Background:Weight change between pregnancies affects gestational diabetes mellitus (GDM) risk in subsequent pregnancies. However, it is unclear whether this impact differs based on the individual's GDM status in a prior pregnancy. Objectives:To evaluate whether prior GDM status modifies the association between interpregnancy-weight-change and GDM risk in a subsequent pregnancy. Study Design:Using Vanderbilt Health's de-identified electronic health record, we identified 4574 individuals with at least 2 recorded pregnancies, with information available on GDM status and body mass index (BMI) at GDM screening. We computed interpregnancy-weight-change as the change in BMI at GDM screening between 2 consecutive-reported pregnancies. Using multivariable linear probability and binomial regression models, we evaluated the association between interpregnancy-weight-change and GDM risk in the second pregnancy, overall, and stratified by GDM status in the first pregnancy. We tested for effect measure modification by calculating the interaction contrast (IC) across the risk differences (RDs). We reported predicted risks for GDM, RD, and Differences in RD in the subsequent pregnancy between patients with and without GDM in their first-recorded pregnancy. Results:On average, patients gained weight (BMI increased by 0.9 kg/m2) between pregnancies and were more likely to have GDM in their second-recorded pregnancy (6.0% vs 4.4%). Individuals with GDM in their first pregnancy were more likely to have GDM in the second pregnancy compared to individuals without GDM in the first pregnancy (30.2% vs 5.0%). The excess risk of GDM for individuals who gained 5 BMI kg/m2 (∼29 pounds [lbs] in patients with BMI of 27.1 kg/m2 and height of 5 feet 4 inches) was substantially higher in those with GDM in their first pregnancy (RD=28.0%; 95% CI=19.1%, 36.9%) compared to those without GDM in their first pregnancy (RD=5.6%; 95% CI=3.8%, 7.4%). The IC was 22.4% (95% CI=13.4%, 31.5%; P<.001) across the RDs,. Similarly, the impact of weight loss (2 BMI units ∼ 12 lbs) on GDM risk reduction in the subsequent pregnancy was greater in individuals with prior GDM in their first pregnancy (RD=-3.9%; 95% CI=-0.7%, -7.2%), than among individuals without prior GDM in their first pregnancy (RD=-1.0%; 95% CI=-0.1%, -1.9%), with some evidence for effect measure modification (IC=-2.9%; 95% CI=-6.3%, 0.5%; P=.091). However, the predicted risk of subsequent GDM in women with prior history of GDM remains high (17.9% risk with 12 lbs weight loss and 15.4% with 29 lbs weight loss) despite substantial risk reduction. Conclusion:Interpregnancy BMI increase is associated with an elevated risk of GDM in subsequent pregnancies for all individuals but is substantially pronounced in individuals with a history of GDM. Individuals with prior GDM may mitigate their risk through weight loss, but not sufficiently to reduce it to levels similar to those without GDM in their previous pregnancy. In counseling patients with a history of GDM considering a subsequent pregnancy, it is important to encourage weight loss for various reasons, while also emphasizing that the risk of GDM remains high even with weight loss.

Nephrotic syndrome is a rare, heterogeneous kidney disorder characterized by proteinuria, hypoalbuminemia, and edema. To elucidate its genetic architecture, we conducted a large-scale, electronic health record (EHR)-linked, multi-ancestry genome-wide association study comprising 5,214 cases and 1,601,060 controls. We identified 37 distinct loci associated with disease risk, including novel associations at JAML and STPG2, and confirmed prior signals at PLA2R1, HMCN1, and APOL1. Fine-mapping of the major histocompatibility complex (MHC) revealed the strongest association at DRB103:01:01G in individuals of European ancestry (OR = 2.01, P = 1.4×10⁻²⁰), alongside nominal ancestry-specific associations in African (DOA01:01:05) and Latino (DPB1*14:01:01G) populations. Transcriptome-wide association analysis (TWAS) identified 484 significant gene-tissue associations, including C4A in kidney cortex. Expression quantitative trait locus (eQTL) mapping revealed numerous cis-eQTLs in glomerular and tubular renal tissues, largely within the MHC region. We observed significant genetic correlation between adult and pediatric nephrotic syndrome (Rg = 0.63, P = 3.5x10-11), suggesting shared genetic etiology. Pathway analyses implicated estrogen receptor signaling and histone modification. Mendelian randomization implicated APOM expression and apomorphine exposure with increased disease risk (OR = 4.93, P = 1.8x10-19). These results expand the understanding of nephrotic syndrome pathogenesis and highlight ancestry-informed targets for therapeutic development.

