1 (ICAM-1 or CD54), interleukin-10 (IL-10), and colony stimulating factor-3 (CSF-3 or G-CSF) and a genetic polymorphism in the cytokine gene interleukin-4 (IL4). The biological factors included in the model support our hypothesized mechanism for the development of AEs involving prolonged stimulation of inflammatory pathways and an imbalance of normal tissue damage repair pathways. This study shows the utility of RF for such analytical tasks, while both enhancing and reinforcing our working model of AE development after smallpox vaccination.}, number={2}, journal={GENES AND IMMUNITY}, author={Reif, D. M. and Motsinger-Reif, A. A. and McKinney, B. A. and Rock, M. T. and Crowe, J. E., Jr. and Moore, J. H.}, year={2009}, month={Mar}, pages={112–119} }
 @article{tsai_hardison_bischoff_thames_jamessd_motsinger-reif_piedrahita_2008, title={262: Molecular signatures of preeclampsia in human term placentas}, volume={199}, ISSN={0002-9378}, url={http://dx.doi.org/10.1016/j.ajog.2008.09.290}, DOI={10.1016/j.ajog.2008.09.290}, number={6}, journal={American Journal of Obstetrics and Gynecology}, publisher={Elsevier BV}, author={Tsai, Shengdar and Hardison, Nicholas and Bischoff, Steve and Thames, Betty and Jamessd, Andra and Motsinger-Reif, Alison and Piedrahita, Jorge}, year={2008}, month={Dec}, pages={S84} }
 @article{motsinger-reif_reif_fanelli_ritchie_2008, title={A Comparison of Analytical Methods for Genetic Association Studies}, volume={32}, ISSN={["1098-2272"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-58149346724&partnerID=MN8TOARS}, DOI={10.1002/gepi.20345}, abstractNote={The explosion of genetic information over the last decade presents an analytical challenge for genetic association studies. As the number of genetic variables examined per individual increases, both variable selection and statistical modeling tasks must be performed during analysis. While these tasks could be performed separately, coupling them is necessary to select meaningful variables that effectively model the data. This challenge is heightened due to the complex nature of the phenotypes under study and the complex underlying genetic etiologies. To address this problem, a number of novel methods have been developed. In the current study, we compare the performance of six analytical approaches to detect both main effects and gene-gene interactions in a range of genetic models. Multifactor dimensionality reduction, grammatical evolution neural networks, random forests, focused interaction testing framework, step-wise logistic regression, and explicit logistic regression were compared. As one might expect, the relative success of each method is context dependent. This study demonstrates the strengths and weaknesses of each method and illustrates the importance of continued methods development.}, number={8}, journal={GENETIC EPIDEMIOLOGY}, publisher={Wiley-Blackwell}, author={Motsinger-Reif, Alison A. and Reif, David M. and Fanelli, Theresa J. and Ritchie, Marylyn D.}, year={2008}, month={Dec}, pages={767–778} }
 @article{motsinger-reif_dudek_hahn_ritchie_2008, title={Comparison of approaches for machine-learning optimization of neural networks for detecting gene-gene interactions in genetic epidemiology}, volume={32}, ISSN={["1098-2272"]}, DOI={10.1002/gepi.20307}, abstractNote={The detection of genotypes that predict common, complex disease is a challenge for human geneticists. The phenomenon of epistasis, or gene-gene interactions, is particularly problematic for traditional statistical techniques. Additionally, the explosion of genetic information makes exhaustive searches of multilocus combinations computationally infeasible. To address these challenges, neural networks (NN), a pattern recognition method, have been used. One limitation of the NN approach is that its success is dependent on the architecture of the network. To solve this, machine-learning approaches have been suggested to evolve the best NN architecture for a particular data set. In this study we provide a detailed technical description of the use of grammatical evolution to optimize neural networks (GENN) for use in genetic association studies. We compare the performance of GENN to that of a previous machine-learning NN application--genetic programming neural networks in both simulated and real data. We show that GENN greatly outperforms genetic programming neural networks in data sets with a large number of single nucleotide polymorphisms. Additionally, we demonstrate that GENN has high power to detect disease-risk loci in a range of high-order epistatic models. Finally, we demonstrate the scalability of the GENN method with increasing numbers of variables--as many as 500,000 single nucleotide polymorphisms.