Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing. Population stratification was adjusted for using meta-analysis across ancestry groups. We replicated two loci identified by the HGI for COVID-19 severity: the LZTFL1/SLC6A20 locus on chromosome 3 and the FOXP4 locus on chromosome 6 (the latter with a variant significant at P < 5E-8). We found novel significant associations with MRAS and WDR89 in gene-based analyses, and constructed a polygenic risk score that explained 1.01% of the variance in severe COVID-19. This study provides independent evidence confirming the robustness of previously identified COVID-19 severity loci by the HGI and identifies novel genes for further investigation.

Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease.

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04-1.18; P 8.43 × 10-4) and 1.13 (95% CI, 1.07-1.20; P 4.51 × 10-6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03-1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95-1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99-1.14; P = 0.07) and 1.07 (1.01-1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

Association of Preinjury Medical Diagnoses With Pediatric Persistent Postconcussion Symptoms in Electronic Health Records.

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.

Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness.

Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.

Social-ecological predictors of school functioning in Hispanic children treated for cancer with central nervous system-directed therapies.

BACKGROUND: Children with brain tumor or acute leukemia are at risk for neurotoxic side effects associated with their cancer therapies. These long-term deficits include poor health-related quality of life (HRQOL) in school and lower educational achievement. Although social-ecological factors may impact these outcomes, it is not known which factors play a role. Our objective was to evaluate the factors affecting school HRQOL in Hispanic childhood cancer survivors, an important at-risk group. PROCEDURE: Multivariable regression analyses examined whether selected social-ecological factors contribute toward suboptimal school HRQOL in 73 Hispanic children treated with central nervous system (CNS)-directed cancer therapies after accounting for effects associated with established cancer-related risk factors. RESULTS: Consistent with expectations from prior research, in our multivariate analysis, the cancer-related factors of having a brain tumor diagnosis and being younger at cancer diagnosis were significant predictors of reduced parent-reported school HRQOL (F(2,65) = 5.46, P < .01) and accounted for 14% of the variance. Adding the social-ecological variables of parent education, child motivation, and parental knowledge accounted for an additional 25% of the variance in school HRQOL, where higher levels were associated with better child school HRQOL. Parenting knowledge was a contributor even after controlling for effects associated with the other variables in the model (F(1,62) = 4.88, P < .05). CONCLUSIONS: Cancer survivorship care should incorporate parent education interventions to enhance the child's school functioning, particularly for Hispanic childhood cancer survivors from predominantly Spanish-speaking families. Future research should consider other at-risk groups and incorporate social-ecological indicators to predict HRQOL outcomes.

Leveraging cell type specific regulatory regions to detect SNPs associated with tissue factor pathway inhibitor plasma levels.

Tissue factor pathway inhibitor (TFPI) regulates the formation of intravascular blood clots, which manifest clinically as ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). TFPI plasma levels are heritable, but the genetics underlying TFPI plasma level variability are poorly understood. Herein we report the first genome-wide association scan (GWAS) of TFPI plasma levels, conducted in 251 individuals from five extended French-Canadian Families ascertained on VTE. To improve discovery, we also applied a hypothesis-driven (HD) GWAS approach that prioritized single nucleotide polymorphisms (SNPs) in (1) hemostasis pathway genes, and (2) vascular endothelial cell (EC) regulatory regions, which are among the highest expressers of TFPI. Our GWAS identified 131 SNPs with suggestive evidence of association (P-value < 5 × 10-8 ), but no SNPs reached the genome-wide threshold for statistical significance. Hemostasis pathway genes were not enriched for TFPI plasma level associated SNPs (global hypothesis test P-value = 0.147), but EC regulatory regions contained more TFPI plasma level associated SNPs than expected by chance (global hypothesis test P-value = 0.046). We therefore stratified our genome-wide SNPs, prioritizing those in EC regulatory regions via stratified false discovery rate (sFDR) control, and reranked the SNPs by q-value. The minimum q-value was 0.27, and the top-ranked SNPs did not show association evidence in the MARTHA replication sample of 1,033 unrelated VTE cases. Although this study did not result in new loci for TFPI, our work lays out a strategy to utilize epigenomic data in prioritization schemes for future GWAS studies.

