Characterizing the Clinical and Genetic Spectrum of Polycystic Ovary Syndrome in Electronic Health Records

Abstract

Context Polycystic ovary syndrome (PCOS) is one of the leading causes of infertility, yet current diagnostic criteria are ineffective at identifying patients whose symptoms reside outside strict diagnostic criteria. As a result, PCOS is under diagnosed and its etiology is poorly understood. Objective We aim to characterize the phenotypic spectrum of PCOS clinical features within and across racial and ethnic groups. Methods We developed a strictly defined PCOS algorithm (PCOSkeyword-strict) using International Classification of Diseases, 9 th and 10 th edition (ICD9/10) and keywords mined from clinical notes in electronic health records (EHRs) data. We then systematically relaxed the inclusion criteria to evaluate the change in epidemiological and genetic associations resulting in three subsequent algorithms (PCOScoded-broad, PCOScoded-strict,PCOSkeyword-broad). We evaluated the performance of each phenotyping approach and characterized prominent clinical features observed in racially and ethnically diverse PCOS patients. Results The best performance came from the PCOScoded-strict algorithm with a positive predictive value (PPV) of 98%. Individuals classified as cases by this algorithm had significantly higher body mass index (BMI), insulin levels, free testosterone values, and genetic risk scores for PCOS, compared to controls. Median BMI was higher in African American females with PCOS compared to White and Hispanic females with PCOS. Conclusions PCOS symptoms are observed across a severity spectrum that parallels the continuous genetic liability to PCOS in the general population. Racial and ethnic group differences exist in PCOS symptomology and metabolic health across different phenotyping strategies.

Sex Modifies the Effect of Genetic Risk Scores for Polycystic Ovary Syndrome on Metabolic Phenotypes

“…PCOS PRS were calculated with PRS-CS software using the weighted sums of the risk allele effects as reported in the summary statistics from the Day et al GWAS of PCOS and applying a Bayesian continuous shrinkage parameter select SNP features and to model linkage disequilibrium [16,30]. The details of these methods have been previously described elsewhere [11]. We calculated PCOS PRS for both EUR and AFR BioVU genotyped ancestry samples which were previously shown to be associated with a PCOS diagnosis defined by a coded strict PCOS definition in our previously published EHR-based algorithm [11].…”

“…In brief, cases required PCOS billing codes and no exclusion codes. Controls excluded individuals who had any inclusion or exclusion codes [11]. All models were adjusted for median age of the individuals medical record, and the top ten PCs for each ancestry.…”

“…However, as previous studies have shown, the genetic risk factors present in patients with metabolic manifestations of PCOS could differ from others who have primary presentations of reproductive dysfunction [9,10]. PCOS is multifactorial and twin studies estimate heritability at 70% [11][12][13][14]. With an underlying polygenic architecture, multiple variants are hypothesized to be involved in the development of PCOS [15,16].…”

“…Despite the small effect size of individual common variants, aggregation of common risk variants together as a polygenic (or genetic) risk score (PRS) reflects the overall additive genetic liability to PCOS in individuals. This marker of disease risk is associated with PCOS diagnosis in multiple ancestries and offers many advantages to parsing out the genetic etiology of PCOS that is entangled with its comorbid presentations [11][12][13]. Furthermore, there is increasing evidence that a spectrum of clinical PCOS manifestations for PCOS is also correlated with the PRS for PCOS [11].…”

“…This marker of disease risk is associated with PCOS diagnosis in multiple ancestries and offers many advantages to parsing out the genetic etiology of PCOS that is entangled with its comorbid presentations [11][12][13]. Furthermore, there is increasing evidence that a spectrum of clinical PCOS manifestations for PCOS is also correlated with the PRS for PCOS [11].…”