Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases.

Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.

Implementation of a Best Practice Advisory to Improve Infection Screening Prior to New Prescriptions of Biologics and Targeted Synthetic Drugs.

OBJECTIVE: Use of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with preexisting tuberculosis (TB), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection can have serious consequences. Although various society guidelines recommend routine screening for these infections before initiating certain b/tsDMARDs, adherence to these recommendations varies widely. This quality improvement initiative evaluated local compliance with screening and assessed whether an automated computerized decision support system in the form of a best practice advisory (BPA) in the electronic health record could improve patient screening. METHODS: Established patients with autoimmune rheumatic disease (ARD) aged 18 years or older with at least one visit to our rheumatology practice between October 1, 2017, and March 3, 2022, were included. When prescribing a new b/tsDMARD, clinicians were alerted via a BPA that showed the most recent results for TB, HBV, and HCV. Screening proportions for TB, HBV, and HCV before BPA initiation were compared with those of eligible patients after the BPA implementation. RESULTS: A total of 711 patients pre-BPA and 257 patients post-BPA implementation were included in the study. The BPA implementation was associated with statistically significant improvement in screening for TB from 66% to 82% (P ≤ 0.001), HCV from 60% to 79% (P ≤ 0.001), hepatitis B core antibody 32% to 51% (P ≤ 0.001), and hepatitis B surface antigen from 51% to 70% (P ≤ 0.001). CONCLUSION: Implementation of a BPA can improve infectious disease screening for patients with ARD who are started on b/tsDMARDs and has potential to improve patient safety.

Return to Play, Performance, and Economic Analysis of National Football League Players After Lisfranc Injury.

Background: A Lisfranc injury can occur to either the ligament or bone, which causes instability when attempting to perform strength and balance maneuvers. Purpose/Hypothesis: The study's aims were to (1) analyze the return-to-play (RTP) rate and performance level of players in the National Football League (NFL) after Lisfranc injury and (2) determine the economic and financial impact of Lisfranc injuries to the NFL. We hypothesized that there would be a low RTP rate following Lisfranc injury in the NFL. Study Design: Case series; Level of evidence, 4. Methods: Multiple online public records were used to identify NFL players with Lisfranc injuries between the 2009 and 2020 seasons. Players were assessed according to their RTP statistics: snap count, approximate value (AV), games played, and games started. Nonparametric methods were used to compare player statistics before and after injury. Also, player salaries while injured were calculated (in 2022 US dollars after adjusting for inflation) to approximate economic loss for those players who returned to play. Results: A total of 33 NFL athletes sustained a Lisfranc injury during the study period. Most Lisfranc injuries were experienced by offensive linemen (n = 8; 24.2%), followed by running backs (n = 7; 21.2%). Overall 27 players (81.8%) returned to play after injury at a median of 11.0 months (IQR, 10.2-11.8 months). There were no significant differences between pre- and postinjury snap counts or number of games played and started. In terms of player performance, there was a statistically significant decrease in AV at 1 year postinjury (median [IQR], 6.0 [4.0-10.0] preinjury vs 5.0 [2.5-7.5] postinjury; P = .022). The overall cost of recovery amounted to $104.7 million, with quarterbacks (n = 4) accounting for the greatest cost at $32.6 million. The next 2 most expensive positions were offensive and defensive linemen (n = 5 each) at $19.4 million each. Conclusion: Our results did not support the hypothesis, as the RTP rate for NFL athletes sustaining Lisfranc injuries was 81.8%. This injury was associated with a significant decrease in AV 1 year postinjury. In terms of economic impact, quarterbacks accounted for almost one-third of expenses while constituting only 14.8% of injuries.

Parathyroid hormone-driven algorithms after thyroid surgery: Not one-size-fits-all.

BACKGROUND: Underreported variation in parathyroid hormone (PTH) assays exists. Using quality improvement methods, we aimed to develop an institution-specific PTH-based protocol to predict hypocalcemia after thyroidectomy. METHODS: We retrospectively reviewed patients who underwent total/completion thyroidectomy. A receiver operating curve (ROC) determined postoperative PTH cut-offs predictive of hypocalcemia. The stakeholders developed PTH-driven calcium management guidelines. Post-implementation outcomes were prospectively measured. RESULTS: Pre-implementation, 95 patients were assessed. PTH ≤1.5 pmol/L (14.1 pg/ml) predicted hypocalcemia (96%sensitivity), and ≥2.8 pmol/L (26.4 pg/ml) predicted normocalcemia (99%specificity) (area under curve = 0.97, SEM = 0.018). PTH on the day of and morning after surgery were identically predictive. Post-implementation, 64 patients were assessed. Hypocalcemia occurred with PTH >2.8 pmol/L in 2 cases (3.1%). Calcium over-prescribing decreased from 13.7% to 3.1% (p = 0.06). Length of stay (LOS) > 2 nights decreased from 13% to 3.1% (p = 0.05). CONCLUSION: A PTH-driven calcium management protocol post-thyroidectomy effectively reduces unnecessary calcium replacement and LOS. Given the variability in PTH assays, each institution may need to use individual cut-offs.

