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Phenotype validation in electronic health records based genetic association studies.

ABSTRACT: The linkage between electronic health records (EHRs) and genotype data makes it plausible to study the genetic susceptibility of a wide range of disease phenotypes. Despite that EHR-derived phenotype data are subjected to misclassification, it has been shown useful for discovering susceptible genes, particularly in the setting of phenome-wide association studies (PheWAS). It is essential to characterize discovered associations using gold standard phenotype data by chart review. In this work, we propose a genotype stratified case-control sampling strategy to select subjects for phenotype validation. We develop a closed-form maximum-likelihood estimator for the odds ratio parameters and a score statistic for testing genetic association using the combined validated and error-prone EHR-derived phenotype data, and assess the extent of power improvement provided by this approach. Compared with case-control sampling based only on EHR-derived phenotype data, our genotype stratified strategy maintains nominal type I error rates, and result in higher power for detecting associations. It also corrects the bias in the odds ratio parameter estimates, and reduces the corresponding variance especially when the minor allele frequency is small.

SUBMITTER: Wang L

PROVIDER: S-EPMC5891135 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Phenotype validation in electronic health records based genetic association studies.

Wang Lu L Damrauer Scott M SM Zhang Hong H Zhang Alan X AX Xiao Rui R Moore Jason H JH Chen Jinbo J

Genetic epidemiology 20171011 8

The linkage between electronic health records (EHRs) and genotype data makes it plausible to study the genetic susceptibility of a wide range of disease phenotypes. Despite that EHR-derived phenotype data are subjected to misclassification, it has been shown useful for discovering susceptible genes, particularly in the setting of phenome-wide association studies (PheWAS). It is essential to characterize discovered associations using gold standard phenotype data by chart review. In this work, we ...[more]

PMID: 29023970

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Project description:Bipolar disorder (BD) is a heritable mood disorder characterized by episodes of mania and depression. Although genomewide association studies (GWAS) have successfully identified genetic loci contributing to BD risk, sample size has become a rate-limiting obstacle to genetic discovery. Electronic health records (EHRs) represent a vast but relatively untapped resource for high-throughput phenotyping. As part of the International Cohort Collection for Bipolar Disorder (ICCBD), we previously validated automated EHR-based phenotyping algorithms for BD against in-person diagnostic interviews (Castro et al. Am J Psychiatry 172:363-372, 2015). Here, we establish the genetic validity of these phenotypes by determining their genetic correlation with traditionally ascertained samples. Case and control algorithms were derived from structured and narrative text in the Partners Healthcare system comprising more than 4.6 million patients over 20 years. Genomewide genotype data for 3330 BD cases and 3952 controls of European ancestry were used to estimate SNP-based heritability (h2g) and genetic correlation (rg) between EHR-based phenotype definitions and traditionally ascertained BD cases in GWAS by the ICCBD and Psychiatric Genomics Consortium (PGC) using LD score regression. We evaluated BD cases identified using 4 EHR-based algorithms: an NLP-based algorithm (95-NLP) and three rule-based algorithms using codified EHR with decreasing levels of stringency-"coded-strict", "coded-broad", and "coded-broad based on a single clinical encounter" (coded-broad-SV). The analytic sample comprised 862 95-NLP, 1968 coded-strict, 2581 coded-broad, 408 coded-broad-SV BD cases, and 3 952 controls. The estimated h2g were 0.24 (p?=?0.015), 0.09 (p?=?0.064), 0.13 (p?=?0.003), 0.00 (p?=?0.591) for 95-NLP, coded-strict, coded-broad and coded-broad-SV BD, respectively. The h2g for all EHR-based cases combined except coded-broad-SV (excluded due to 0 h2g) was 0.12 (p?=?0.004). These h2g were lower or similar to the h2g observed by the ICCBD?+?PGCBD (0.23, p?=?3.17E-80, total N?=?33,181). However, the rg between ICCBD?+?PGCBD and the EHR-based cases were high for 95-NLP (0.66, p?=?3.69?×?10-5), coded-strict (1.00, p?=?2.40?×?10-4), and coded-broad (0.74, p?=?8.11?×?10-7). The rg between EHR-based BD definitions ranged from 0.90 to 0.98. These results provide the first genetic validation of automated EHR-based phenotyping for BD and suggest that this approach identifies cases that are highly genetically correlated with those ascertained through conventional methods. High throughput phenotyping using the large data resources available in EHRs represents a viable method for accelerating psychiatric genetic research.

