To weight or not to weight? The effect of selection bias in 3 large electronic health record-linked biobanks and recommendations for practice.

OBJECTIVES: To develop recommendations regarding the use of weights to reduce selection bias for commonly performed analyses using electronic health record (EHR)-linked biobank data. MATERIALS AND METHODS: We mapped diagnosis (ICD code) data to standardized phecodes from 3 EHR-linked biobanks with varying recruitment strategies: All of Us (AOU; n = 244 071), Michigan Genomics Initiative (MGI; n = 81 243), and UK Biobank (UKB; n = 401 167). Using 2019 National Health Interview Survey data, we constructed selection weights for AOU and MGI to represent the US adult population more. We used weights previously developed for UKB to represent the UKB-eligible population. We conducted 4 common analyses comparing unweighted and weighted results. RESULTS: For AOU and MGI, estimated phecode prevalences decreased after weighting (weighted-unweighted median phecode prevalence ratio [MPR]: 0.82 and 0.61), while UKB estimates increased (MPR: 1.06). Weighting minimally impacted latent phenome dimensionality estimation. Comparing weighted versus unweighted phenome-wide association study for colorectal cancer, the strongest associations remained unaltered, with considerable overlap in significant hits. Weighting affected the estimated log-odds ratio for sex and colorectal cancer to align more closely with national registry-based estimates. DISCUSSION: Weighting had a limited impact on dimensionality estimation and large-scale hypothesis testing but impacted prevalence and association estimation. When interested in estimating effect size, specific signals from untargeted association analyses should be followed up by weighted analysis. CONCLUSION: EHR-linked biobanks should report recruitment and selection mechanisms and provide selection weights with defined target populations. Researchers should consider their intended estimands, specify source and target populations, and weight EHR-linked biobank analyses accordingly.

To weight or not to weight? Studying the effect of selection bias in three large EHR-linked biobanks.

Objective: To explore the role of selection bias adjustment by weighting electronic health record (EHR)-linked biobank data for commonly performed analyses. Materials and methods: We mapped diagnosis (ICD code) data to standardized phecodes from three EHR-linked biobanks with varying recruitment strategies: All of Us (AOU; n=244,071), Michigan Genomics Initiative (MGI; n=81,243), and UK Biobank (UKB; n=401,167). Using 2019 National Health Interview Survey data, we constructed selection weights for AOU and MGI to be more representative of the US adult population. We used weights previously developed for UKB to represent the UKB-eligible population. We conducted four common descriptive and analytic tasks comparing unweighted and weighted results. Results: For AOU and MGI, estimated phecode prevalences decreased after weighting (weighted-unweighted median phecode prevalence ratio [MPR]: 0.82 and 0.61), while UKB's estimates increased (MPR: 1.06). Weighting minimally impacted latent phenome dimensionality estimation. Comparing weighted versus unweighted PheWAS for colorectal cancer, the strongest associations remained unaltered and there was large overlap in significant hits. Weighting affected the estimated log-odds ratio for sex and colorectal cancer to align more closely with national registry-based estimates. Discussion: Weighting had limited impact on dimensionality estimation and large-scale hypothesis testing but impacted prevalence and association estimation more. Results from untargeted association analyses should be followed by weighted analysis when effect size estimation is of interest for specific signals. Conclusion: EHR-linked biobanks should report recruitment and selection mechanisms and provide selection weights with defined target populations. Researchers should consider their intended estimands, specify source and target populations, and weight EHR-linked biobank analyses accordingly.

A large pulmonary nodule in a rheumatoid arthritis patient treated with tofacitinib.

Pulmonary rheumatoid nodules are rare extra-articular manifestations of rheumatoid arthritis (RA). They are usually asymptomatic but may form cavities and cause clinical symptoms. These nodules are difficult to differentiate clinically and radiologically from tuberculosis, fungal infection, or lung malignancies. Histopathological studies help in the differential diagnosis of pulmonary nodules in patients with RA; however, an effective treatment for rheumatoid lung nodules has not yet been established. This study reports a case of active RA with interstitial lung disease and a large inflammatory lung nodule that was improved with tofacitinib treatment.

A Case of Palisaded Neutrophilic and Granulomatous Dermatitis Associated with an Initial Presentation in Ankylosing Spondylitis.