Increased Snap Counts Were Not Seen Prior to Lisfranc Injuries in the National Football League.

Introduction Athletes in the National Football League (NFL) subject their bodies to a great deal of physical strain, which places them at an increased risk for injury. The purpose of this study was to determine if there was an increase in snap counts played during a player's injury game or season that may have contributed to an increased risk of sustaining a Lisfranc injury in the NFL. We hypothesized that players who play more snaps than they have in seasons prior will be at an increased risk of injury. Methods NFL players with Lisfranc injuries were identified by cross-referencing multiple online resources. Information on a player's position, draft year, draft round selection, height, weight, snap counts, approximate value (AV), quarter of injury (first, second, third, fourth), quarter of a season (games one through four, five through eight, nine through twelve, thirteen through sixteen), and injured foot laterality was collected. A control group of players without a Lisfranc injury was then selected to compare performance data with our injured cohort that returned to play. Results Twenty-one NFL players, who met inclusion criteria, sustained a Lisfranc injury between the years 2013 and 2021. Players played significantly fewer snaps before sustaining a Lisfranc injury compared to their season average (33.9 ± 21.9 vs. 50.3 ± 15.8; p=<0.001), but when comparing the number of snaps played per game in their injury year with the number of snaps played per game over their career before injury, there was no significant difference (50.3 ± 15.8 vs. 45.7 ± 17.1; p=0.20). Most injuries occurred in either the first (42.9%) or second (33.3%) quarter of a regular season (games one through eight). During a game, the timing of most injuries was either the second (38.1%) or fourth (33.3%) quarter. There was no significant difference between injured players and controls post-injury between the number of average seasons played, AV, and snaps played per game. Conclusion Increased snap counts were not seen prior to Lisfranc injuries in the NFL.

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis.

Background: Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. Research Question: How does in-hospital mortality compare with intermediate- versus prophylactic-dose anticoagulation, and separately with in-hospital aspirin versus no antiplatelet therapy, in treatment of COVID-19? Study Design and Methods: Using data from 2785 hospitalized adult COVID-19 patients, we established two separate, nested cohorts of patients (1) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (2) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). Propensity score matching utilizing various markers of illness severity and other patient-specific covariates yielded treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Results: Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). Interpretation: In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis.

Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. We examined in-hospital mortality with intermediate- compared to prophylactic-dose anticoagulation, and separately with in-hospital aspirin compared to no antiplatelet therapy, in a large, retrospective study of 2785 hospitalized adult COVID-19 patients. In this analysis, we established two separate, nested cohorts of patients (a) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (b) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). To minimize bias and adjust for confounding factors, we incorporated propensity score matching and multivariable regression utilizing various markers of illness severity and other patient-specific covariates, yielding treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.

Otolaryngology Applicant Characteristics and Trends: Comparing OTO-HNS with Peer Specialties.

PURPOSE: To evaluate the recent Otolaryngology-Head and Neck Surgery (OTO-HNS) applicant characteristics, to identify which applicant characteristics are associated with successful match into OTO-HNS, and to compare OTO-HNS applicant trends and characteristics to that of peer surgical specialties (PS). MATERIALS AND METHODS: Data were obtained from official reports by the National Residency Matching Program (NRMP) for OTO-HNS, plastic and reconstructive surgery, orthopedic surgery, neurosurgery, and dermatology from 2006 to 2019. Alpha Omega Alpha (AOA) membership, United States Medical Licensing Examination (USMLE) scores, research productivity, graduation from a top-40 NIH-funded U.S. medical school, and additional graduate degree were recorded. Odds ratios (OR) were calculated to evaluate the relationship between applicant qualifications and match success. RESULTS: From 2014 to 2018, the OTO-HNS applicant pool shrunk from 443 to 333, representing the largest drop of all PS. Furthermore, OTO-HNS reported the most unfilled positions and highest match rates in 2017 (n = 14; 92.1%) and 2018 (n = 12; 94.6%) among any PS. Despite recent trends, 2019 NRMP data revealed a 38.74% increase in OTO-HNS applicant numbers compared to 2018. AOA membership (OR, 7.3; P = .030), USMLE Step 2 scores between 241 and 260 (OR, 6.5; P = .009), and research productivity (OR, 5.6; P = .005) significantly increased the odds of matching into OTO-HNS. CONCLUSIONS: Despite recent fluctuations in application trends, OTO-HNS continues to successfully match highly qualified applicants, including applicants with AOA membership, high Step 2 scores, and high research productivity. An understanding of the qualifications used to evaluate residency applicants may be helpful to both applicants and residency programs of OTO-HNS.

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

Friend or foe? Lactobacillus in the context of autoimmune disease.

