Quantitative Foveal Structural Metrics as Predictors of Visual Acuity in Human Albinism.

Purpose: To assess the degree to which quantitative foveal structural measurements account for variation in best-corrected visual acuity (BCVA) in human albinism. Methods: BCVA was measured and spectral domain optical coherence tomography (SD-OCT) images were acquired for 74 individuals with albinism. Categorical foveal hypoplasia grades were assessed using the Leicester Grading System for Foveal Hypoplasia. Foveal anatomical specialization (foveal versus parafoveal value) was quantified for inner retinal layer (IRL) thickness, outer segment (OS) length, and outer nuclear layer (ONL) thickness. These metrics, participant sex, and age were used to build a multiple linear regression of BCVA. This combined linear model's predictive properties were compared to those of categorical foveal hypoplasia grading. Results: The cohort included three participants with type 1a foveal hypoplasia, 23 participants with type 1b, 33 with type 2, ten with type 3, and five with type 4. BCVA ranged from 0.08 to 1.00 logMAR (mean ± SD: 0.53 ± 0.21). IRL ratio, OS ratio, and ONL ratio were measured in all participants and decreased with increasing severity of foveal hypoplasia. The best-fit combined linear model included all three quantitative metrics and participant age expressed as a binary variable (divided into 0-18 years and 19 years or older; adjusted R2 = 0.500). This model predicted BCVA more accurately than a categorical foveal hypoplasia model (adjusted R2 = 0.352). Conclusions: A quantitative model of foveal specialization accounts for more variance in BCVA in albinism than categorical foveal hypoplasia grading. Other factors, such as optical aberrations and eye movements, may account for the remaining unexplained variance.

Estimating the efficacy of pharmacogenomics over a lifetime.

It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given prescriptions over a lifetime that could be contraindicated by their pharmacogenomic profiles. To determine the clinical utility of pharmacogenomics over a lifetime in a general patient population, we sequenced the genomes of 300 deceased Marshfield Clinic patients linked to lifelong medical records. Genetic variants in 33 pharmacogenes were evaluated for their lifetime impact on drug prescribing using extensive electronic health records. Results show that 93% of the 300 deceased patients carried clinically relevant variants. Nearly 80% were prescribed approximately three medications on average that may have been impacted by these variants. Longitudinal data suggested that the optimal age for pharmacogenomic testing was prior to age 50, but the optimal age is greatly influenced by the stability of the population in the healthcare system. This study emphasizes the broad clinical impact of pharmacogenomic testing over a lifetime and demonstrates the potential application of genomic medicine in a general patient population for the advancement of precision medicine.

Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence.

Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41-71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients' glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System's pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10-3) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10-3) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer's disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62-5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10-6) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11-0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47-58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings.

FMR1 CGG Repeats and Stress Influence Self-Reported Cognitive Functioning in Mothers.

Variation in the FMR1 gene may affect aspects of cognition, such as executive function and memory. Environmental factors, such as stress, may also negatively impact cognitive functioning. Participants included 1,053 mothers of children with and without developmental disabilities. Participants completed self-report measures of executive function, memory, and stress (i.e., life events, parenting status), and provided DNA to determine CGG repeat length (ranging from 7 to 192 CGGs). Stress exposure significantly predicted greater self-reported difficulties in executive function and the likelihood of memory problems. Cubic CGG effects independently predicted executive function and memory difficulties, suggesting effects of both genetic variation and environmental stress exposure on cognitive functioning.

Mild Neurological Signs in FMR1 Premutation Women in an Unselected Community-Based Cohort.

BACKGROUND: Premutation-sized (55-200) CGG repeat expansions in the FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS). Most studies of premutation carriers utilized reverse ascertainment to identify patients, leading to a selection bias for larger repeats. As shorter CGG premutation repeats are common in the population, understanding their impact on health outcomes has a potentially large public health footprint. OBJECTIVE: The study's objective was to compare an unselected group of premutation carriers (n = 35, 55-101 CGG repeats) with matched controls (n = 61, 29-39 CGG repeats) with respect to FXTAS-type signs using structured neurological assessments. METHODS: Three neurologists independently rated signs, using an adapted version of the FXTAS Rating Scale (Leehey MA, Berry-Kravis E, Goetz CG, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008). This was a double-blind study, as genetic status (premutation vs. control) was known neither by the participants nor by any of the neurologists. Analyses controlled potentially confounding comorbid conditions in the electronic health record (eg, osteoarthritis and stroke) and probed the association of age with signs. RESULTS: Although there was no overall difference between carriers and controls, among individuals without any potentially confounding comorbid diagnoses, there was a statistically significant age-associated elevation in FXTAS-type signs in premutation carriers compared to controls. CONCLUSIONS: Among those who do not have other comorbid diagnoses, women who have CGG repeats at the lower end of the premutation range may be at greater risk for ataxia and parkinsonism than their age peers, although their overall risk of developing such clinical features is low. This study should provide reassurance to those who share characteristics with the present cohort. © 2021 International Parkinson and Movement Disorder Society.