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is an inflammatory dermatosis associated with systemic immune-mediated diseases such as rheumatoid arthritis, systemic sclerosis, lupus erythematosus, and ulcerative colitis. Histologically, serial development of leukocytoclastic vasculitis is shown from an early stage, which can progress to palisading granuloma in the fully developed stage and to fibrosis in the final stage. A 32-year-old man presented with ankylosing spondylitis showing multiple erythematous papules on his fingers, elbows, knees, and left auricle. Histologic examination from his skin lesion revealed a perforating palisading granuloma with leukocytoclastic vasculitis, which was consistent with PNGD. Therefore, this study reported a case of PNGD accompanied by ankylosing spondylitis as an initial presentation.

Analysis of appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors as the first-line urate-lowering therapy in patients with gout using the Korean Health Insurance Review and Assessment Service database.

INTRODUCTION: We investigated the appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors (XOIs) as first-line urate-lowering therapy (ULT) in patients with gout. This was a nationwide population-based retrospective cohort study using the Korean Health Insurance Review and Assessment database. METHODS: Patients with gout aged ≥20 years who were newly initiated on XOIs, such as allopurinol or febuxostat, from July 2015 to June 2017 and received these medications for ≥6 months were analyzed and followed up until June 2019. Persistence of XOIs was compared according to the 6-month duration of colchicine prophylaxis. For additional subgroup analysis, we also compared the persistence of XOIs according to the 3-month duration of colchicine prophylaxis. RESULTS: This study included 43 926 patients. The frequencies of patients with gout receiving colchicine prophylaxis for ≥6 months and ≥3 months were 6.3% and 7.6%, respectively. Allopurinol (65.2%) was prescribed more frequently than febuxostat (34.8%). During the study period, 23 475 patients (53.4%) stopped using XOIs. Colchicine prophylaxis for ≥6 months did not significantly reduce the risk of XOI discontinuation in multivariable Cox regression models. Colchicine prophylaxis for ≥3 months was significantly associated with a lower risk of non-persistence to XOIs after adjusting for confounding factors (hazard ratio = 0.95, p = .041). CONCLUSION: Our data suggest that at least 3 months of colchicine prophylaxis may be more appropriate than at least 6 months in terms of maximizing the persistence of XOIs in patients with gout.

FAT10 Induces cancer cell migration by stabilizing phosphorylated ABI3/NESH.

The WAVE regulatory complex (WRC) is involved in various cellular processes by regulating actin polymerization. The dysregulation of WRC components is associated with cancer development. ABI family member 3 (ABI3)/new molecule including SH3 (NESH) is one of the WRC components and it has been reported that ABI3 phosphorylation can affect WRC function. Although several residues of ABI3 have been reported to be possible phosphorylation sites, it is still unclear which residues are important for the function of ABI3. Furthermore, it is unclear how the phosphorylated form of ABI3 is regulated. Here, we demonstrate that ABI3 is stabilized by its interaction with human leukocyte antigen-F adjacent transcript 10 (FAT10). Using phospho-dead or phospho-mimetic mutants of ABI3, we showed that serine 213 and 216 are important phosphorylation sites of ABI3. In particular, FAT10 has a higher affinity for the phosphorylated form of ABI3 than the non-phosphorylated form, and it stabilizes the phosphorylated form more than the non-phosphorylated form through this differential affinity. The interaction between FAT10 and the phosphorylated form of ABI3 promoted cancer cell migration. Therefore, our results suggest that FAT10 stabilizes the phosphorylated form of ABI3, which may lead to WRC activation, thereby promoting cancer cell migration.

High Baseline Neutrophil-to-Lymphocyte Ratio Could Serve as a Biomarker for Tumor Necrosis Factor-Alpha Blockers and Their Discontinuation in Patients with Ankylosing Spondylitis.

BACKGROUND: This study explores the association of neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), and platelet-to-lymphocyte (PLR) ratios with the 3-month treatment response and persistence of tumor necrosis factor-alpha (TNF-α) blockers in patients with ankylosing spondylitis (AS). METHODS: This retrospective cohort study investigated 279 AS patients who were newly initiated on TNF-α blockers between April 2004 and October 2019 and 171 sex- and age-matched healthy controls. Response to TNF-α blockers was defined as a reduction in the Bath AS Disease Activity Index of ≥50% or 20 mm, and persistence referred to the time interval from the initiation to discontinuation of TNF-α blockers. RESULTS: Patients with AS had significantly increased NLR, MLR, and PLR ratios as compared to controls. The frequency of non-response at 3 months was 3.7%, and TNF-α blockers' discontinuation occurred in 113 (40.5%) patients during the follow-up period. A high baseline NLR but not high baseline MLR and PLR showed an independently significant association with a higher risk of non-response at 3 months (OR = 12.3, p = 0.025) and non-persistence with TNF-α blockers (HR = 1.66, p = 0.01). CONCLUSIONS: NLR may be a potential marker for predicting the clinical response and persistence of TNF-α blockers in AS patients.

