Browsing by Subject "Adverse Drug Reaction Reporting Systems"

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    Random control selection for conducting high-throughput adverse drug events screening using large-scale longitudinal health data
    (Wiley, 2021-09) Chiang, Chien-Wei; Zhang, Penyue; Donneyong, Macarius; Chen, You; Su, Yu; Li, Lang; Biostatistics, School of Public Health
    Case-control design based high-throughput pharmacoinformatics study using large-scale longitudinal health data is able to detect new adverse drug event (ADEs) signals. Existing control selection approaches for case-control design included the dynamic/super control selection approach. The dynamic/super control selection approach requires all individuals to be evaluated at all ADE case index dates, as the individuals' eligibilities as control depend on ADE/enrollment history. Thus, using large-scale longitudinal health data, the dynamic/super control selection approach requires extraordinarily high computational time. We proposed a random control selection approach in which ADE case index dates were matched by randomly generated control index dates. The random control selection approach does not depend on ADE/enrollment history. It is able to significantly reduce computational time to prepare case-control data sets, as it requires all individuals to be evaluated only once. We compared the performance metrics of all control selection approaches using two large-scale longitudinal health data and a drug-ADE gold standard including 399 drug-ADE pairs. The F-scores for the random control selection approach were between 0.586 and 0.600 compared to between 0.545 and 0.562 for dynamic/super control selection approaches. The random control selection approach was ~ 1000 times faster than dynamic/super control selection approach on preparing case-control data sets. With large-scale longitudinal health data, a case-control design-based pharmacoinformatics study using random control selection is able to generate comparable ADE signals than the existing control selection approaches. The random control selection approach also significantly reduces computational time to prepare the case-control data sets.
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    Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity
    (Elsevier, 2015-09) Hayashi, Paul H.; Fontana, Robert J.; Chalasani, Naga; Stolz, Andrew A.; Talwalker, Jay A.; Navarro, Victor J.; Lee, William M.; Davern, Timothy J.; Kleiner, David E.; Gu, Jiezhun; Hoofnagle, Jay H.; Department of Medicine, IU School of Medicine
    IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.