}, number={4}, journal={GENETIC EPIDEMIOLOGY}, author={Motsinger-Reif, Alison A. and Dudek, Scott M. and Hahn, Lance W. and Ritchie, Marylyn D.}, year={2008}, month={May}, pages={325–340} }
 @article{reif_mckinney_motsinger_chanock_edwards_rock_moore_crowe, jr._2008, title={Genetic Basis for Adverse Events after Smallpox Vaccination}, volume={198}, ISSN={0022-1899 1537-6613}, url={http://dx.doi.org/10.1086/588670}, DOI={10.1086/588670}, abstractNote={Identifying genetic factors associated with the development of adverse events might allow screening before vaccinia virus administration. Two independent clinical trials of the smallpox vaccine (Aventis Pasteur) were conducted in healthy, vaccinia virus-naive adult volunteers. Volunteers were assessed repeatedly for local and systemic adverse events (AEs) associated with the receipt of vaccine and underwent genotyping for 1442 single-nucleotide polymorphisms (SNPs). In the first study, 36 SNPs in 26 genes were associated with systemic AEs (P ≤ .05); these 26 genes were tested in the second study. In the final analysis, 3 SNPs were consistently associated with AEs in both studies. The presence of a nonsynonymous SNP in the methylenetetrahydrofolate reductase (MTHFR) gene was associated with the risk of AE in both trials (odds ratio [OR], 2.3 [95% confidence interval {CI}1.1–5.2] [P = .04] and OR, 4.1 [95% CI, 1.4–11.4] [P<.01]). Two SNPs in the interferon regulatory factor-1 (IRF1) gene were associated with the risk of AE in both sample sets (OR, 3.2 [95% CI, 1.1–9.8] [P = .03] and OR, 3.0 [95% CI, 1.1–8.3] [P = .03]). Genetic polymorphisms in genes expressing an enzyme previously associated with adverse reactions to a variety of pharmacologic agents (MTHFR) and an immunological transcription factor (IRF1) were associated with AEs after smallpox vaccination in 2 independent study samples.}, number={1}, journal={The Journal of Infectious Diseases}, publisher={Oxford University Press (OUP)}, author={Reif, David M. and McKinney, Brett A. and Motsinger, Alison A. and Chanock, Stephen J. and Edwards, Kathryn M. and Rock, Michael T. and Moore, Jason H. and Crowe, Jr., James E.}, year={2008}, month={Jul}, pages={16–22} }
 @article{hulgan_tebas_canter_mulligan_haas_dubé_grinspoon_robbins_motsinger_kallianpur_2008, title={Hemochromatosis Gene Polymorphisms, Mitochondrial Haplogroups, and Peripheral Lipoatrophy during Antiretroviral Therapy}, volume={197}, ISSN={0022-1899 1537-6613}, url={http://dx.doi.org/10.1086/528697}, DOI={10.1086/528697}, abstractNote={BackgroundAntiretroviral therapy (ART)–associated lipoatrophy involves mitochondrial dysfunction. Iron metabolism impacts mitochondrial function and oxidative stress. Mitochondrial haplogroups and hemochromatosis gene (HFE) polymorphisms have been associated with ART-induced neuropathy. We assessed relationships between these variants and lipoatrophy MethodsThe AIDS Clinical Trials Group 384 study randomized ART-naive individuals to receive didanosine-stavudine or zidovudine-lamivudine, combined with efavirenz and/or nelfinavir. Substudy A5005s evaluated fat distribution by dual-energy X-ray absorptiometry (DEXA). We characterized HFE polymorphisms 845G>A and 187C>G and European mitochondrial haplogroups in A5005s participants who consented to genetic analyses ResultsAmong 96 participants (58% were white, and 10% were female) with baseline and 48 or 64 week DEXA data, the median limb fat change was −8.8% (interquartile range, −28.7% to +15.6%). HFE 187C/G heterozygotes (n=23) had less limb fat loss than 187C/C homozygotes (n=71) (+6.1% vs. −12.5%; P=.02) and were less likely to develop lipoatrophy after adjustment for age, sex, race, and ART randomization (odds ratio, 0.31; 95% confidence interval, 0.10–0.95; P=.04). Among non-Hispanic white