Status of Glucocorticoid-Induced Osteoporosis Preventive Care in Korea: A Retrospective Cohort Study on the Korean National Health Insurance Service Database.

Background and Objectives: It is crucial to prevent osteoporosis in patients receiving long-term glucocorticoid (GC) treatment. This study aimed to investigate the frequency and associated factors of preventive care for glucocorticoid-induced osteoporosis (GIOP) in Korea. Materials and Methods: Using the Korean National Health Insurance Service database, we identified 37,133 individuals aged ≥ 20 years who commenced long-term (≥90 days) oral GC between 2011 and 2012. High-quality GIOP preventive care was defined as either a bone mineral density (BMD) test, calcium and/or vitamin D supplementation, or prescription osteoporosis medications within 6 months of GC initiation. Multivariable logistic regression models were used to calculate odds ratios (ORs) for associated factors for high-quality GIOP preventive care. Results: The mean age was 49.8 years, and 18,476 (49.8%) patients were female. The frequency of high-quality GIOP preventive care was only 3.68% (BMD test, 1.46%; osteoporosis medications, 1.65%; calcium/vitamin D, 1.63%). Increasing age (OR = 2.53, p < 0.001; 40-49 years, OR = 3.99, p < 0.001; 50-59 years, OR = 5.17, p < 0.001; 60-69 years, OR = 8.07, p < 0.001; ≥70 years, respectively), systemic autoimmune disease (OR = 3.08, p < 0.001), rural residence (OR = 1.19, p = 0.046), concomitant hyperthyroidism (OR = 1.58, p = 0.007), and malignancy (OR = 1.59, p < 0.001) were significantly associated with a higher likelihood of receiving high-quality GIOP preventive care. Male sex (OR = 0.26, p < 0.001) and GC prescription in primary care clinics and nursing hospitals (OR = 0.66, p < 0.001) were associated with a lower rate of high-quality GIOP preventive care. Conclusions: Most Korean patients treated with GC did not receive appropriate preventive care for GIOP in real-world practice. More efforts are needed by clinicians to prevent, screen, and treat GIOP.

Treatment pattern, satisfaction, and productivity loss of patients with ankylosing spondylitis treated with tumor necrosis factor inhibitors in Korea: A multicenter cross-sectional observational study.

AIM: To provide in-depth understanding of real-world tumor necrosis factor inhibitor (TNFi) treatment patterns in patients with ankylosing spondylitis (AS) and treatment satisfaction, productivity loss, and associated factors. METHODS: This was a multicenter observational hybrid retrospective chart review and cross-sectional survey study. Disease activity and physical functioning were measured using the Bath AS Disease Activity Index and Bath AS Functional Index, respectively. Treatment satisfaction was determined with the Treatment Satisfaction Questionnaire for Medication (TSQM). Productivity loss was evaluated using the Korean version of the World Health Organization-Health and Work Performance Questionnaire. RESULTS: A total of 497 patients were enrolled (mean age 40.3 years, 85.3% male, mean AS duration 10 years). The mean duration of TNFi treatment was 6.2 years. Among the four TNFi considered, adalimumab (39.6%) and etanercept (23.5%) were most commonly used at study enrollment. The TSQM convenience domain score was lower than scores in the effectiveness, adverse effects, and global satisfaction domains. Subcutaneous syringe-type injection and intravenous injection were associated with lower patient convenience satisfaction than subcutaneous pen-type injection. Increased costs of lost productivity time were associated with female sex, unemployed status, and higher disease activity. CONCLUSIONS: The most frequently prescribed TNFi was adalimumab, followed by etanercept. Etanercept was used for the longest duration. More convenient treatment options may enhance overall treatment satisfaction. Considerable loss in productivity due to AS was observed in this study. To reflect patients' perspectives, further attention should be paid to factors associated with treatment satisfaction and productivity loss when selecting treatment options.

