Genetic susceptibility for major depressive disorder associates with trajectories of depressive symptoms across childhood and adolescence.

BACKGROUND: Early-onset depression during childhood and adolescence is associated with a worse course of illness and outcome than adult onset. However, the genetic factors that influence risk for early-onset depression remain mostly unknown. Using data collected over 13 years, we examined whether polygenic risk scores (PRS) that capture genetic risk for depression were associated with depressive symptom trajectories assessed from childhood to adolescence. METHODS: Data came from the Avon Longitudinal Study of Parents and Children, a prospective, longitudinal birth cohort (analytic sample = 7,308 youth). We analyzed the relationship between genetic susceptibility to depression and three time-dependent measures of depressive symptoms trajectories spanning 4-16.5 years of age (class, onset, and cumulative burden). Trajectories were constructed using a growth mixture model with structured residuals. PRS were generated from the summary statistics of a genome-wide association study of depression risk using data from the Psychiatric Genomics Consortium, UK Biobank, and 23andMe, Inc. We used MAGMA to identify gene-level associations with these measures. RESULTS: Youth were classified into six classes of depressive symptom trajectories: high/renitent (27.9% of youth), high/reversing (9.1%), childhood decrease (7.3%), late childhood peak (3.3%), adolescent spike (2.5%), and minimal symptoms (49.9%). PRS discriminated between youth in the late childhood peak, high/reversing, and high/renitent classes compared to the minimal symptoms and childhood decrease classes. No significant associations were detected at the gene level. CONCLUSIONS: This study highlights differences in polygenic loading for depressive symptoms across childhood and adolescence, particularly among youths with high symptoms in early adolescence, regardless of age-independent patterns.

Prospective study of polygenic risk, protective factors, and incident depression following combat deployment in US Army soldiers.

BACKGROUND: Whereas genetic susceptibility increases the risk for major depressive disorder (MDD), non-genetic protective factors may mitigate this risk. In a large-scale prospective study of US Army soldiers, we examined whether trait resilience and/or unit cohesion could protect against the onset of MDD following combat deployment, even in soldiers at high polygenic risk. METHODS: Data were analyzed from 3079 soldiers of European ancestry assessed before and after their deployment to Afghanistan. Incident MDD was defined as no MDD episode at pre-deployment, followed by a MDD episode following deployment. Polygenic risk scores were constructed from a large-scale genome-wide association study of major depression. We first examined the main effects of the MDD PRS and each protective factor on incident MDD. We then tested the effects of each protective factor on incident MDD across strata of polygenic risk. RESULTS: Polygenic risk showed a dose-response relationship to depression, such that soldiers at high polygenic risk had greatest odds for incident MDD. Both unit cohesion and trait resilience were prospectively associated with reduced risk for incident MDD. Notably, the protective effect of unit cohesion persisted even in soldiers at highest polygenic risk. CONCLUSIONS: Polygenic risk was associated with new-onset MDD in deployed soldiers. However, unit cohesion - an index of perceived support and morale - was protective against incident MDD even among those at highest genetic risk, and may represent a potent target for promoting resilience in vulnerable soldiers. Findings illustrate the value of combining genomic and environmental data in a prospective design to identify robust protective factors for mental health.

Physical activity offsets genetic risk for incident depression assessed via electronic health records in a biobank cohort study.

BACKGROUND: Physical activity is increasingly recognized as an important modifiable factor for depression. However, the extent to which individuals with stable risk factors for depression, such as high genetic vulnerability, can benefit from the protective effects of physical activity, remains unknown. Using a longitudinal biobank cohort integrating genomic data from 7,968 individuals of European ancestry with high-dimensional electronic health records and lifestyle survey responses, we examined whether physical activity was prospectively associated with reduced risk for incident depression in the context of genetic vulnerability. METHODS: We identified individuals with incident episodes of depression, based on two or more diagnostic billing codes for a depressive disorder within 2 years following their lifestyle survey, and no such codes in the year prior. Polygenic risk scores were derived based on large-scale genome-wide association results for major depression. We tested main effects of physical activity and polygenic risk scores on incident depression, and effects of physical activity within stratified groups of polygenic risk. RESULTS: Polygenic risk was associated with increased odds of incident depression, and physical activity showed a protective effect of similar but opposite magnitude, even after adjusting for BMI, employment status, educational attainment, and prior depression. Higher levels of physical activity were associated with reduced odds of incident depression across all levels of genetic vulnerability, even among individuals at highest polygenic risk. CONCLUSIONS: Real-world data from a large healthcare system suggest that individuals with high genetic vulnerability are more likely to avoid incident episodes of depression if they are physically active.