Medical records-based chronic kidney disease phenotype for clinical care and "big data" observational and genetic studies.

Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate ("A-by-G" grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.

FMR1 Low Zone CGG Repeats: Phenotypic Associations in the Context of Parenting Stress.

The FMR1 gene on the X chromosome has varying numbers of CGG repeats. The modal number is 30, and expansion to >200 results in fragile X syndrome, but the copy number extends down to 6. Past research suggests that individuals whose CGGs are in the "low zone" (LZ; defined here as ≤ 25 CGGs) may be more environmentally-reactive than those with normal range repeats (26-40 CGGs)-a gene x environment interaction. Using a population-based DNA biobank, in our primary analysis we compared 96 mothers with LZ CGG repeats on both alleles to 280 mothers who had CGG repeats in the normal range. Secondarily, we conducted parallel analyses on fathers. We investigated how parents in these two CGG repeat categories differentially responded to stress, defined as parenting a child with disabilities. Significant gene x environment interactions indicated that LZ mothers who had children with disabilities had greater limitations (in executive functioning, depression, anxiety, daily health symptoms, and balance) than LZ mothers whose children did not have disabilities. In contrast, mothers with normal-range CGG repeats did not differ based on stress exposure. For fathers, a similar pattern was evident for one phenotype only (hand tremors). Although on average LZ CGGs are not associated with compromised functioning, the average masks differential response to the environment.

Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis.

IMPORTANCE: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations. OBJECTIVE: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018. MAIN OUTCOMES AND MEASURES: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression. RESULTS: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (ß = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4). CONCLUSIONS AND RELEVANCE: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

Heritability and genome-wide association study of benign prostatic hyperplasia (BPH) in the eMERGE network.

Benign prostatic hyperplasia (BPH) results in a significant public health burden due to the morbidity caused by the disease and many of the available remedies. As much as 70% of men over 70 will develop BPH. Few studies have been conducted to discover the genetic determinants of BPH risk. Understanding the biological basis for this condition may provide necessary insight for development of novel pharmaceutical therapies or risk prediction. We have evaluated SNP-based heritability of BPH in two cohorts and conducted a genome-wide association study (GWAS) of BPH risk using 2,656 cases and 7,763 controls identified from the Electronic Medical Records and Genomics (eMERGE) network. SNP-based heritability estimates suggest that roughly 60% of the phenotypic variation in BPH is accounted for by genetic factors. We used logistic regression to model BPH risk as a function of principal components of ancestry, age, and imputed genotype data, with meta-analysis performed using METAL. The top result was on chromosome 22 in SYN3 at rs2710383 (p-value = 4.6 × 10-7; Odds Ratio = 0.69, 95% confidence interval = 0.55-0.83). Other suggestive signals were near genes GLGC, UNCA13, SORCS1 and between BTBD3 and SPTLC3. We also evaluated genetically-predicted gene expression in prostate tissue. The most significant result was with increasing predicted expression of ETV4 (chr17; p-value = 0.0015). Overexpression of this gene has been associated with poor prognosis in prostate cancer. In conclusion, although there were no genome-wide significant variants identified for BPH susceptibility, we present evidence supporting the heritability of this phenotype, have identified suggestive signals, and evaluated the association between BPH and genetically-predicted gene expression in prostate.

Probing the Virtual Proteome to Identify Novel Disease Biomarkers.

BACKGROUND: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a "virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. METHODS: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmö Diet and Cancer Study; n=651). RESULTS: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-ß predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-ß. CONCLUSIONS: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases.

The Henle Fiber Layer in Albinism: Comparison to Normal and Relationship to Outer Nuclear Layer Thickness and Foveal Cone Density.

Purpose: Directional optical coherence tomography (D-OCT) allows the visualization of the Henle fiber layer (HFL) in vivo. Here, we used D-OCT to characterize the HFL and outer nuclear layer (ONL) in albinism and examine the relationship between true foveal ONL and peak cone density. Methods: Horizontal D-OCT B-scans were acquired, registered, and averaged for 12 subjects with oculocutaneous albinism and 26 control subjects. Averaged images were manually segmented to extract HFL and ONL thickness. Adaptive optics scanning light ophthalmoscopy was used to acquire images of the foveal cone mosaic in 10 subjects with albinism, from which peak cone density was assessed. Results: Across the foveal region, the HFL topography was different between subjects with albinism and normal controls. In particular, foveal HFL thickness was thicker in albinism than in normal controls (P < 0.0001), whereas foveal ONL thickness was thinner in albinism than in normal controls (P < 0.0001). The total HFL and ONL thickness was not significantly different between albinism and controls (P = 0.3169). Foveal ONL thickness was positively correlated with peak cone density in subjects with albinism (r = 0.8061, P = 0.0072). Conclusions: Foveal HFL and ONL topography are significantly altered in albinism relative to normal controls. Our data suggest that increased foveal cone packing drives the formation of Henle fibers, more so than the lateral displacement of inner retinal neurons (which is reduced in albinism). The ability to quantify foveal ONL and HFL may help further stratify grading schemes used to assess foveal hypoplasia.