Two-year clinical outcomes after discontinuation of long-term golimumab therapy in Korean patients with rheumatoid arthritis.

BACKGROUND/AIMS: The aim of this study was to investigate long-term post-discontinuation outcomes in patients with rheumatoid arthritis (RA) who had been treated with tumor necrosis factor-α inhibitors (TNF-αi) which was then discontinued. METHODS: Sixty Korean patients with RA who participated in a 5-year GO-BEFORE and GO-FORWARD extension trials were included in this retrospective study. Golimumab was deliberately discontinued after the extension study (baseline). Patients were then followed by their rheumatologists. We reviewed their medical records for 2 years (max 28 months) following golimumab discontinuation. Patients were divided into a maintained benefit (MB) group and a loss-of-benefit (LB) group based on treatment pattern after golimumab discontinuation. The LB group included patients whose conventional disease-modifying antirheumatic drug(s) were stepped-up or added/switched (SC) and those who restarted biologic therapy (RB). RESULTS: The mean age of patients at baseline was 56.5 years and 55 (91.7%) were females. At the end of follow-up, 23 (38.3%) patients remained in the MB group. In the LB group, 75.7% and 24.3% were assigned into SC and RB subgroups, respectively. Fifty percent of patients lost MB after 23.3 months. Demographics and clinical variables at baseline were comparable between MB and LB groups except for age, C-reactive protein level, and corticosteroid use. Restarting biologic therapy was associated with swollen joint count (adjusted hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.01 to 3.55) and disease duration (adjusted HR, 1.12; 95% CI, 1.02 to 1.23) at baseline. CONCLUSION: Treatment strategies after discontinuing TNF-αi are needed to better maintain disease control and quality of life of patients with RA.

Understanding the Patterns of Serological Testing for COVID-19 Pre- and Post-Vaccination Rollout in Michigan.

Testing for SARS-CoV-2 antibodies is commonly used to determine prior COVID-19 infections and to gauge levels of infection- or vaccine-induced immunity. Michigan Medicine, a primary regional health center, provided an ideal setting to understand serologic testing patterns over time. Between 27 April 2020 and 3 May 2021, characteristics for 10,416 individuals presenting for SARS-CoV-2 antibody tests (10,932 tests in total) were collected. Relative to the COVID-19 vaccine roll-out date, 14 December 2020, the data were split into a pre- (8026 individuals) and post-vaccine launch (2587 individuals) period and contrasted with untested individuals to identify factors associated with tested individuals and seropositivity. Exploratory analysis of vaccine-mediated seropositivity was performed in 347 fully vaccinated individuals. Predictors of tested individuals included age, sex, smoking, neighborhood variables, and pre-existing conditions. Seropositivity in the pre-vaccine launch period was 9.2% and increased to 46.7% in the post-vaccine launch period. In the pre-vaccine launch period, seropositivity was significantly associated with age (10 year; OR = 0.80 (0.73, 0.89)), ever-smoker status (0.49 (0.35, 0.67)), respiratory disease (4.38 (3.13, 6.12)), circulatory disease (2.09 (1.48, 2.96)), liver disease (2.06 (1.11, 3.84)), non-Hispanic Black race/ethnicity (2.18 (1.33, 3.58)), and population density (1.10 (1.03, 1.18)). Except for the latter two, these associations remained statistically significant in the post-vaccine launch period. The positivity rate of fully vaccinated individual was 296/347(85.3% (81.0%, 88.8%)).

On cross-ancestry cancer polygenic risk scores.

Polygenic risk scores (PRS) can provide useful information for personalized risk stratification and disease risk assessment, especially when combined with non-genetic risk factors. However, their construction depends on the availability of summary statistics from genome-wide association studies (GWAS) independent from the target sample. For best compatibility, it was reported that GWAS and the target sample should match in terms of ancestries. Yet, GWAS, especially in the field of cancer, often lack diversity and are predominated by European ancestry. This bias is a limiting factor in PRS research. By using electronic health records and genetic data from the UK Biobank, we contrast the utility of breast and prostate cancer PRS derived from external European-ancestry-based GWAS across African, East Asian, European, and South Asian ancestry groups. We highlight differences in the PRS distributions of these groups that are amplified when PRS methods condense hundreds of thousands of variants into a single score. While European-GWAS-derived PRS were not directly transferrable across ancestries on an absolute scale, we establish their predictive potential when considering them separately within each group. For example, the top 10% of the breast cancer PRS distributions within each ancestry group each revealed significant enrichments of breast cancer cases compared to the bottom 90% (odds ratio of 2.81 [95%CI: 2.69,2.93] in European, 2.88 [1.85, 4.48] in African, 2.60 [1.25, 5.40] in East Asian, and 2.33 [1.55, 3.51] in South Asian individuals). Our findings highlight a compromise solution for PRS research to compensate for the lack of diversity in well-powered European GWAS efforts while recruitment of diverse participants in the field catches up.