Economic burden associated with tuberous sclerosis complex in patients with epilepsy.

OBJECTIVES: Data on the economic burden associated with tuberous sclerosis complex (TSC) among patients with epilepsy in the United States (US) are limited. This study aimed to assess all-cause and epilepsy-related healthcare resource utilization (HRU) and healthcare costs in the US among patients with epilepsy and TSC compared with patients with epilepsy but without TSC. METHODS: This retrospective study was conducted using the Symphony Health Solutions claims database (April 1, 2017-June 30, 2019). Patients with ≥1 medical claim with a diagnosis code representing epilepsy or seizures were assigned to the cohort with TSC if they had ≥1 medical claim for TSC; the remaining patients were assigned to the cohort without TSC. Patients in the cohort with TSC were exactly matched 1:5 on demographics to patients in the cohort without TSC. All-cause and epilepsy-related HRU, medical charges, prescription drug costs, and the use of antiepileptic drugs (AEDs) were compared between the matched cohorts over the 1-year study period. RESULTS: A total of 2028 patients with epilepsy and TSC were matched to 10,140 patients with epilepsy but without TSC. Patients with TSC were more likely to have a diagnosis code for refractory epilepsy (38.7% vs. 10.2%, p < 0.001) and more likely to have used an AED (89.5% vs. 71.2%, p < 0.001) than patients without TSC over the study period. On average, patients with TSC received 2.1 distinct AEDs versus 1.3 distinct AEDs among patients without TSC. Compared with patients without TSC, patients with TSC had numerically but not statistically higher incidence rates of all-cause outpatient, clinic, office, and other visits; significantly lower rates of all-cause inpatient and emergency room visits (p < 0.001); and statistically significantly higher incidence rates of epilepsy-related outpatient, inpatient, office, and other visits (p ≤ 0.001). All-cause prescription drug costs were significantly higher among patients with TSC than patients without TSC (cost difference per patient: $14,179, p < 0.001). All-cause medical service charges were numerically higher for patients with TSC, but the differences were not statistically significant (charge difference per patient: $4293 for medical services, p = 0.707). Epilepsy-related costs were significantly higher for patients with TSC; the cost difference per patient was $14,639 for prescription costs (p < 0.001), and the charge difference per patient was $16,838 for medical charges (p = 0.019). CONCLUSION: The results of this study underscore the high epilepsy-related HRU and costs incurred by patients with epilepsy and TSC relative to those incurred by patients with epilepsy but without TSC.

Serum antigliadin antibodies in cerebellar ataxias: a systematic review and meta-analysis.

BACKGROUND: Gluten sensitivity refers to prominent immunological responses to gluten, usually in conjunction with elevated levels of serum antigliadin antibody (AGA). The association between AGA and cerebellar ataxias has been inconsistently reported. METHODS: We performed a systematic literature search and a meta-analysis to study the weighted pooled OR of idiopathic cerebellar ataxia (IDCA) cases to controls or to hereditary ataxia (HA) for AGA seropositivity using fixed effect model. RESULTS: Eleven studies were included, with a total of 847 IDCA cases, 1654 controls and 445 HA cases. IDCA cases had fourfold higher odds than controls (OR 4.28, 95% CI 3.10 to 5.90) and twofold higher odds than HA cases (OR 2.23, 95% CI 1.45 to 3.44) of having AGA seropositivity. Sensitivity analysis excluding the most weighted study, which accounted for 69% of the total weight, still showed similar associations (IDCA vs controls, OR 3.18, 95% CI 1.79 to 5.67 and IDCA vs HA, OR 1.72, 95% CI 1.03 to 2.86, respectively). The subgroup analysis showed that, when compared with controls, IDCA cases of both East Asian and Western countries had approximately threefold to fourfold higher odds to have AGA seropositivity (OR 3.41, 95% CI 1.67 to 6.97 and OR 4.53, 95% CI 3.16 to 6.49, respectively), suggesting the lack of ethnic heterogeneity. The odds of AGA seropositivity for HA cases was not significantly higher than controls (OR 1.41, 95% CI 0.82 to 2.44). CONCLUSION: Our study indicates the association between AGA and IDCA, across different geographic regions.

NIPSA: a new scale for measuring non-illness predictors of sickness absence.