BACKGROUND:The burden of comorbidities in those with uterine fibroids compared to those without fibroids is understudied. We performed a phenome-wide association study to systematically assess the association between fibroids and other conditions. METHODS:Vanderbilt University Medical Center's Synthetic Derivative and Geisinger Health System Database, two electronic health record databases, were used for discovery and validation. Non-Hispanic Black and White females were included. Fibroid cases were identified through a previously validated algorithm. Race-stratified and multi-population phenome-wide association analyses, adjusting for age and body mass index, were performed before statistically significant, validated results were meta-analyzed. RESULTS:There were 52,295 and 26,918 (9022 and 10,232 fibroid cases) females included in discovery and validation analyses. In multi-population meta-analysis, 389 conditions were associated with fibroid risk, with evidence of enrichment of circulatory, dermatologic, genitourinary, musculoskeletal, and sense organ conditions. The strongest associations within and across racial groups included conditions previously associated with fibroids. Numerous novel diagnoses, including cancers in female genital organs, were tied to fibroid status. CONCLUSIONS:Overall, individuals with fibroids have a marked increase in comorbidities compared to those without fibroids. This approach to evaluate the health context of fibroids highlights the potential to understand fibroid etiology through studying the common biology of comorbid diagnoses and through disease networks.

Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci.

Objective: To identify risk factors and generate hypotheses for pediatric persistent postconcussion symptoms (PPCS). Setting: A regional healthcare system in the Southeastern United States. Participants: An electronic health record-based algorithm was developed and validated to identify PPCS cases and controls from an institutional database of more than 2.8 million patients. PPCS cases (n = 274) were patients aged 5 to 18 years with PPCS-related diagnostic codes or with PPCS key words identified by natural language processing of clinical notes. Age, sex, and year of index event-matched controls (n = 1096) were patients with mild traumatic brain injury codes only. Patients with moderate or severe traumatic brain injury were excluded. All patients used our healthcare system at least 3 times 180 days before their injury. Design: Case-control study. Main Measures: The outcome was algorithmic classification of PPCS. Exposures were all preinjury medical diagnoses assigned at least 180 days before the injury. Results: Cases and controls both had a mean of more than 9 years of healthcare system use preinjury. Of 221 preinjury medical diagnoses, headache disorder was associated with PPCS after accounting for multiple testing (odds ratio [OR] = 2.9; 95% confidence interval [CI]: 1.6-5.0; P = 2.1e-4). Six diagnoses were associated with PPCS at a suggestive threshold for statistical significance (false discovery rate P < .10): gastritis/duodenitis (OR = 2.8; 95% CI: 1.6-5.1; P = 5.0e-4), sleep disorders (OR = 2.3; 95% CI: 1.4-3.7; P = 7.4e-4), abdominal pain (OR = 1.6; 95% CI: 1.2-2.2; P = 9.2e-4), chronic sinusitis (OR = 2.8; 95% CI: 1.5-5.2; P = 1.3e-3), congenital anomalies of the skin (OR = 2.9; 95% CI: 1.5-5.5; P = 1.9e-3), and chronic pharyngitis/nasopharyngitis (OR = 2.4; 95% CI: 1.4-4.3; P = 2.5e-3). Conclusions: These results support the strong association of preinjury headache disorders with PPCS. An association of PPCS with prior gastritis/duodenitis, sinusitis, and pharyngitis/nasopharyngitis suggests a role for chronic inflammation in PPCS pathophysiology and risk, although results could equally be attributable to a higher likelihood of somatization among PPCS cases. Identified risk factors should be investigated further and potentially considered during the management of pediatric mild traumatic brain injury cases.

Abstract African Americans (AAs) experience a high burden of hypertension but have been underrepresented in genetic studies of blood pressure. We performed common and rare variant genome-wide association studies (GWAS) of systolic (SBP) and diastolic (DBP) blood pressure, pulse pressure and hypertension in 95,457 AAs from the Million Veteran Program and Continental Origins and Genetic Epidemiology Network (COGENT) consortium with replication in up to 41,014 African-ancestry participants. GWAS meta-analysis confirmed 26 previously reported loci including 15 with SBP, four with DBP, 10 with pulse pressure and five with hypertension. Predicted gene expression analysis identified 25 genes newly associated with blood pressure. We provide validated African-ancestry polygenic scores for SBP and DBP that are strongly associated with hypertension. This work provides evidence for similar genetic architectures of hypertension and blood pressure across racial/ethnic groups and demonstrates the utility of predicted expression analysis in identifying novel genes beyond GWAS alone.