Bicycling crashes on streetcar (tram) or train tracks: mixed methods to identify prevention measures.

BACKGROUND: Streetcar or train tracks in urban areas are difficult for bicyclists to negotiate and are a cause of crashes and injuries. This study used mixed methods to identify measures to prevent such crashes, by examining track-related crashes that resulted in injuries to cyclists, and obtaining information from the local transit agency and bike shops. METHODS: We compared personal, trip, and route infrastructure characteristics of 87 crashes directly involving streetcar or train tracks to 189 crashes in other circumstances in Toronto, Canada. We complemented this with engineering information about the rail systems, interviews of personnel at seven bike shops about advice they provide to customers, and width measurements of tires on commonly sold bikes. RESULTS: In our study, 32 % of injured cyclists had crashes that directly involved tracks. The vast majority resulted from the bike tire being caught in the rail flangeway (gap in the road surface alongside rails), often when cyclists made unplanned maneuvers to avoid a collision. Track crashes were more common on major city streets with parked cars and no bike infrastructure, with left turns at intersections, with hybrid, racing and city bikes, among less experienced and less frequent bicyclists, and among women. Commonly sold bikes typically had tire widths narrower than the smallest track flangeways. There were no track crashes in route sections where streetcars and trains had dedicated rights of way. CONCLUSIONS: Given our results, prevention efforts might be directed at individual knowledge, bicycle tires, or route design, but their potential for success is likely to differ. Although it may be possible to reach a broader audience with continued advice about how to avoid track crashes, the persistence and frequency of these crashes and their unpredictable circumstances indicates that other solutions are needed. Using tires wider than streetcar or train flangeways could prevent some crashes, though there are other considerations that lead many cyclists to have narrower tires. To prevent the majority of track-involved injuries, route design measures including dedicated rail rights of way, cycle tracks (physically separated bike lanes), and protected intersections would be the best strategy.

Willingness to participate in a parental training intervention to reduce neurocognitive late effects among Latino parents of childhood cancer survivors.

The purpose of the study was to examine correlates of Spanish-speaking Latino parents' interest for participation in an educational intervention to improve learning and school success in children with cancer-related cognitive and behavioral late effects. Participants included 73 Latino caregivers of school-age children who are survivors of brain tumor or leukemia and at risk for cognitive late effects. The parents completed a battery of surveys relating to interest in and barriers to intervention participation, as well as measures of parental knowledge and beliefs and their children's cognitive functioning, and health-related quality of life. Results showed that the majority of parents expressed interest in participating in the proposed 8-week intervention, with over 90% indicating interest in learning more about improving grades, making learning more exciting, being a role model, and the impact of cancer on memory. The factors most strongly related to interest in intervention included lower maternal education as well as perceptions of greater child cognitive difficulties and lower health-related quality of life. The barriers most highly endorsed by the most parents were difficulty paying for gas, child care responsibility, and too much stress in other parts of life. Also highly endorsed as barriers were statements relating to the child's lack of interest and need for services (i.e., my child is doing fine). These findings are consistent with the Health Belief Model wherein decisions to engage in health-related behaviors are made by weighing the potential benefits relative to the costs and barriers.

The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies.

The endothelial protein C receptor (EPCR) limits thrombus formation by enhancing activation of the protein C anticoagulant pathway, and therefore may play a role in the etiology of thrombotic disorders. The rs867186 single-nucleotide polymorphism in the PROCR gene (g.6936A > G, c.4600A > G), resulting in a serine-to-glycine substitution at codon 219, has been associated with reduced activation of the protein C pathway, although its association with thrombosis risk remains unclear. The present study is a highly comprehensive systematic review and meta-analysis, including unpublished genome-wide association study results, conducted to evaluate the evidence for an association between rs867186 and 2 common thrombotic outcomes, venous thromboembolism (VTE) and myocardial infarction (MI), which are hypothesized to share some etiologic pathways. MEDLINE, EMBASE, and HuGE Navigator were searched through July 2011 to identify relevant epidemiologic studies, and data were summarized using random-effects meta-analysis. Twelve candidate genes and 13 genome-wide association studies were analyzed (11 VTE and 14 MI, including 37,415 cases and 84,406 noncases). Under the additive genetic model, the odds of VTE increased by a factor of 1.22 (95% confidence interval, 1.11-1.33, P < .001) for every additional copy of the G allele. No evidence for association with MI was observed.