Parents' attitudes toward consent and data sharing in biobanks: A multisite experimental survey.

BACKGROUND: The factors influencing parents' willingness to enroll their children in biobanks are poorly understood. This study sought to assess parents' willingness to enroll their children, and their perceived benefits, concerns, and information needs under different consent and data-sharing scenarios, and to identify factors associated with willingness. METHODS: This large, experimental survey of patients at the 11 eMERGE Network sites used a disproportionate stratified sampling scheme to enrich the sample with historically underrepresented groups. Participants were randomized to receive one of three consent and data-sharing scenarios. RESULTS: In total, 90,000 surveys were mailed and 13,000 individuals responded (15.8% response rate). 5737 respondents were parents of minor children. Overall, 55% (95% confidence interval 50-59%) of parents were willing to enroll their youngest minor child in a hypothetical biobank; willingness did not differ between consent and data-sharing scenarios. Lower educational attainment, higher religiosity, lower trust, worries about privacy, and attitudes about benefits, concerns, and information needs were independently associated with less willingness to allow their child to participate. Of parents who were willing to participate themselves, 25% were not willing to allow their child to participate. Being willing to participate but not willing to allow one's child to participate was independently associated with multiple factors, including race, lower educational attainment, lower annual household income, public health care insurance, and higher religiosity. CONCLUSIONS: Fifty-five percent of parents were willing to allow their youngest minor child to participate in a hypothetical biobank. Building trust, protecting privacy, and addressing attitudes may increase enrollment and diversity in pediatric biobanks.

A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers.

Defining the full spectrum of human disease associated with a biomarker is necessary to advance the biomarker into clinical practice. We hypothesize that associating biomarker measurements with electronic health record (EHR) populations based on shared genetic architectures would establish the clinical epidemiology of the biomarker. We use Bayesian sparse linear mixed modeling to calculate SNP weightings for 53 biomarkers from the Atherosclerosis Risk in Communities study. We use the SNP weightings to computed predicted biomarker values in an EHR population and test associations with 1139 diagnoses. Here we report 116 associations meeting a Bonferroni level of significance. A false discovery rate (FDR)-based significance threshold reveals more known and undescribed associations across a broad range of biomarkers, including biometric measures, plasma proteins and metabolites, functional assays, and behaviors. We confirm an inverse association between LDL-cholesterol level and septicemia risk in an independent epidemiological cohort. This approach efficiently discovers biomarker-disease associations.

Using machine learning to identify patterns of lifetime health problems in decedents with autism spectrum disorder.

Very little is known about the health problems experienced by individuals with autism spectrum disorder (ASD) throughout their life course. We retrospectively analyzed diagnostic codes associated with de-identified electronic health records using a machine learning algorithm to characterize diagnostic patterns in decedents with ASD and matched decedent community controls. Participants were 91 decedents with ASD and 6,186 sex and birth year matched decedent community controls who had died since 1979, the majority of whom were middle aged or older adults at the time of their death. We analyzed all ICD-9 codes, V-codes, and E-codes available in the electronic health record and Elixhauser comorbidity categories associated with those codes. Diagnostic patterns distinguished decedents with ASD from decedent community controls with 75% sensitivity and 94% specificity solely based on their lifetime ICD-9 codes, V-codes, and E-codes. Decedents with ASD had higher rates of most conditions, including cardiovascular disease, motor problems, ear problems, urinary problems, digestive problems, side effects from long-term medication use, and nonspecific lab tests and encounters. In contrast, decedents with ASD had lower rates of cancer. Findings suggest distinctive lifetime diagnostic patterns among decedents with ASD and highlight the need for more research on health outcomes across the lifespan as the population of individuals with ASD ages. As a large wave of individuals with ASD diagnosed in the 1990s enters adulthood and middle age, knowledge about lifetime health problems will become increasingly important for care and prevention efforts. Autism Res 2018, 11: 1120-1128. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study looked at patterns of lifetime health problems to find differences between people with autism who had died and community controls who had died. People with autism had higher rates of most health problems, including cardiovascular, urinary, respiratory, digestive, and motor problems, in their electronic health records. They also had lower rates of cancer. More research is needed to understand these potential health risks as a large number of individuals with autism enter adulthood and middle age.