participants, median limb fat change was +26.1% among 5 participants with mitochondrial haplogroup J, compared with −9.7% among 49 participants with other mitochondrial haplogroups (P=.07) ConclusionsHFE 187C>G and, possibly, mitochondrial haplogroup J gave relative protection against lipoatrophy during ART in A5005s. These associations should be replicated in other studies}, number={6}, journal={The Journal of Infectious Diseases}, publisher={Oxford University Press (OUP)}, author={Hulgan, Todd and Tebas, Pablo and Canter, Jeffrey A. and Mulligan, Kathleen and Haas, David W. and Dubé, Michael and Grinspoon, Steven and Robbins, Gregory K. and Motsinger, Alison A. and Kallianpur, Asha R.}, year={2008}, month={Mar}, pages={858–866} }
 @article{velez_white_motsinger_bush_ritchie_williams_moore_2007, title={A balanced accuracy function for epistasis modeling in imbalanced datasets using multifactor dimensionality reduction}, volume={31}, ISSN={0741-0395 1098-2272}, url={http://dx.doi.org/10.1002/gepi.20211}, DOI={10.1002/gepi.20211}, abstractNote={Multifactor dimensionality reduction (MDR) was developed as a method for detecting statistical patterns of epistasis. The overall goal of MDR is to change the representation space of the data to make interactions easier to detect. It is well known that machine learning methods may not provide robust models when the class variable (e.g. case-control status) is imbalanced and accuracy is used as the fitness measure. This is because most methods learn patterns that are relevant for the larger of the two classes. The goal of this study was to evaluate three different strategies for improving the power of MDR to detect epistasis in imbalanced datasets. The methods evaluated were: (1) over-sampling that resamples with replacement the smaller class until the data are balanced, (2) under-sampling that randomly removes subjects from the larger class until the data are balanced, and (3) balanced accuracy [(sensitivity+specificity)/2] as the fitness function with and without an adjusted threshold. These three methods were compared using simulated data with two-locus epistatic interactions of varying heritability (0.01, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4) and minor allele frequency (0.2, 0.4) that were embedded in 100 replicate datasets of varying sample sizes (400, 800, 1600). Each dataset was generated with different ratios of cases to controls (1 : 1, 1 : 2, 1 : 4). We found that the balanced accuracy function with an adjusted threshold significantly outperformed both over-sampling and under-sampling and fully recovered the power. These results suggest that balanced accuracy should be used instead of accuracy for the MDR analysis of epistasis in imbalanced datasets.}, number={4}, journal={Genetic Epidemiology}, publisher={Wiley}, author={Velez, Digna R. and White, Bill C. and Motsinger, Alison A. and Bush, William S. and Ritchie, Marylyn D. and Williams, Scott M. and Moore, Jason H.}, year={2007}, month={May}, pages={306–315} }
 @article{motsinger_brassat_caillier_erlich_walker_steiner_barcellos_pericak-vance_schmidt_gregory_et al._2007, title={Complex gene–gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes}, volume={8}, ISSN={1364-6745 1364-6753}, url={http://dx.doi.org/10.1007/S10048-006-0058-9}, DOI={10.1007/S10048-006-0058-9}, number={1}, journal={Neurogenetics}, publisher={Springer Science and Business Media LLC}, author={Motsinger, Alison A. and Brassat, David and Caillier, Stacy J. and Erlich, Henry A. and Walker, Karen and Steiner, Lori L. and Barcellos, Lisa F. and Pericak-Vance, Margaret A. and Schmidt, Silke and Gregory, Simon and et al.}, year={2007}, pages={11–20} }