Measuring Acculturation Gap Conflicts among Hispanics: Implications for Psychosocial and Academic Adjustment.

This study examined the factor structure and validity of the Acculturation Gap Conflicts Inventory (AGCI), a new instrument developed to measure the types of recurring conflicts that young people experience as part of the parent-child acculturation gap. Participants included 283 Hispanic young adults who completed the AGCI and existing measures of acculturation, family dynamics, psychosocial, and academic adjustment. Principal axis factor analysis revealed three factors with good internal consistency: Autonomy Conflicts, Conflicts over Preferred-Culture, and Dating/Being Out Late Conflicts. These factors correlated in the expected direction with acculturative stress and family dynamics variables. Autonomy Conflicts explained more than 25% of the variance in the acculturation gap conflicts items investigated, and this factor demonstrated incremental validity in predicting psychosocial and academic adjustment beyond the variance accounted for by other acculturative stress variables. The AGCI can be valuable to researchers from a variety of disciplines interested in measuring acculturation-related intergenerational conflicts among Hispanic youth that may be predictive of adjustment.

Predictors of hookup behaviors among Asian and Asian American college students in the United States.

Objective: With the rapid growth in the population of Asian and Asian American college students in the United States, there is a need for research examining their participation in potentially risky sexual behaviors in order to expand understanding of this group's needs. This study focused on attachment orientation and hookup motives as predictors of hookup behaviors, which involve engaging in sexual behaviors without expectation of a long-term relationship.Methods: Participants included 169 Asian or Asian American college students ranging in age from 18 to 27 years who completed an online survey.Results: Results indicated that over half of participants reported engaging in hookup behaviors. The strongest predictors of hookup behaviors were increased age, liberal sexual attitudes, motivations to achieve excitement/sexual enhancement, and motivations to find a long-term partner. However, attachment orientations did not predict hookup behaviors. Results provide insight into a profile of Asian American college students increasingly exploring sexuality throughout young adulthood.

Sex-dependent placental methylation quantitative trait loci provide insight into the prenatal origins of childhood onset traits and conditions.

Molecular quantitative trait loci (QTLs) allow us to understand the biology captured in genome-wide association studies (GWASs). The placenta regulates fetal development and shows sex differences in DNA methylation. We therefore hypothesized that placental methylation QTL (mQTL) explain variation in genetic risk for childhood onset traits, and that effects differ by sex. We analyzed 411 term placentas from two studies and found 49,252 methylation (CpG) sites with mQTL and 2,489 CpG sites with sex-dependent mQTL. All mQTL were enriched in regions that typically affect gene expression in prenatal tissues. All mQTL were also enriched in GWAS results for growth- and immune-related traits, but male- and female-specific mQTL were more enriched than cross-sex mQTL. mQTL colocalized with trait loci at 777 CpG sites, with 216 (28%) specific to males or females. Overall, mQTL specific to male and female placenta capture otherwise overlooked variation in childhood traits.

Neurocognitive and behavioral outcomes in Latino childhood cancer survivors.