Project description:BackgroundElectronic health record (EHR) systems are widely used in the United States to document care delivery and outcomes. Health information exchange (HIE) networks, which integrate EHR data from the various health care providers treating patients, are increasingly used to analyze population-level data. Existing methods for population health surveillance of essential hypertension by public health authorities may be complemented using EHR data from HIE networks to characterize disease burden at the community level.ObjectiveWe aimed to derive and validate computable phenotypes (CPs) to estimate hypertension prevalence for population-based surveillance using an HIE network.MethodsUsing existing data available from an HIE network, we developed 6 candidate CPs for essential (primary) hypertension in an adult population from a medium-sized Midwestern metropolitan area in the United States. A total of 2 independent clinician reviewers validated the phenotypes through a manual chart review of 150 randomly selected patient records. We assessed the precision of CPs by calculating sensitivity, specificity, positive predictive value (PPV), F1-score, and validity of chart reviews using prevalence-adjusted bias-adjusted κ. We further used the most balanced CP to estimate the prevalence of hypertension in the population.ResultsAmong a cohort of 548,232 adults, 6 CPs produced PPVs ranging from 71% (95% CI 64.3%-76.9%) to 95.7% (95% CI 84.9%-98.9%). The F1-score ranged from 0.40 to 0.91. The prevalence-adjusted bias-adjusted κ revealed a high percentage agreement of 0.88 for hypertension. Similarly, interrater agreement for individual phenotype determination demonstrated substantial agreement (range 0.70-0.88) for all 6 phenotypes examined. A phenotype based solely on diagnostic codes possessed reasonable performance (F1-score=0.63; PPV=95.1%) but was imbalanced with low sensitivity (47.6%). The most balanced phenotype (F1-score=0.91; PPV=83.5%) included diagnosis, blood pressure measurements, and medications and identified 210,764 (38.4%) individuals with hypertension during the study period (2014-2015).ConclusionsWe identified several high-performing phenotypes to identify essential hypertension prevalence for local public health surveillance using EHR data. Given the increasing availability of EHR systems in the United States and other nations, leveraging EHR data has the potential to enhance surveillance of chronic disease in health systems and communities. Yet given variability in performance, public health authorities will need to decide whether to seek optimal balance or declare a preference for algorithms that lean toward sensitivity or specificity to estimate population prevalence of disease.

Project description:BackgroundElectronic health records (EHRs) provide rich data on many domains not routinely available in other data, as such, they are a promising source to study changes in health outcomes using longitudinal study designs (eg, cohort studies, natural experiments, etc.). Yet, patient attrition rates in these data are unknown.ObjectiveThe objective of this study was to estimate overall and among adults with diabetes or hypertension: (1) patient attrition over a 3-year period at community health centers; and (2) the likelihood that patients with Medicaid permanently switched their source of primary care.Research designA retrospective cohort study of 2012-2017 data from the Accelerating Data Value Across a National Community Health Center Network (ADVANCE) Clinical Data Research Network of community health centers were used to assess EHR data attrition. Oregon Medicaid enrollment and claims data were used to estimate the likelihood of changing the source of primary care.SubjectsA total of 827,657 patients aged 19-64 with ≥1 ambulatory visit from 76 community health center systems across 20 states. In all, 232,891 Oregon Medicaid enrollees (aged 19-64) with a gap of ≥6 months following a claim for a visit billed to a primary care source.MeasuresPercentage of patients not returning within 3 years of their qualifying visit (attrition). The probability that a patient with Medicaid permanently changed their primary care source.ResultsAttrition over the 3 years averaged 33.5%; attrition rates were lower (<25%) among patients with diabetes and/or hypertension. Among Medicaid enrollees, the percentage of provider change after a 6-month gap between visits was 12% for community health center patients compared with 39% for single-provider practice patients. Over 3 years, the likelihood of a patient changing to a new provider increased with length of time since their last visit but remained lowest among community health center patients.ConclusionThis study demonstrates the use of the EHR dataset is a reliable source of data to support longitudinal studies while highlighting variability in attrition by primary care source and chronic conditions.

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Phenotype validation in electronic health records based genetic association studies.

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Phenotype validation in electronic health records based genetic association studies.

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