 @article{ritchie_edwards_fanelli_motsinger_2007, title={Genetic heterogeneity is not as threatening as you might think}, volume={31}, ISSN={0741-0395 1098-2272}, url={http://dx.doi.org/10.1002/gepi.20256}, DOI={10.1002/gepi.20256}, abstractNote={Genetic EpidemiologyVolume 31, Issue 7 p. 797-800 Letter to the Editor Genetic heterogeneity is not as threatening as you might think Marylyn D. Ritchie, Corresponding Author Marylyn D. Ritchie ritchie@chgr.mc.vanderbilt.edu Vanderbilt University, Center for Human Genetics Research, Nashville, TennesseeCenter for Human Genetics Research, Department of Molecular Physiology and Biophysics, 519 Light Hall, Vanderbilt University Medical School, Nashville, TN, 37232-0700===Search for more papers by this authorTodd L. Edwards, Todd L. Edwards Vanderbilt University, Center for Human Genetics Research, Nashville, TennesseeSearch for more papers by this authorTheresa J. Fanelli, Theresa J. Fanelli Vanderbilt University, Center for Human Genetics Research, Nashville, TennesseeSearch for more papers by this authorAlison A. Motsinger, Alison A. Motsinger Vanderbilt University, Center for Human Genetics Research, Nashville, TennesseeSearch for more papers by this author Marylyn D. Ritchie, Corresponding Author Marylyn D. Ritchie ritchie@chgr.mc.vanderbilt.edu Vanderbilt University, Center for Human Genetics Research, Nashville, TennesseeCenter for Human Genetics Research, Department of Molecular Physiology and Biophysics, 519 Light Hall, Vanderbilt University Medical School, Nashville, TN, 37232-0700===Search for more papers by this authorTodd L. Edwards, Todd L. Edwards Vanderbilt University, Center for Human Genetics Research, Nashville, TennesseeSearch for more papers by this authorTheresa J. Fanelli, Theresa J. Fanelli Vanderbilt University, Center for Human Genetics Research, Nashville, TennesseeSearch for more papers by this authorAlison A. Motsinger, Alison A. Motsinger Vanderbilt University, Center for Human Genetics Research, Nashville, TennesseeSearch for more papers by this author First published: 24 July 2007 https://doi.org/10.1002/gepi.20256Citations: 13AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume31, Issue7November 2007Pages 797-800 RelatedInformation}, number={7}, journal={Genetic Epidemiology}, publisher={Wiley}, author={Ritchie, Marylyn D. and Edwards, Todd L. and Fanelli, Theresa J. and Motsinger, Alison A.}, year={2007}, pages={797–800} }
 @article{ritchie_motsinger_bush_coffey_moore_2007, title={Genetic programming neural networks: A powerful bioinformatics tool for human genetics}, volume={7}, ISSN={1568-4946}, url={http://dx.doi.org/10.1016/j.asoc.2006.01.013}, DOI={10.1016/j.asoc.2006.01.013}, abstractNote={The identification of genes that influence the risk of common, complex disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. This challenge is partly due to the limitations of parametric statistical methods for detecting genetic effects that are dependent solely or partially on interactions. We have previously introduced a genetic programming neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of genetic and gene–environment combinations associated with disease risk. Previous empirical studies suggest GPNN has excellent power for identifying gene–gene and gene–environment interactions. The goal of this study was to compare the power of GPNN to stepwise logistic regression (SLR) and classification and regression trees (CART) for identifying gene–gene and gene–environment interactions. SLR and CART are standard methods of analysis for genetic association studies. Using simulated data, we show that GPNN has higher power to identify gene–gene and gene–environment interactions than SLR and CART. These results indicate that GPNN may be a useful pattern recognition approach for detecting gene–gene and gene–environment interactions in studies of human disease.}, number={1}, journal={Applied Soft Computing}, publisher={Elsevier BV}, author={Ritchie, Marylyn D. and Motsinger, Alison A. and Bush, William S. and Coffey, Christopher S. and Moore, Jason H.}, year={2007}, month={Jan}, pages={471–479} }
 @article{canter_summar_smith_rice_hall_ritchie_motsinger_christian_drinkwater_scholl_et al._2007, title={Genetic variation in the mitochondrial enzyme carbamyl-phosphate synthetase I predisposes children to increased pulmonary artery pressure following surgical repair of congenital heart defects: A validated genetic association study}, volume={7}, ISSN={1567-7249}, url={http://dx.doi.org/10.1016/j.mito.2006.11.001}, DOI={10.1016/j.mito.2006.11.001}, abstractNote={Increased pulmonary artery pressure (PAP) can complicate the postoperative care of children undergoing surgical repair of congenital heart defects. Endogenous NO regulates PAP and is derived from arginine supplied by the urea