BACKGROUND: Children with brain tumors and leukemia are at risk for neurocognitive and behavioral late effects due to central nervous system-directed therapies. Few studies have examined these outcomes in ethnic minority samples, despite speculation that socio-demographic factors may increase vulnerability for adverse neurobehavioral outcomes. We evaluated the neurocognitive and behavioral outcomes and their impact on the health-related quality of life in survivors of childhood cancer drawn from Latino families in the Los Angeles region. PROCEDURE: Using culturally-relevant recruitment strategies, 73 predominantly Spanish-speaking parents of pediatric brain tumor or leukemia survivors completed standardized questionnaires, including the Conners parent-report and the Bidimensional Acculturation Scales. Clinical and socio-demographic factors influencing the development of neurocognitive and behavioral dysfunction were examined. RESULTS: Approximately 50% of the children placed at or above the "elevated" level for difficulties with attention, school-based learning, and peer relations. Younger age at diagnosis significantly predicted dysfunction in inattention, learning problems, and hyperactivity/impulsivity. Children whose parents were less adherent to the non-Hispanic white culture were more likely to have problems with peer relations and executive functioning. HRQL was significantly lower in survivors with neurocognitive and behavioral dysfunction relative to those with normal range scores on the Conners scale. CONCLUSIONS: In addition to the child's age at diagnosis, acculturation appears to predict select neurocognitive and behavioral outcomes in this socio-demographically homogeneous sample of Latino families. Further research is needed to understand the interaction of ethnic and cultural factors with therapeutic exposures in determining the adverse neurobehavioral outcomes, so as to optimally design interventions.

A qualitative study understanding immigrant Latinas, violence, and available mental health care.

Women from Latin American countries experience high levels of psychological and physical abuse and violence. Immigrant Latina women are often subjected to a patriarchal system in both family and government, which has resulted in a variety of complex and far-reaching outcomes. This qualitative study sought to understand the experiences of immigrant Latina women who were exposed to violence, as well as their access to mental health care. This study used 20 interviews with immigrant Latina women from El Salvador, Guatemala, and Mexico who had accessed mental health services in California. The primary themes that emerged from analysis of the data included motivating factors for seeking services (e.g., motherhood, community, hope, and mental health needs), barriers to accessing services (e.g., fatalism, marianismo, stigma, finances, language barriers, threats, abuse, and systemic insensitivity), and treatment and solutions (e.g., empathy, advocacy, and community approaches). These results appeared to be indicative of the importance of addressing sociopolitical, historical, and cultural trauma as an imperative component of effective treatment. In this context, the authors explore liberation psychology, a concept and approach that promotes social justice values and emphasizes the empowerment of immigrant Latina women in clinical practice. It is recommended that the historical sociocultural abuse of immigrant Latina women be thoughtfully considered and discussed in the therapeutic process to create lasting psychological change. Future research, policy efforts, and program development, including psychotherapeutic treatment modalities, should focus specifically on marginalized groups facing barriers to mental health care in order to increase access and effectiveness of treatment.

The sustainability of upper limb robotic therapy for stroke survivors in an inpatient rehabilitation setting.

PURPOSE: To investigate the sustainability of Robot-assisted upper limb therapy (RT-UL) as part of routine occupational therapy and physiotherapy clinical practice. METHODS: Two separate audits, 12 months apart, of RT-UL computer data records were undertaken to determine sustainability in a subacute rehabilitation unit. Records of the two audits were compared in terms of the number of early subacute stroke survivors using RT-UL, the number of RT-UL sessions, duration of RT-UL sessions, and disciplines prescribing RT-UL. RESULTS: During Audit 1 58% (n = 18) of stroke survivors received RT-UL compared to 50% (n = 7) in Audit 2. The total number of RT-UL sessions reduced between audits (148 vs. 36 sessions) reflecting the overall reduction in admission rates for stroke survivors. There was no significant difference between audits in the average number of RT-UL sessions per patient (p = 0.203) nor the length of sessions (p = 0.762). Patients engaged in active therapy more than three-quarters of the time when on the robotic device. Physiotherapists were the primary prescribers of RT-UL when compared to occupational therapists. CONCLUSIONS: RT-UL was in continued and regular use with stroke survivors 2 years after initial implementation within an inpatient rehabilitation setting. RT-UL practice was intensive and used routinely with patients.IMPLICATIONS FOR REHABILITATIONRT-UL is a sustainable and intensive intervention for stroke survivors within an inpatient rehabilitative setting.The cost-benefits of RT-UL should be evaluated from the perspective of the whole rehabilitation service not just at an individual patient level.RT-UL may be considered a "bridging" form of UL practice for those with more limited active UL movement until there is sufficient UL movement and power for more complex real-world task-specific practice.