Background: Congenital heart defects (CHDs) affect 40 000 US births per year, half of which require surgical intervention. Individual differences in surgical outcomes including mortality and complications are not well understood but may be due to genetic variability. We hypothesized that polygenic risk scores (PRSs) for blood pressure in adults are associated with treatments and postsurgical outcomes in children with CHD, as CHD survivors are at higher risk of negative cardiometabolic disease. Methods: We used imputed genotype data from pediatric participants requiring surgery for CHD (median age at surgery, 201 days; n max =2498). Base data for the systolic and diastolic blood pressure PRSs (n max =760 226) came from published genome-wide association study. The blood pressure PRSs were tested for association with postsurgical outcomes. All effects presented are per SD increase in PRS and adjusted for age, sex, body mass index, surgical complexity score, and first 10 principal components of ancestry. Results: A higher diastolic blood pressure PRS was associated with decreased in-hospital mortality risk (odds ratio, 0.57 [0.39–0.82]; P =0.0022). Additional analyses suggest an interaction between diastolic blood pressure PRS and vasopressor dose. Those with a diastolic blood pressure PRS 1 SD above the mean, receiving a vasopressor dose in the top tertile, were estimated to have 52% (32%–66%) lower risk of in-hospital mortality compared with those with a vasopressor dose in the bottom tertile. Conclusions: These results suggest a genetically determined postsurgical survival advantage for CHD patients with blood pressure increasing alleles. Further study may reveal novel mechanisms contributing to postoperative morbidity and mortality, and this approach may assist in early identification of children at risk for adverse postoperative outcomes.

Uterine fibroids (UF) are common pelvic tumors in women, heritable, and genome-wide association studies (GWAS) have identified ~ 30 loci associated with increased risk in UF. Using summary statistics from a previously published UF GWAS performed in a non-Hispanic European Ancestry (NHW) female subset from the Electronic Medical Records and Genomics (eMERGE) Network, we constructed a polygenic risk score (PRS) for UF. UF-PRS was developed using PRSice and optimized in the separate clinical population of BioVU. PRS was validated using parallel methods of 10-fold cross-validation logistic regression and phenome-wide association study (PheWAS) in a seperate subset of eMERGE NHW females (validation set), excluding samples used in GWAS. PRSice determined pt < 0.001 and after linkage disequilibrium pruning (r2 < 0.2), 4458 variants were in the PRS which was significant (pseudo-R2 = 0.0018, p = 0.041). 10-fold cross-validation logistic regression modeling of validation set revealed the model had an area under the curve (AUC) value of 0.60 (95% confidence interval [CI] 0.58–0.62) when plotted in a receiver operator curve (ROC). PheWAS identified six phecodes associated with the PRS with the most significant phenotypes being 218 ‘benign neoplasm of uterus’ and 218.1 ‘uterine leiomyoma’ (p = 1.94 × 10–23, OR 1.31 [95% CI 1.26–1.37] and p = 3.50 × 10–23, OR 1.32 [95% CI 1.26–1.37]). We have developed and validated the first PRS for UF. We find our PRS has predictive ability for UF and captures genetic architecture of increased risk for UF that can be used in further studies.

OBJECTIVE:High maternal folic acid exposure has been studied as a risk factor for child asthma with inconclusive results. Folic acid supplementation that begins before pregnancy may propagate high exposures during pregnancy, particularly in regions with fortified food supplies. We investigated whether folic acid supplementation initiated periconceptionally is associated with childhood asthma in a US cohort. MATERIALS AND METHODS:We re-contacted mother-child dyads previously enrolled in a prospective pregnancy cohort and included children age 4 to 8 years at follow-up (n = 540). Using first trimester interviews, we assessed whether initial folic acid-containing supplement (FACS) use occurred near/before estimated conception ("periconceptional") or after (during the "first trimester"). Follow-up questionnaires were used to determine if a child ever had an asthma diagnosis ("ever asthma") or asthma diagnosis with prevalent symptoms or medication use ("current asthma"). We examined associations between FACS initiation and asthma outcomes using logistic regression, excluding preterm births and adjusting for child age, sex, maternal race, maternal education, and parental asthma. RESULTS:Approximately half of women initiated FACS use periconceptionally (49%). Nine percent of children had "ever asthma" and 6% had "current asthma." Periconceptional initiation was associated with elevated odds of ever asthma [adjusted odds ratio (95% Confidence Interval): 1.65 (0.87, 3.14)] and current asthma [1.87 (0.88, 4.01)], relative to first trimester initiation. CONCLUSION:We observed positive, but imprecisely estimated associations between periconceptional FACS initiation and child asthma. Folic acid prevents birth defects and is recommended. However, larger studies of folic acid dosing and timing, with consideration for childhood asthma, are needed.