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets.

Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Pilot screening study of targeted genetic polymorphisms for association with seasonal influenza hospital admission.

Host response to influenza is highly variable, suggesting a potential role of host genetic variation. To investigate the host genetics of severe influenza in a targeted fashion, 32 single nucleotide polymorphisms (SNPs) within viral immune response genes were evaluated for association with seasonal influenza hospitalization in an adult study population with European ancestry. SNP allele and genotype frequencies were compared between hospitalized influenza patients (cases) and population controls in a case-control study that included a discovery group (26 cases and 993 controls) and two independent, validation groups (1 with 84 cases and 4076 controls; the other with 128 cases and 9187 controls). Cases and controls had similar allele frequencies for variant rs12252 in interferon-inducible transmembrane protein 3 (IFITM3) (P > 0.05), and the study did not replicate the previously reported association of rs12252 with hospitalized influenza. In the discovery group, the preliminary finding of an association with a nonsense polymorphism (rs8072510) within the schlafen family member 13 (SFLN13) gene (P = 0.0099) was not confirmed in either validation group. Neither rs12252 nor rs8072510 showed an association according to the presence of clinical risk factors for influenza complications (P > 0.05), suggesting that these factors did not modify associations between the SNPs and hospitalized influenza. No other SNPs showed a statistically significant association with hospitalized influenza. Further research is needed to identify genetic factors involved in host response to seasonal influenza infection and to assess whether rs12252, a low-frequency variant in Europeans, contributes to influenza severity in populations with European ancestry.

Applying family analyses to electronic health records to facilitate genetic research.

Motivation: Pedigree analysis is a longstanding and powerful approach to gain insight into the underlying genetic factors in human health, but identifying, recruiting and genotyping families can be difficult, time consuming and costly. Development of high throughput methods to identify families and foster downstream analyses are necessary. Results: This paper describes simple methods that allowed us to identify 173 368 family pedigrees with high probability using basic demographic data available in most electronic health records (EHRs). We further developed and validate a novel statistical method that uses EHR data to identify families more likely to have a major genetic component to their diseases risk. Lastly, we showed that incorporating EHR-linked family data into genetic association testing may provide added power for genetic mapping without additional recruitment or genotyping. The totality of these results suggests that EHR-linked families can enable classical genetic analyses in a high-throughput manner. Availability and implementation: Pseudocode is provided as supplementary information. Contact: HEBBRING.SCOTT@marshfieldresearch.org. Supplementary information: Supplementary data are available at Bioinformatics online.

PLATO software provides analytic framework for investigating complexity beyond genome-wide association studies.

Genome-wide, imputed, sequence, and structural data are now available for exceedingly large sample sizes. The needs for data management, handling population structure and related samples, and performing associations have largely been met. However, the infrastructure to support analyses involving complexity beyond genome-wide association studies is not standardized or centralized. We provide the PLatform for the Analysis, Translation, and Organization of large-scale data (PLATO), a software tool equipped to handle multi-omic data for hundreds of thousands of samples to explore complexity using genetic interactions, environment-wide association studies and gene-environment interactions, phenome-wide association studies, as well as copy number and rare variant analyses. Using the data from the Marshfield Personalized Medicine Research Project, a site in the electronic Medical Records and Genomics Network, we apply each feature of PLATO to type 2 diabetes and demonstrate how PLATO can be used to uncover the complex etiology of common traits.

Prototype Development: Context-Driven Dynamic XML Ophthalmologic Data Capture Application.

BACKGROUND: The capture and integration of structured ophthalmologic data into electronic health records (EHRs) has historically been a challenge. However, the importance of this activity for patient care and research is critical. OBJECTIVE: The purpose of this study was to develop a prototype of a context-driven dynamic extensible markup language (XML) ophthalmologic data capture application for research and clinical care that could be easily integrated into an EHR system. METHODS: Stakeholders in the medical, research, and informatics fields were interviewed and surveyed to determine data and system requirements for ophthalmologic data capture. On the basis of these requirements, an ophthalmology data capture application was developed to collect and store discrete data elements with important graphical information. RESULTS: The context-driven data entry application supports several features, including ink-over drawing capability for documenting eye abnormalities, context-based Web controls that guide data entry based on preestablished dependencies, and an adaptable database or XML schema that stores Web form specifications and allows for immediate changes in form layout or content. The application utilizes Web services to enable data integration with a variety of EHRs for retrieval and storage of patient data. CONCLUSIONS: This paper describes the development process used to create a context-driven dynamic XML data capture application for optometry and ophthalmology. The list of ophthalmologic data elements identified as important for care and research can be used as a baseline list for future ophthalmologic data collection activities.

Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: a multi-cohort analysis.

Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10-27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10-5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.