cycle. The rate-limiting step in the urea cycle is catalyzed by a mitochondrial enzyme, carbamoyl-phosphate synthetase I (CPSI). A well-characterized polymorphism in the gene encoding CPSI (T1405N) has previously been implicated in neonatal pulmonary hypertension. A consecutive modeling cohort of children (N = 131) with congenital heart defects requiring surgery was prospectively evaluated to determine key factors associated with increased postoperative PAP, defined as a mean PAP > 20 mmHg for at least 1 h during the 48 h following surgery measured by an indwelling pulmonary artery catheter. Multiple dimensionality reduction (MDR) was used to both internally validate observations and develop optimal two-variable through five-variable models that were tested prospectively in a validation cohort (N = 41). Unconditional logistic regression analysis of the modeling cohort revealed that age (OR = 0.92, p = 0.01), CPSI T1405N genotype (AC vs. AA: OR = 4.08, p = 0.04, CC vs. AA: OR = 5.96, p = 0.01), and Down syndrome (OR = 5.25, p = 0.04) were independent predictors of this complex phenotype. MDR predicted that the best two-variable model consisted of age and CPSI T1405N genotype (p < 0.001). This two-variable model correctly predicted 73% of the outcomes from the validation cohort. A five-variable model that added race, gender and Down’s syndrome was not significantly better than the two-variable model. In conclusion, the CPSI T1405N genotype appears to be an important new factor in predicting susceptibility to increased PAP following surgical repair of congenital cardiac defects in children.}, number={3}, journal={Mitochondrion}, publisher={Elsevier BV}, author={Canter, Jeffrey A. and Summar, Marshall L. and Smith, Heidi B. and Rice, Geraldine D. and Hall, Lynn D. and Ritchie, Marylyn D. and Motsinger, Alison A. and Christian, Karla G. and Drinkwater, Davis C., Jr. and Scholl, Frank G. and et al.}, year={2007}, month={May}, pages={204–210} }
 @article{motsinger_haas_hulgan_ritchie_2007, title={Human Genomic Association Studies: A Primer for the Infectious Diseases Specialist}, volume={195}, ISSN={0022-1899 1537-6613}, url={http://dx.doi.org/10.1086/518247}, DOI={10.1086/518247}, abstractNote={Medical science is undergoing a genomic revolution. In coming years, insights from human genomic research will increasingly influence all aspects of infectious diseases, ranging from fundamental laboratory research and clinical care to epidemiology and global health. Infectious disease specialists unfamiliar with genomic methods and computational techniques may shy away from publications that involve human genomics analyses. In this article, we discuss selected aspects of study design and statistical analysis in this area, emphasizing important pitfalls that may compromise the validity of some studies. Our goal is to provide the infectious diseases specialist with information that will aid in the critical evaluation of publications that include human genomic analyses.}, number={12}, journal={The Journal of Infectious Diseases}, publisher={Oxford University Press (OUP)}, author={Motsinger, Alison A. and Haas, David W. and Hulgan, Todd and Ritchie, Marylyn D.}, year={2007}, month={Jun}, pages={1737–1744} }
 @article{darbar_motsinger_ritchie_gainer_roden_2007, title={Polymorphism modulates symptomatic response to antiarrhythmic drug therapy in patients with lone atrial fibrillation}, volume={4}, ISSN={1547-5271}, url={http://dx.doi.org/10.1016/j.hrthm.2007.02.006}, DOI={10.1016/j.hrthm.2007.02.006}, abstractNote={Background The angiotensin-converting enzyme (ACE) deletion allele, ACE D, is associated with increased ACE activity and adverse outcomes in cardiovascular disease. Although activation of the renin-angiotensin-aldosterone system (RAAS) now appears to play a role in the pathophysiology of atrial fibrillation (AF), it remains to be determined if ACE genotype impacts response to conventional AAD therapy in patients with AF. Objectives The purpose of this study was to investigate whether response to antiarrhythmic drug (AAD) therapy in patients with AF is modulated by the ACE I/D polymorphism. Methods We studied 213 patients (147 men, 66 women; ages 52 ± 15 years) prospectively enrolled in the Vanderbilt AF