Understanding the patterns of repeated testing for COVID-19: Association with patient characteristics and outcomes.

Importance The diagnostic tests for COVID-19 have a high false negative rate, but not everyone with an initial negative result is re-tested. Michigan Medicine, being one of the primary regional centers accepting COVID-19 cases, provided an ideal setting for studying COVID-19 repeated testing patterns during the first wave of the pandemic. Objective To identify the characteristics of patients who underwent repeated testing for COVID-19 and determine if repeated testing was associated with patient characteristics and with downstream outcomes among positive cases. Design This cross-sectional study described the pattern of testing for COVID-19 at Michigan Medicine. The main hypothesis under consideration is whether patient characteristics differed between those tested once and those who underwent multiple tests. We then restrict our attention to those that had at least one positive test and study repeated testing patterns in patients with severe COVID-19 related outcomes (testing positive, hospitalization and ICU care). Setting Demographic and clinical characteristics, test results, and health outcomes for 15,920 patients presenting to Michigan Medicine between March 10 and June 4, 2020 for a diagnostic test for COVID-19 were collected from their electronic medical records on June 24, 2020. Data on the number and types of tests administered to a given patient, as well as the sequences of patient-specific test results were derived from records of patient laboratory results. Participants Anyone tested between March 10 and June 4, 2020 at Michigan Medicine with a diagnostic test for COVID-19 in their Electronic Health Records were included in our analysis. Exposures Comparison of repeated testing across patient demographics, clinical characteristics, and patient outcomes Main Outcomes and Measures Whether patients underwent repeated diagnostic testing for SARS CoV-2 in Michigan Medicine Results Between March 10th and June 4th, 19,540 tests were ordered for 15,920 patients, with most patients only tested once (13596, 85.4%) and never testing positive (14753, 92.7%). There were 5 patients who got tested 10 or more times and there were substantial variations in test results within a patient. After fully adjusting for patient and neighborhood socioeconomic status (NSES) and demographic characteristics, patients with circulatory diseases (OR: 1.42; 95% CI: (1.18, 1.72)), any cancer (OR: 1.14; 95% CI: (1.01, 1.29)), Type 2 diabetes (OR: 1.22; 95% CI: (1.06, 1.39)), kidney diseases (OR: 1.95; 95% CI: (1.71, 2.23)), and liver diseases (OR: 1.30; 95% CI: (1.11, 1.50)) were found to have higher odds of undergoing repeated testing when compared to those without. Additionally, as compared to non-Hispanic whites, non-Hispanic blacks were found to have higher odds (OR: 1.21; 95% CI: (1.03, 1.43)) of receiving additional testing. Females were found to have lower odds (OR: 0.86; 95% CI: (0.76, 0.96)) of receiving additional testing than males. Neighborhood poverty level also affected whether to receive additional testing. For 1% increase in proportion of population with annual income below the federal poverty level, the odds ratio of receiving repeated testing is 1.01 (OR: 1.01; 95% CI: (1.00, 1.01)). Focusing on only those 1167 patients with at least one positive result in their full testing history, patient age in years (OR: 1.01; 95% CI: (1.00, 1.03)), prior history of kidney diseases (OR: 2.15; 95% CI: (1.36, 3.41)) remained significantly different between patients who underwent repeated testing and those who did not. After adjusting for both patient demographic factors and NSES, hospitalization (OR: 7.44; 95% CI: (4.92, 11.41)) and ICU-level care (OR: 6.97; 95% CI: (4.48, 10.98)) were significantly associated with repeated testing. Of these 1167 patients, 306 got repeated testing and 1118 tests were done on these 306 patients, of which 810 (72.5%) were done during inpatient stays, substantiating that most repeated tests for test positive patients were done during hospitalization or ICU care. Additionally, using repeated testing data we estimate the "real world" false negative rate of the RT-PCR diagnostic test was 23.8% (95% CI: (19.5%, 28.5%)). Conclusions and Relevance This study sought to quantify the pattern of repeated testing for COVID-19 at Michigan Medicine. While most patients were tested once and received a negative result, a meaningful subset of patients (2324, 14.6% of the population who got tested) underwent multiple rounds of testing (5,944 tests were done in total on these 2324 patients, with an average of 2.6 tests per person), with 10 or more tests for five patients. Both hospitalizations and ICU care differed significantly between patients who underwent repeated testing versus those only tested once as expected. These results shed light on testing patterns and have important implications for understanding the variation of repeated testing results within and between patients.