Background Fibroids are present in approximately one in ten pregnancies and are inconsistently linked with preterm birth. We sought to determine the association between fibroids and preterm birth in a prospective cohort with standardized research ultrasounds for characterizing fibroids in early pregnancy while accounting for the clinical paths that precede preterm birth. Methods Participants who were pregnant or planning a pregnancy were recruited from communities in three states between 2000 and 2012. Members of this prospective cohort had a research ultrasound in the first trimester to establish pregnancy dating and to record detailed information about the presence, size, number, and location of fibroids. Baseline information from time of enrollment and a detailed first trimester interview contributed key information about candidate confounders. Birth outcomes, including clinical classification of type of preterm birth (preterm labor, preterm premature rupture of membranes, and medically indicated preterm birth) were cross-validated from participant report, labor and delivery records, and birth certificate data. Results Among 4,622 women with singleton pregnancies, 475 had at least one fibroid (10.3%) and 352 pregnancies resulted in preterm birth (7.6%). Prevalence of fibroids was similar for women with preterm and term births (10.2% vs. 10.3%). Fibroids were not associated with increased risk of preterm birth after taking into account confounding (risk ratio adjusted for race/ethnicity and maternal age, 0.88; 95% confidence interval, 0.62-1.24) nor any clinical subtype of preterm birth. No fibroid characteristic or combination of characteristics was associated with risk. Conclusions If fibroids increase risk of preterm birth, the effect is substantially smaller than previous estimates. Given lack of effect in a large population of women from the general population, rather than higher risk academic tertiary populations previously most studied, we encourage a reconsideration of the clinical impression that presence of fibroids is a major risk factor for preterm birth.

OBJECTIVES:Ethnic disparities in hypertension prevalence are well documented, though the influence of genetic ancestry is unclear. The aim of this study was to evaluate associations of geographic genetic ancestry with hypertension and underlying blood pressure traits. METHODS:We tested genetically inferred ancestry proportions from five 1000 Genomes reference populations (GBR, PEL, YRI, CHB, and LWK) for association with four continuous blood pressure (BP) traits (SBP, DBP, PP, MAP) and the dichotomous outcomes hypertension and apparent treatment-resistant hypertension in 220 495 European American, 59 927 African American, and 21 273 Hispanic American individuals from the Million Veteran Program. Ethnicity stratified results were meta-analyzed to report effect estimates per 10% difference for a given ancestry proportion in all samples. RESULTS:Percentage GBR was negatively associated with BP (P = 2.13 × 10-19, 7.92 × 10-8, 4.41 × 10-11, and 3.57 × 10-13 for SBP, DBP, PP, and MAP, respectively; coefficient range -0.10 to -0.21 mmHg per 10% increase in ancestry proportion) and was protective against hypertension [P = 2.59 × 10-5, odds ratio (OR) = 0.98] relative to other ancestries. YRI percentage was positively associated with BP (P = 1.63 × 10-23, 1.94 × 10-26, 0.012, and 3.26 × 10-29 for SBP, DBP, PP, and MAP, respectively; coefficient range 0.06-0.32 mmHg per 10% increase in ancestry proportion) and was positively associated with hypertension risk (P = 3.10 × 10-11, OR = 1.04) and apparent treatment-resistant hypertension risk (P = 1.86 × 10-4, OR = 1.04) compared with other ancestries. Percentage PEL was inversely associated with DBP (P = 2.84 × 10-5, beta = -0.11 mmHg per 10% increase in ancestry proportion). CONCLUSION:These results demonstrate that risk for BP traits varies significantly by genetic ancestry. Our findings provide insight into the geographic origin of genetic factors underlying hypertension risk and establish that a portion of BP trait ethnic disparities are because of genetic differences between ancestries.