Registry. AAD therapy outcome was defined prospectively as response if there was a ≥75% reduction in symptomatic AF burden or nonresponse if AF burden was unchanged, necessitating a change in drugs or therapy. Results Lone AF (age <65 years, no identifiable cause) was present in 72 (34%) patients, whereas hypertension was the most common underlying disease in the remaining 141 (41%). AF was paroxysmal in 170 (80%) and persistent in 43 (20%). The frequencies of the DD, ID, and II genotypes were in Hardy-Weinberg equilibrium. Lone AF and DD/ID genotypes were highly significant predictors of failure of drug therapy (P <.005). In patients with lone AF, failure of drug response was 5%, 41%, and 47% in patients with II, ID, and DD genotypes, respectively, (P <.005, II vs. ID/DD). Conclusions These results provide further evidence for a role of RAAS activation in the pathophysiology of AF and point to a potential role for stratification of therapeutic approaches by ACE genotype. The angiotensin-converting enzyme (ACE) deletion allele, ACE D, is associated with increased ACE activity and adverse outcomes in cardiovascular disease. Although activation of the renin-angiotensin-aldosterone system (RAAS) now appears to play a role in the pathophysiology of atrial fibrillation (AF), it remains to be determined if ACE genotype impacts response to conventional AAD therapy in patients with AF. The purpose of this study was to investigate whether response to antiarrhythmic drug (AAD) therapy in patients with AF is modulated by the ACE I/D polymorphism. We studied 213 patients (147 men, 66 women; ages 52 ± 15 years) prospectively enrolled in the Vanderbilt AF Registry. AAD therapy outcome was defined prospectively as response if there was a ≥75% reduction in symptomatic AF burden or nonresponse if AF burden was unchanged, necessitating a change in drugs or therapy. Lone AF (age <65 years, no identifiable cause) was present in 72 (34%) patients, whereas hypertension was the most common underlying disease in the remaining 141 (41%). AF was paroxysmal in 170 (80%) and persistent in 43 (20%). The frequencies of the DD, ID, and II genotypes were in Hardy-Weinberg equilibrium. Lone AF and DD/ID genotypes were highly significant predictors of failure of drug therapy (P <.005). In patients with lone AF, failure of drug response was 5%, 41%, and 47% in patients with II, ID, and DD genotypes, respectively, (P <.005, II vs. ID/DD). These results provide further evidence for a role of RAAS activation in the pathophysiology of AF and point to a potential role for stratification of therapeutic approaches by ACE genotype.}, number={6}, journal={Heart Rhythm}, publisher={Elsevier BV}, author={Darbar, Dawood and Motsinger, Alison A. and Ritchie, Marylyn D. and Gainer, James V. and Roden, Dan M.}, year={2007}, month={Jun}, pages={743–749} }
 @inbook{motsinger_dudek_hahn_ritchie_2006, place={Berlin Heidelberg}, series={Lecture Notes in Computer Science}, title={Comparison of Neural Network Optimization Approaches for Studies of Human Genetics}, ISBN={9783540332374 9783540332381}, ISSN={0302-9743 1611-3349}, url={http://dx.doi.org/10.1007/11732242_10}, DOI={10.1007/11732242_10}, abstractNote={A major goal of human genetics is the identification of susceptibility genes associated with common, complex diseases. The preponderance of gene-gene and gene-environment interactions comprising the genetic architecture of common diseases presents a difficult challenge. To address this, novel computational approaches have been applied to studies of human disease. These novel approaches seek to capture the complexity inherent in common diseases. Previously, we developed a genetic programming neural network (GPNN) to optimize network architecture for the detection of disease susceptibility genes in association studies. While GPNN was a successful endeavor, we wanted to address the limitations in its flexibility and ease of development. To this end, we developed a grammatical evolution neural network (GENN) approach that accounts for the drawbacks of GPNN. In this study we show that this new method has high power to detect gene-gene interactions in simulated data. We also compare the performance of GENN to GPNN, a traditional back-propagation neural network (BPNN) and a random search algorithm. GENN outperforms both BPNN and the random search, and performs at least as well as GPNN. This study demonstrates the utility of using GE to evolve NN in studies of complex human disease.}, booktitle={Applications of Evolutionary Computing. EvoWorkshops 2006}, publisher={Springer}, author={Motsinger, Alison A. and Dudek, Scott M. and Hahn, Lance W. and Ritchie, Marylyn D.}, editor={Rothlauf, F.Editor}, year={2006}, pages={103–114}, collection={Lecture Notes in Computer Science} }