Comparison of persistence rates between allopurinol and febuxostat as first-line urate-lowering therapy in patients with gout: an 8-year retrospective cohort study.

INTRODUCTION/OBJECTIVES: Lifelong urate-lowering therapy (ULT) with xanthine oxidase inhibitors (XOIs), such as allopurinol and febuxostat, is the cornerstone of gout treatment. This study aimed to compare drug persistence between allopurinol and febuxostat as first-line ULT in patients with gout in real practice. METHOD: In this retrospective cohort study, we evaluated 602 patients with gout in whom allopurinol or febuxostat was newly initiated from December 2011 to November 2018 at a tertiary rheumatology centre. Persistence was defined as the duration from the first description date to the end of treatment with XOIs or the end of the study period (November 2019). RESULTS: Among the 602 gout patients, the mean age was 60.2 years and 234 (38.9%) patients had tophi. Allopurinol and febuxostat were started in 237 (39.3%) and 365 (60.6%) patients, respectively. During the study period, 282 (46.8%) patients stopped taking XOIs, and the most common reason for XOI withdrawal was poor health literacy (61.3%). The 1- and 5-year persistence rates of XOIs were 67.2% and 40.9%, respectively. In the Kaplan-Meier analysis, persistence rates of allopurinol were significantly lower than those of febuxostat (p < 0.001). In the multivariable Cox regression model, allopurinol use was a significant risk factor for discontinuation of XOIs (HR = 2.01, p < 0.001). In addition, the presence of tophi and symptom duration < 24 months was independently associated with a higher risk of XOI withdrawal. CONCLUSIONS: Long-term persistence of XOIs was suboptimal, and allopurinol had worse persistence rates than febuxostat among patients with gout. Key Points • Long-term persistence of xanthine oxidase inhibitors (XOIs) as first-line urate-lowering therapy (ULT) among patients with gout was suboptimal, and the major reason for XOI discontinuation was poor health literacy in our study. • We demonstrated that allopurinol had worse persistence rates than febuxostat among patients with gout, suggesting that febuxostat is a better option for long-term ULT in light of medication adherence in a real-world setting. • Patients with gout with tophi and shorter symptom duration were found to be at high risk for poor persistence of XOIs.

Heritability of the Fibromyalgia Phenotype Varies by Age.

OBJECTIVE: Many studies suggest a strong familial component to fibromyalgia (FM). However, those studies have nearly all been confined to individuals with primary FM, i.e., FM without any other accompanying disorder. The current 2011 and 2016 criteria for diagnosing FM construct a score using a combination of the number of painful body sites and the severity of somatic symptoms (FM score). This study was undertaken to estimate the genetic heritability of the FM score across sex and age groups to identify subgroups of individuals with greater heritability, which may help in the design of future genetic studies. METHODS: We collected data on 26,749 individuals of European ancestry undergoing elective surgery at the University of Michigan (Michigan Genomics Initiative study). We estimated the single-nucleotide polymorphism-based heritability of FM score by age and sex categories using genome-wide association study data and a linear mixed-effects model. RESULTS: Overall, the FM score had an estimated heritability of 13.9% (SE 2.9%) (P = 1.6 × 10-7 ). Estimated FM score heritability was highest in individuals ≤50 years of age (23.5%; SE 7.9%) (P = 3.0 ×10-4 ) and lowest in individuals >60 years of age (7.5%; SE 8.1%) (P = 0.41). These patterns remained the same when we analyzed FM as a case-control phenotype. Even though women had an ~30% higher average FM score than men across age categories, FM score heritability did not differ significantly by sex. CONCLUSION: Younger individuals appear to have a much stronger genetic component to the FM score than older individuals. Older individuals may be more likely to have what was previously called "secondary FM." Regardless of the cause, these results have implications for future genetic studies of FM and associated conditions.