Breast cancer risk in relation to alcohol consumption and BRCA gene mutations--a case-only study of gene-environment interaction.

The variable penetrance of the BRCA1 and BRCA2 genes suggests that other genetic or environmental factors may interact with these mutations to modify breast cancer risk. The objective of this study was to measure departures from multiplicative effects of alcohol consumption and BRCA gene mutations. A cohort of French-Canadian breast cancer patients was tested for BRCA gene mutations and completed a food frequency questionnaire. The case-only odds ratio (COR) was calculated. A total of 857 women, including 10 BRCA1 and 33 BRCA2 mutation carriers, participated in the study. No significant interaction between alcohol consumption and BRCA1 mutations was detected, although the interaction with wine consumption suggested a sub-multiplicative effect (COR = 0.38, 95% CI: 0.08-1.81). Consumption of alcohol other than wine interacted significantly with BRCA2 mutations (COR = 2.15, 95% CI: 1.03-4.49). Consumption of wine may protect against BRCA1-associated tumors, while women with BRCA2 mutations may be at greater risk of alcohol-induced breast cancer.

Clinical laboratory test-wide association scan of polygenic scores identifies biomarkers of complex disease.

BACKGROUND: Clinical laboratory (lab) tests are used in clinical practice to diagnose, treat, and monitor disease conditions. Test results are stored in electronic health records (EHRs), and a growing number of EHRs are linked to patient DNA, offering unprecedented opportunities to query relationships between genetic risk for complex disease and quantitative physiological measurements collected on large populations. METHODS: A total of 3075 quantitative lab tests were extracted from Vanderbilt University Medical Center's (VUMC) EHR system and cleaned for population-level analysis according to our QualityLab protocol. Lab values extracted from BioVU were compared with previous population studies using heritability and genetic correlation analyses. We then tested the hypothesis that polygenic risk scores for biomarkers and complex disease are associated with biomarkers of disease extracted from the EHR. In a proof of concept analyses, we focused on lipids and coronary artery disease (CAD). We cleaned lab traits extracted from the EHR performed lab-wide association scans (LabWAS) of the lipids and CAD polygenic risk scores across 315 heritable lab tests then replicated the pipeline and analyses in the Massachusetts General Brigham Biobank. RESULTS: Heritability estimates of lipid values (after cleaning with QualityLab) were comparable to previous reports and polygenic scores for lipids were strongly associated with their referent lipid in a LabWAS. LabWAS of the polygenic score for CAD recapitulated canonical heart disease biomarker profiles including decreased HDL, increased pre-medication LDL, triglycerides, blood glucose, and glycated hemoglobin (HgbA1C) in European and African descent populations. Notably, many of these associations remained even after adjusting for the presence of cardiovascular disease and were replicated in the MGBB. CONCLUSIONS: Polygenic risk scores can be used to identify biomarkers of complex disease in large-scale EHR-based genomic analyses, providing new avenues for discovery of novel biomarkers and deeper understanding of disease trajectories in pre-symptomatic individuals. We present two methods and associated software, QualityLab and LabWAS, to clean and analyze EHR labs at scale and perform a Lab-Wide Association Scan.

The effects of provincial bicycle helmet legislation on helmet use and bicycle ridership in Canada.

BACKGROUND: Bicycle helmet legislation has been variably implemented in six of 10 Canadian provinces. The objectives of this study were to determine the association between the comprehensiveness of helmet legislation and both helmet use and bicycle ridership. METHODS: Analysis of helmet use was based on data from the 2005 Canadian Community Health Survey (CCHS) and included respondents from three Canadian provinces (Saskatchewan, Ontario, and Nova Scotia). Analysis of bicycle use was based on data from the 2000-01, 2003, 2005, and 2007 cycles of the CCHS and included respondents from all provinces. In the time between the 2000-01 and 2007 cycles, two provinces (Prince Edward Island (PEI) and Alberta) implemented helmet legislation. RESULTS: Helmets were reportedly worn by 73.2% (95% CI 69.3% to 77.0%) of respondents in Nova Scotia, where legislation applies to all ages, by 40.6% (95% CI 39.2% to 42.0%) of respondents in Ontario, where legislation applies to those less than 18 years of age, and by 26.9% (95% CI 23.9% to 29.9%) of respondents in Saskatchewan, where no legislation exists. Though legislation applied to youth in both Ontario and Nova Scotia, helmet use was lower among youth in Ontario than among youth in Nova Scotia (46.7% (95% CI 44.1% to 49.4%) vs 77.5% (95% CI 70.9% to 84.1%)). Following the implementation of legislation in PEI and Alberta, recreational and commuting bicycle use remained unchanged among youth and adults. CONCLUSIONS: Canadian youth and adults are significantly more likely to wear helmets as the comprehensiveness of helmet legislation increases. Helmet legislation is not associated with changes in ridership.