 @article{ritchie_haas_motsinger_donahue_erdem_raffanti_rebeiro_george_kim_haines_et al._2006, title={Drug Transporter and Metabolizing Enzyme Gene Variants and Nonnucleoside Reverse-Transcriptase Inhibitor Hepatotoxicity}, volume={43}, ISSN={1058-4838 1537-6591}, url={http://dx.doi.org/10.1086/507101}, DOI={10.1086/507101}, abstractNote={This nested case-control study examined relationships between MDR1, CYP2B6, and CYP3A4 variants and hepatotoxicity during antiretroviral therapy with either efavirenz- or nevirapine-containing regimens. Decreased risk of hepatotoxicity was associated with MDR1 3435C→;T (odds ratio, 0.254; P = .021). An interaction between MDR1 and hepatitis B surface antigen status predicted risk with 82% accuracy (P < .001).}, number={6}, journal={Clinical Infectious Diseases}, publisher={Oxford University Press (OUP)}, author={Ritchie, M. D. and Haas, D. W. and Motsinger, A. A. and Donahue, J. P. and Erdem, H. and Raffanti, S. and Rebeiro, P. and George, A. L. and Kim, R. B. and Haines, J. L. and et al.}, year={2006}, month={Sep}, pages={779–782} }
 @article{haas_geraghty_andersen_mar_motsinger_d’aquila_unutmaz_benson_ritchie_landay_2006, title={Immunogenetics of CD4 Lymphocyte Count Recovery during Antiretroviral Therapy: An AIDS Clinical Trials Group Study}, volume={194}, ISSN={0022-1899 1537-6613}, url={http://dx.doi.org/10.1086/507313}, DOI={10.1086/507313}, abstractNote={During antiretroviral therapy, CD4 lymphocyte count increases are modest in some patients despite virologic control. We explored whether polymorphisms in genes important for T cell expansion, survival, and apoptosis are associated with the magnitude of CD4 lymphocyte count recovery during antiretroviral therapy. We studied treatment-naive individuals who achieved sustained control of plasma viremia (<400 HIV-1 RNA copies/mL) for at least 48 weeks after initiation of antiretroviral therapy and compared genotypes among individuals who had an increase of either <200 or ⩾200 CD4 cells/mm3 from baseline. A total of 137 single-nucleotide polymorphisms across 17 genes were characterized in 873 study participants. In multivariate analyses that controlled for clinical variables, polymorphisms in genes encoding tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL), TNF-α, Bcl-2–interacting molecule (Bim), interleukin (IL)–15, and IL-15 receptor α chain (IL-15Rα) were associated with the magnitude of the increase in CD4 lymphocyte count, as were haplotypes in genes encoding interferon-α, IL-2, and IL-15Rα (P<.05, for each). Multifactor dimensionality reduction identified a gene-gene interaction between IL-2/IL-15 receptor common β chain and IL-2/IL-7/IL-15 receptor common γ chain. Immune recovery during antiretroviral therapy is a complex phenotype that is influenced by multiple genetic variants. Future studies should validate these tentative associations and define underlying mechanisms}, number={8}, journal={The Journal of Infectious Diseases}, publisher={Oxford University Press (OUP)}, author={Haas, David W. and Geraghty, Daniel E. and Andersen, Janet and Mar, Jessica and Motsinger, Alison A. and D’Aquila, Richard T. and Unutmaz, Derya and Benson, Constance A. and Ritchie, Marylyn D. and Landay, Alan}, year={2006}, month={Oct}, pages={1098–1107} }