PURPOSE:To determine if fibroids or their characteristics are associated with birthweight and/or gestational age, and to assess the impact of race or ethnicity. METHODS:Right from the Start (2000-2012) is a prospective cohort that enrolled women from the southern US in early pregnancy. Transvaginal ultrasounds were used to measure fibroid characteristics and confirm gestational age. Date of birth and birthweight were obtained from vital or medical records. We assessed whether fibroid presence, number, type, and volume were associated with birthweight and/or gestational age using multivariate analysis of covariance, accounting for a priori confounders. RESULTS:Among 3926 women, 416 had one or more fibroids. Mean infant birthweight and gestational age were similar among women with and without fibroids. When adjusting for race or ethnicity, all associations were attenuated. Overall, women with and without fibroids had infants of similar birthweight (-20 grams, 95% confidence interval [CI] -77, 36) and gestational age (0.4 days, 95% CI -0.9, 1.8). Women with three or more fibroids were more likely to have lighter infants (-201 grams, 95% CI -345, -58). CONCLUSIONS:Race or ethnicity substantially confounds the associations. The clinical belief that uterine fibroids impair fetal growth is supported only by a significant decrease in birthweight for women with multiple fibroids.

Objective To identify risk factors and generate hypotheses for pediatric post-concussion syndrome (PCS) using a phenome-wide association study (PheWAS). Methods A PheWAS (case-control) was conducted following the development and validation of a novel electronic health record-based algorithm that identified PCS cases and controls from an institutional database of >2.8 million patients. Cases were patients ages 5-18 with PCS codes or keywords identified by natural language processing of clinical notes. Controls were patients with mild traumatic brain injury (mTBI) codes only. Patients with moderate or severe brain injury were excluded. All patients used our healthcare system at least three times 180 days before their injury. Exposures included all pre-injury medical diagnoses assigned at least 180 days prior. Results The algorithm identified 274 pediatric PCS cases (156 females) and 1,096 controls that were age and sex matched to cases. Cases and controls both had a mean of >8 years of healthcare system use pre-injury. Of 202 pre-injury medical, four were associated with PCS after controlling for multiple testing: headache disorders (OR=5.3; 95%CI 2.8-10.1; P= 3.8e-7), sleep disorders (OR=3.1; 95%CI 1.8-5.2; P= 2.6e-5), gastritis/duodenitis (OR=3.6, 95%CI 1.8-7.0; P= 2.1e-4), and chronic pharyngitis (OR=3.3; 95%CI 1.8-6.3; P= 2.2e-4). Conclusions These results confirm the strong association of pre-injury headache disorders with PCS and provides evidence for the association of pre-injury sleep disorders with PCS. An association of PCS with prior chronic gastritis/duodenitis and pharyngitis was seen that suggests a role for chronic inflammation in PCS pathophysiology and risk. These factors should be considered during the management of pediatric mTBI cases.

Importance Functional seizures (formerly psychogenic nonepileptic seizures), paroxysmal episodes that are often similar to epileptic seizures in their clinical presentation and display no aberrant brain electrical patterns, are understudied. Patients experience a long diagnostic delay, few treatment modalities, a high rate of comorbidities, and significant stigma due to the lack of knowledge about functional seizures. Objective To characterize the clinical epidemiology of a population of patients with functional seizures observed at Vanderbilt University Medical Center (VUMC). Design, Setting, and Participants This case-control study included patients with functional seizures identified in the VUMC electronic health record (VUMC-EHR) system from October 1989 to October 2018. Patients with epilepsy were excluded from the study and all remaining patients in the VUMC medical center system were used as controls. In total, the study included 1431 patients diagnosed with functional seizures, 2251 with epilepsy and functional seizures, 4715 with epilepsy without functional seizures, and 502 200 control patients who received treatment at VUMC for a minimum of a 3 years. Data were analyzed from November 2018 to March 2020. Exposure Diagnosis of functional seizures, as identified from the VUMC-EHR system by an automated phenotyping algorithm that incorporated International Classification of Diseases, Ninth Revision (ICD-9) codes, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, Current Procedural Terminology codes, and natural language processing. Main Outcomes and Measures Associations of functional seizures with comorbidities and risk factors, measured in odds ratios (ORs). Results Of 2 346 808 total patients in the VUMC-EHR aged 18 years or older, 3341 patients with functional seizures were identified (period prevalence, 0.14%), 1062 (74.2%) of whom were women and for which the median (interquartile range) age was 49.3 (39.4-59.9) years. This assessment replicated previously reported associations with psychiatric disorders including posttraumatic stress disorder (PTSD) (OR, 1.22; 95% CI, 1.21-1.24; P < 3.02 x 10(-5)), anxiety (OR, 1.14; 95% CI, 1.13-1.15; P < 3.02 x 10(-5)), and depression (OR, 1.14; 95% CI, 1.13-1.15; P < 3.02 x 10(-5)), and identified novel associations with cerebrovascular disease (OR, 1.08; 95% CI, 1.06-1.09; P < 3.02 x 10(-5)). An association was found between functional seizures and the known risk factor sexual assault trauma (OR, 10.26; 95% CI, 10.09-10.44; P < 3.02 x 10(-5)), and sexual assault trauma was found to mediate nearly a quarter of the association between female sex and functional seizures in the VUMC-EHR. Conclusions and Relevance This case-control study found evidence to support previously reported associations, discovered new associations between functional seizures and PTSD, anxiety, and depression. An association between cerebrovascular disease and functional seizures was also found. Results suggested that sexual trauma may be a mediating factor in the association between female sex and functional seizures. Question What is the period prevalence and comorbidity of patients with functional seizures? Findings This case-control study including 3341 patients with functional seizures (period prevalence, 0.14%) identified from all patients at a university medical center found that posttraumatic stress disorder and sexual assault trauma were associated with functional seizures. Novel associations were identified, including cerebrovascular disease. Meaning The findings of this study suggest that patients who present with seizures and additional psychiatric comorbidities, sexual assault trauma history, or cerebrovascular disease should be referred for video electroencephalogram diagnostic assessment. This case-control study of patients at a large university medical center provides an epidemiological assessment of functional seizures and their association with comorbidities (eg, cerebrovascular disease) and risk factors (eg, sexual assault trauma).