Diagnostic Algorithms to Study Post-Concussion Syndrome Using Electronic Health Records: Validating a Method to Capture an Important Patient Population.

Post-concussion syndrome (PCS) is characterized by persistent cognitive, somatic, and emotional symptoms after a mild traumatic brain injury (mTBI). Genetic and other biological variables may contribute to PCS etiology, and the emergence of biobanks linked to electronic health records (EHRs) offers new opportunities for research on PCS. We sought to validate the EHR data of PCS patients by comparing two diagnostic algorithms deployed in the Vanderbilt University Medical Center de-identified database of 2.8 million patient EHRs. The algorithms identified individuals with PCS by: 1) natural language processing (NLP) of narrative text in the EHR combined with structured demographic, diagnostic, and encounter data; or 2) coded billing and procedure data. The predictive value of each algorithm was assessed, and cases and controls identified by each approach were compared on demographic and medical characteristics. The NLP algorithm identified 507 cases and 10,857 controls. The negative predictive value in controls was 78% and the positive predictive value (PPV) in cases was 82%. Conversely, the coded algorithm identified 1142 patients with two or more PCS billing codes and had a PPV of 76%. Comparisons of PCS controls to both case groups recovered known epidemiology of PCS: cases were more likely than controls to be female and to have pre-morbid diagnoses of anxiety, migraine, and post-traumatic stress disorder. In contrast, controls and cases were equally likely to have attention deficit hyperactive disorder and learning disabilities, in accordance with the findings of recent systematic reviews of PCS risk factors. We conclude that EHRs are a valuable research tool for PCS. Ascertainment based on coded data alone had a predictive value comparable to an NLP algorithm, recovered known PCS risk factors, and maximized the number of included patients.

Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia in 106,160 Patients Across Four Health Care Systems.

OBJECTIVE: Individuals at high risk for schizophrenia may benefit from early intervention, but few validated risk predictors are available. Genetic profiling is one approach to risk stratification that has been extensively validated in research cohorts. The authors sought to test the utility of this approach in clinical settings and to evaluate the broader health consequences of high genetic risk for schizophrenia. METHODS: The authors used electronic health records for 106,160 patients from four health care systems to evaluate the penetrance and pleiotropy of genetic risk for schizophrenia. Polygenic risk scores (PRSs) for schizophrenia were calculated from summary statistics and tested for association with 1,359 disease categories, including schizophrenia and psychosis, in phenome-wide association studies. Effects were combined through meta-analysis across sites. RESULTS: PRSs were robustly associated with schizophrenia (odds ratio per standard deviation increase in PRS, 1.55; 95% CI=1.4, 1.7), and patients in the highest risk decile of the PRS distribution had up to 4.6-fold higher odds of schizophrenia compared with those in the bottom decile (95% CI=2.9, 7.3). PRSs were also positively associated with other phenotypes, including anxiety, mood, substance use, neurological, and personality disorders, as well as suicidal behavior, memory loss, and urinary syndromes; they were inversely related to obesity. CONCLUSIONS: The study demonstrates that an available measure of genetic risk for schizophrenia is robustly associated with schizophrenia in health care settings and has pleiotropic effects on related psychiatric disorders as well as other medical syndromes. The results provide an initial indication of the opportunities and limitations that may arise with the future application of PRS testing in health care systems.