 @article{brassat_motsinger_caillier_erlich_walker_steiner_cree_barcellos_pericak-vance_schmidt_et al._2006, title={Multifactor dimensionality reduction reveals gene–gene interactions associated with multiple sclerosis susceptibility in African Americans}, volume={7}, ISSN={1466-4879 1476-5470}, url={http://dx.doi.org/10.1038/sj.gene.6364299}, DOI={10.1038/sj.gene.6364299}, abstractNote={Multiple sclerosis (MS) is a common disease of the central nervous system characterized by inflammation, myelin loss, gliosis, varying degrees of axonal pathology, and progressive neurological dysfunction. Multiple sclerosis exhibits many of the characteristics that distinguish complex genetic disorders including polygenic inheritance and environmental exposure risks. Here, we used a highly efficient multilocus genotyping assay representing variation in 34 genes associated with inflammatory pathways to explore gene-gene interactions and disease susceptibility in a well-characterized African-American case-control MS data set. We applied the multifactor dimensionality reduction (MDR) test to detect epistasis, and identified single-IL4R(Q576R)- and three-IL4R(Q576R), IL5RA(-80), CD14(-260)- locus association models that predict MS risk with 75-76% accuracy (P<0.01). These results demonstrate the importance of exploring both main effects and gene-gene interactions in the study of complex diseases.}, number={4}, journal={Genes & Immunity}, publisher={Springer Science and Business Media LLC}, author={Brassat, D and Motsinger, A A and Caillier, S J and Erlich, H A and Walker, K and Steiner, L L and Cree, B A C and Barcellos, L F and Pericak-Vance, M A and Schmidt, S and et al.}, year={2006}, month={Apr}, pages={310–315} }
 @article{motsinger_ritchie_2006, title={The effect of reduction in cross-validation intervals on the performance of multifactor dimensionality reduction}, volume={30}, ISSN={0741-0395 1098-2272}, url={http://dx.doi.org/10.1002/gepi.20166}, DOI={10.1002/gepi.20166}, abstractNote={Multifactor Dimensionality Reduction (MDR) was developed to detect genetic polymorphisms that present an increased risk of disease. Cross-validation (CV) is an important part of the MDR algorithm, as it prevents over-fitting and allows the predictive ability of a model to be evaluated. CV is a computationally intensive step in the MDR algorithm. Traditionally, MDR has been implemented using 10-fold CV. In order to reduce computation time and therefore allow MDR analysis to be applied to larger datasets, we evaluated the possibility of eliminating or reducing the number of CV intervals used for analysis. We found that eliminating CV made final model selection impossible, but that reducing the number of CV intervals from ten to five caused no loss of power, thereby reducing the computation time of the algorithm by half. The validity of this reduction was confirmed with data from an Alzheimer's disease (AD) study. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc.}, number={6}, journal={Genetic Epidemiology}, publisher={Wiley}, author={Motsinger, Alison A. and Ritchie, Marylyn D.}, year={2006}, pages={546–555} }
 @inbook{bush_motsinger_dudek_ritchie_2005, place={Berlin Heidelberg}, series={Lecture Notes in Computer Science}, title={Can Neural Network Constraints in GP Provide Power to Detect Genes Associated with Human Disease?}, ISBN={9783540253969 9783540320036}, ISSN={0302-9743 1611-3349}, url={http://dx.doi.org/10.1007/978-3-540-32003-6_5}, DOI={10.1007/978-3-540-32003-6_5}, abstractNote={A major goal of human genetics is the identification of susceptibility genes associated with common, complex diseases. Identifying gene-gene and gene-environment interactions which comprise the genetic architecture for a majority of common diseases is a difficult challenge. To this end, novel computational approaches have been applied to studies of human disease. Previously, a GP neural network (GPNN) approach was employed. Although the GPNN method has been quite successful, a clear comparison of GPNN and GP alone to detect genetic effects has not been made. In this paper, we demonstrate that using NN evolved by GP can be more powerful than GP alone. This is most likely due to the confined search space of the GPNN approach, in comparison to a free form GP. This study demonstrates the utility of using GP to evolve NN in studies of the genetics of common, complex human disease.}, booktitle={Applications of Evolutionary Computing. EvoWorkshops 2005}, publisher={Springer}, author={Bush, William S. and Motsinger, Alison A. and Dudek, Scott M. and Ritchie, Marylyn D.}, editor={Rothlauf, F.Editor}, year={2005}, pages={44–53}, collection={Lecture Notes in Computer Science} }