Clinical characteristics and survival of 413 patients with systemic lupus erythematosus in southeastern areas of South Korea: A multicenter retrospective cohort study.

AIMS: To investigate demographic, clinical, laboratory, and immunological characteristics of patients with systemic lupus erythematosus (SLE) in southeastern areas of South Korea, and to perform survival analysis. METHODS: We retrospectively evaluated 413 patients with SLE diagnosed in 3 tertiary rheumatology centers in South Korea from 1992 to 2016 by reviewing their medical charts. All patients fulfilled the 1997 revised American College of Rheumatology classification criteria for SLE. RESULTS: Most patients were women (92%), and the mean (±standard deviation) age at diagnosis was 30.9 (±12.9) years. The most common clinical manifestation was leukopenia (74.3%), followed by lymphopenia (73.6%), arthritis (59.1%), malar rash (48.4%), thrombocytopenia (46.5%), oral ulcer (35.1%), and biopsy-proven lupus nephritis (31.2%). Anti-nuclear, anti-double-stranded DNA, anti-Smith, and anti-Ro antibodies were positive in 97.8%, 70.1%, 38.4%, and 63% of patients, respectively. Twenty (4.8%) patients died during a median follow-up of 83 months, and the cumulative 5-year and 10-year survival rates were 96.9% and 95.5%, respectively. The major causes of death were infection (50%) and lupus flare-up (50%). Male (hazards ratio [HR] = 7.19, P = .001), pleuritis and/or pericarditis (HR = 3.28, P = .012), childhood-onset (HR = 3.57, P = .012), and late-onset (HR = 4.65, P = .011) were independent risk factors for death. Compared with SLE cohorts in other ethnicities or countries, our patients tended to have a higher frequency of anti-Ro antibodies and hematologic disorders. CONCLUSION: This study describes clinical features of SLE in South Korea and suggests a remarkable phenotypic heterogeneity of SLE.

Protein phosphatase magnesium-dependent 1A induces inflammation in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly inflammatory autoimmune disease. Although proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-6, play a key role in the pathogenesis of RA, the causes of chronic inflammation are not fully understood. Here, we report that protein phosphatase magnesium-dependent 1A (PPM1A) levels were increased in RA synovial fluid compared with osteoarthritis (OA) synovial fluid and positively correlated with TNF levels. In addition, PPM1A expression was increased in synovial tissue from RA patients and joint tissue from a mouse model of arthritis. Finally, extracellular PPM1A induced inflammation by stimulating macrophages to produce TNF through toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MyD88) signaling pathway. Our findings suggest that extracellular PPM1A may contribute to the pathogenesis of RA by functioning as a damage-associated molecular pattern (DAMP) to induce inflammation.

UK Biobank Whole-Exome Sequence Binary Phenome Analysis with Robust Region-Based Rare-Variant Test.

In biobank data analysis, most binary phenotypes have unbalanced case-control ratios, and this can cause inflation of type I error rates. Recently, a saddle point approximation (SPA) based single-variant test has been developed to provide an accurate and scalable method to test for associations of such phenotypes. For gene- or region-based multiple-variant tests, a few methods exist that can adjust for unbalanced case-control ratios; however, these methods are either less accurate when case-control ratios are extremely unbalanced or not scalable for large data analyses. To address these problems, we propose SKAT- and SKAT-O- type region-based tests; in these tests, the single-variant score statistic is calibrated based on SPA and efficient resampling (ER). Through simulation studies, we show that the proposed method provides well-calibrated p values. In contrast, when the case-control ratio is 1:99, the unadjusted approach has greatly inflated type I error rates (90 times that of exome-wide sequencing α = 2.5 × 10-6). Additionally, the proposed method has similar computation time to the unadjusted approaches and is scalable for large sample data. In our application, the UK Biobank whole-exome sequence data analysis of 45,596 unrelated European samples and 791 PheCode phenotypes identified 10 rare-variant associations with p value < 10-7, including the associations between JAK2 and myeloproliferative disease, HOXB13 and cancer of prostate, and F11 and congenital coagulation defects. All analysis summary results are publicly available through a web-based visual server, and this availability can help facilitate the identification of the genetic basis of complex diseases.