OBJECTIVES: We describe the development and initial validation of a new scale for measuring non-illness factors that are important in predicting occupational outcomes, called the NIPSA (non-illness predictors of sickness absence) scale. METHODS: Forty-two questions were developed which covered a broad range of potential non-illness-related risk factors for sickness absence. 682 participants in the South East London Community Health study answered these questions and a range of questions regarding both short-term and long-term sickness absence. Factor analysis was conducted prior to examining the links between each identified factor and sickness absence outcomes. RESULTS: Exploratory factor analysis using the oblique rotation method suggested the questionnaire should contain 26 questions and extracted four factors with eigenvalues greater than 1: perception of psychosocial work environment (factor 1), perceived vulnerability (factor 2), rest-focused attitude towards recovery (factor 3) and attitudes towards work (factor 4). Three of these factors (factors 1, 2 and 3) showed significant associations with long-term sickness absence measures (p<0.05), meaning a final questionnaire that included 20 questions with three subscales. CONCLUSIONS: The NIPSA is a new tool that will hopefully allow clinicians to quickly assess for the presence of non-illness factors that may be important in predicting occupational outcomes and tailor treatments and interventions to address the barriers identified. To the best of our knowledge, this is the first time that a scale focused on transdiagnostic, non-illness-related predictors of sickness absence has been developed.

Is the prevalence of mental illness increasing in Australia? Evidence from national health surveys and administrative data, 2001-2014.

OBJECTIVES: To assess changes in the prevalence rates of probable common mental disorders (CMDs) and in rates of disability support pensions (DSPs) for people with psychiatric disorders in Australia between 2001 and 2014. DESIGN, SETTING AND PARTICIPANTS: Secondary analysis of data from five successive Australian national health surveys of representative samples of the working age population (18-65 years of age) and national data on DSP recipients. MAIN OUTCOME MEASURES: Prevalence of probable CMDs with very high symptom level (defined by a Kessler Psychological Distress Scale [K10] score of 30 or more) or with high symptom level (K10 score of 22 or more); the proportion of working age Australians receiving DSPs for psychiatric conditions. RESULTS: There was no change in the prevalence rate of probable CMDs with very high symptom levels between 2001 and 2014, but a slight decrease in the prevalence of probable CMDs with high symptoms levels, particularly among those under 45 years of age. Over the same period, the proportion of working age individuals receiving DSPs for psychiatric conditions increased by 51% (for trend, P < 0.001), equivalent to one additional DSP for every 182 working age Australians. CONCLUSIONS: Contrary to popular belief, the prevalence of probable CMDs in Australia was stable between 2001 and 2014. However, the proportion of the working age population receiving DSPs for psychiatric conditions increased dramatically over the same period. This conundrum is a major public health problem that should be further examined.

Supported employment for people with severe mental illness: systematic review and meta-analysis of the international evidence.

BACKGROUND: Individual placement and support (IPS) is a vocational rehabilitation programme that was developed in the USA to improve employment outcomes for people with severe mental illness. Its ability to be generalised to other countries and its effectiveness in varying economic conditions remains to be ascertained. AIMS: To investigate whether IPS is effective across international settings and in different economic conditions. METHOD: A systematic review and meta-analysis of randomised controlled trials comparing IPS with traditional vocational services was undertaken; 17 studies, as well as 2 follow-up studies, were included. Meta-regressions were carried out to examine whether IPS effectiveness varied according to geographic location, unemployment rates or gross domestic product (GDP) growth. RESULTS: The overall pooled risk ratio for competitive employment using IPS compared with traditional vocational rehabilitation was 2.40 (95% CI 1.99-2.90). Meta-regressions indicated that neither geographic area nor unemployment rates affected the overall effectiveness of IPS. Even when a country's GDP growth was less than 2% IPS was significantly more effective than traditional vocational training, and its benefits remained evident over 2 years. CONCLUSIONS: Individual placement and support is an effective intervention across a variety of settings and economic conditions and is more than twice as likely to lead to competitive employment when compared with traditional vocational rehabilitation.

Prevalence, psychosocial correlates and service utilization of depressive and anxiety disorders in Hong Kong: the Hong Kong Mental Morbidity Survey (HKMMS).

PURPOSE: Data on mental disorder prevalence and health service utilization required to inform healthcare management and planning are lacking in Hong Kong. The current study determined the prevalence of common mental disorders (CMD), and examined the patterns of mental health service utilization and associated factors. METHODS: We analyzed data from the Hong Kong Mental Morbidity Survey (HKMMS) of 5,719 Chinese adults aged 16-75 years in the general Hong Kong population, using the Chinese Revised Clinical Interview Schedule (CIS-R). RESULTS: The weighted prevalence estimate for any past-week CMD was 13.3 %, with mixed anxiety and depressive disorder being the most frequent diagnoses. CMD was positively associated with female gender, being divorced or separated, alcohol misuse, substance dependence, lack of regular physical exercise, and a family history of mental disorder. Among individuals with CMD, only 26 % had consulted mental health services in the past year; less than 10 % consulted general practitioners or family physicians. Lack of mental health service usage was significantly more likely in men and those with lower educational attainment. CONCLUSIONS: Apart from attention to psychosocial risks, health and lifestyle factors are important considerations for mental health promotion. Service utilization for individuals with CMD in Hong Kong remains suboptimal, and would be enhanced by strengthening community primary care.