BACKGROUND: Half of women use alcohol in the first weeks of gestation, but most stop once pregnancy is detected. The relationship between timing of alcohol use cessation in early pregnancy and spontaneous abortion risk has not been determined. OBJECTIVE: This study aimed to evaluate the association between week-by-week alcohol consumption in early pregnancy and spontaneous abortion. STUDY DESIGN: Participants in Right from the Start, a community-based prospective pregnancy cohort, were recruited from 8 metropolitan areas in the United States (2000-2012). In the first trimester, participants provided information about alcohol consumed in the prior 4 months, including whether they altered alcohol use; date of change in use; and frequency, amount, and type of alcohol consumed before and after change. We assessed the association between spontaneous abortion and week of alcohol use, cumulative weeks exposed, number of drinks per week, beverage type, and binge drinking. RESULTS: Among 5353 participants, 49.7% reported using alcohol during early pregnancy and 12.0% miscarried. Median gestational age at change in alcohol use was 29 days (interquartile range, 15-35 days). Alcohol use during weeks 5 through 10 from last menstrual period was associated with increased spontaneous abortion risk, with risk peaking for use in week 9. Each successive week of alcohol use was associated with an 8% increase in spontaneous abortion relative to those who did not drink (adjusted hazard ratio, 1.08; 95% confidence interval, 1.04-1.12). This risk is cumulative. In addition, risk was not related to number of drinks per week, beverage type, or binge drinking. CONCLUSION: Each additional week of alcohol exposure during the first trimester increases risk of spontaneous abortion, even at low levels of consumption and when excluding binge drinking.

Rationale Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality in the United States. Electronic health records provide large-scale healthcare data for clinical research, but have been underutilized in COPD research due to challenges identifying these individuals, especially in the absence of pulmonary function testing data. Objectives To develop an algorithm to electronically phenotype individuals with COPD at a large tertiary care center. Methods We identified individuals over 45 years of age at last clinic visit within Vanderbilt University Medical Center electronic health records. We tested phenotyping algorithms using combinations of both structured and unstructured text and examined the clinical characteristics of the resulting case sets. Measurement and Main Results A simple algorithm consisting of 3 International Classification of Disease codes for COPD achieved a sensitivity of 97.6%, a specificity of 76.0%, a positive predictive value of 57.1%, and a negative predictive value of 99.0%. A more complex algorithm consisting of both billing codes and a mention of oxygen on the problem list that achieved a positive predictive value of 86.5%. However, the association of known risk factors with chronic obstructive pulmonary disease was consistent in both algorithm sets, suggesting a simple code-only algorithm may suffice for many research applications. Conclusions Simple code-only phenotyping algorithms for chronic obstructive pulmonary disease can identify case populations with epidemiologic and genetic profiles consistent with published literature. Implementation of this phenotyping algorithm will expand opportunities for clinical research and pragmatic trials for COPD.