Over the last decade, the interplay between the gut microbiota, the consortium of intestinal microbes that colonizes intestinal mucosal barriers, and its host immune system has been increasingly better understood. Disruption of the delicate balance between beneficial and pathogenic commensals, known as dysbiosis, contributes to a variety of chronic immunologic and metabolic diseases. Complicating this paradigm are bacterial strains that can operate paradoxically both as instigators and attenuators of inflammatory responses, depending on host background. Here, we review the role of several strains in the genus Lactobacillus within the context of autoimmune and other chronic disorders with a predominant focus on L. reuteri. While strains within this species have been shown to provide immune health benefits, they have also been demonstrated to act as a pathobiont in autoimmune-prone hosts. Beneficial functions in healthy hosts include competing with pathogenic microbes, promoting regulatory T cell development, and protecting the integrity of the gut barrier. On the other hand, certain strains can also break through a dysfunctional gut barrier, colonize internal tissues such as the spleen or liver and promote inflammatory responses in host tissues that lead to autoimmune disease. This review summarizes the manifold roles that these commensals play in the context of health and disease.

Mechanisms and consequences of gut commensal translocation in chronic diseases.

Humans and other mammalian hosts have evolved mechanisms to control the bacteria colonizing their mucosal barriers to prevent invasion. While the breach of barriers by bacteria typically leads to overt infection, increasing evidence supports a role for translocation of commensal bacteria across an impaired gut barrier to extraintestinal sites in the pathogenesis of autoimmune and other chronic, non-infectious diseases. Whether gut commensal translocation is a cause or consequence of the disease is incompletely defined. Here we discuss factors that lead to translocation of live bacteria across the gut barrier. We expand upon our recently published demonstration that translocation of the gut pathobiont Enterococcus gallinarum can induce autoimmunity in susceptible hosts and postulate on the role of Enterococcus species as instigators of chronic, non-infectious diseases.

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Benchmarker: An Unbiased, Association-Data-Driven Strategy to Evaluate Gene Prioritization Algorithms.

Genome-wide association studies (GWASs) are valuable for understanding human biology, but associated loci typically contain multiple associated variants and genes. Thus, algorithms that prioritize likely causal genes and variants for a given phenotype can provide biological interpretations of association data. However, a critical, currently missing capability is to objectively compare performance of such algorithms. Typical comparisons rely on "gold standard" genes harboring causal coding variants, but such gold standards may be biased and incomplete. To address this issue, we developed Benchmarker, an unbiased, data-driven benchmarking method that compares performance of similarity-based prioritization strategies to each other (and to random chance) by leave-one-chromosome-out cross-validation with stratified linkage disequilibrium (LD) score regression. We first applied Benchmarker to 20 well-powered GWASs and compared gene prioritization based on strategies employing three different data sources, including annotated gene sets and gene expression; genes prioritized based on gene sets had higher per-SNP heritability than those prioritized based on gene expression. Additionally, in a direct comparison of three methods, DEPICT and MAGMA outperformed NetWAS. We also evaluated combinations of methods; our results indicated that combining data sources and algorithms can help prioritize higher-quality genes for follow-up. Benchmarker provides an unbiased approach to evaluate any similarity-based method that provides genome-wide prioritization of genes, variants, or gene sets and can determine the best such method for any particular GWAS. Our method addresses an important unmet need for rigorous tool assessment and can assist in mapping genetic associations to causal function.

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

The microbiome in systemic autoimmune disease: mechanistic insights from recent studies.

PURPOSE OF REVIEW: The resident bacterial communities and the host immune system have coevolved for millennia. However, recent changes in modern societies have disrupted this coevolutionary homeostasis and contributed to a rise in immune-mediated conditions. The purpose of this review is to provide an overview of recently elucidated mechanisms of how certain taxa within the bacterial microbiome propagate autoimmunity. RECENT FINDINGS: Interactions between the bacterial microbiome with innate and adaptive immune cells propagate autoreactivity, chronic inflammation, and tissue damage in susceptible hosts. These interactions contribute to autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, which are the focus of this review. Recent findings suggest that autoimmune manifestations in genetically susceptible individuals can arise through cross-reactivity with commensal orthologs of autoantigens or commensal-mediated posttranslational modification of autoantigens. Physiologic responses to gut, oral, or skin commensal bacteria can thus be misdirected toward such autoantigens in susceptible hosts. In addition, recent studies highlight that a breach of the gut barrier and translocation of commensal bacteria to non-gut organs can trigger several autoimmune pathways that can be prevented by commensal vaccination or dietary interventions. SUMMARY: Complex host-microbiota interactions contribute to systemic autoimmunity outside the gut. On a molecular level, posttranslational modification of, and cross-reactivity with, autoantigens represent mechanisms of how the microbiota mediates autoimmunity. On a cellular level, translocation of live gut bacteria across a dysfunctional gut barrier allows for direct interactions with immune and tissue cells, instigating autoimmunity systemically.