Preventing the development of depression at work: a systematic review and meta-analysis of universal interventions in the workplace.

BACKGROUND: Depression is a major public health problem among working-age adults. The workplace is potentially an important location for interventions aimed at preventing the development of depression, but to date, the mental health impact of universal interventions in the workplace has been unclear. METHOD: A systematic search was conducted in relevant databases to identify randomized controlled trials of workplace interventions aimed at universal prevention of depression. The quality of studies was assessed using the Downs and Black checklist. A meta-analysis was performed using results from studies of adequate methodological quality, with pooled effect size estimates obtained from a random effects model. RESULTS: Nine workplace-based randomized controlled trials (RCT) were identified. The majority of the included studies utilized cognitive behavioral therapy (CBT) techniques. The overall standardized mean difference (SMD) between the intervention and control groups was 0.16 (95% confidence interval (CI): 0.07, 0.24, P = 0.0002), indicating a small positive effect. A separate analysis using only CBT-based interventions yielded a SMD of 0.12 (95% CI: -0.01, 0.24, P = 0.07). [corrected]. CONCLUSIONS: There is good quality evidence that universally delivered workplace mental health interventions can reduce the level of depression symptoms among workers. There is more evidence for the effectiveness of CBT-based programs than other interventions. Evidence-based workplace interventions should be a key component of efforts to prevent the development of depression among adults.

Matching-Adjusted Indirect Comparisons of Filgotinib vs Vedolizumab, Tofacitinib, and Ustekinumab for Moderately to Severely Active Ulcerative Colitis.

BACKGROUND: Where head-to-head trials are lacking, indirect comparative effectiveness can aid treatment decisions. We conducted matching-adjusted indirect comparisons of clinical outcomes with filgotinib vs recently approved comparators (vedolizumab, tofacitinib, ustekinumab) in patients with moderately to severely active ulcerative colitis (UC). METHODS: Individual patient data from the SELECTION trial (NCT02914522) for filgotinib 200 mg were weighted to match average baseline characteristics of active treatment and placebo arms in comparator trials. Efficacy outcomes were compared for biologic-naive and biologic-experienced subgroups in induction and maintenance populations, if data were available. Safety and health-related quality of life outcomes were compared in the overall maintenance population. RESULTS: Filgotinib had a similar effect on efficacy outcomes compared with tofacitinib, ustekinumab, and subcutaneous vedolizumab in both the induction and maintenance populations. Filgotinib showed improved clinical response vs intravenous (IV) vedolizumab (odds ratio, 2.4; 95% confidence interval [CI], 1.0 to 5.5; P < .05) among the biologic-experienced induction population, and improved corticosteroid-free clinical remission (odds ratio, 15.2; 95% CI, 1.6 to 139.9; P < .05) among the biologic-naive maintenance population. Improved efficacy outcomes were reported with filgotinib compared with ustekinumab among the maintenance population. Higher estimates of serious adverse events were reported for filgotinib compared with vedolizumab IV 300 mg and tofacitinib 5 mg; however, imbalances were noted in their placebo groups. Health-related quality of life outcomes were similar between filgotinib and comparators. CONCLUSIONS: Matching-adjusted indirect comparison results suggest superiority of filgotinib 200 mg over vedolizumab IV in terms of clinical response and corticosteroid-free clinical remission in certain patient populations, noting small sample sizes and wide CIs, which may aid the selection of advanced therapies for moderately to severely active UC. A potential increased risk of serious adverse events was reported for filgotinib 200 mg vs vedolizumab IV and tofacitinib 5 mg, but findings should be interpreted with caution owing to underlying imbalances observed between the placebo groups of SELECTION and comparator trials.

Matching-adjusted indirect comparisons between filgotinib and subcutaneous vedolizumab, tofacitinib, and ustekinumab demonstrated similar effects on efficacy, safety, and health-related quality of life in patients with ulcerative colitis. Clinical response and corticosteroid-free remission were improved with filgotinib compared with intravenous vedolizumab.

Clinical and Economic Burden in Patients With Systemic Lupus Erythematosus During the First Year After Initiating Oral Corticosteroids: A Retrospective US Database Study.

OBJECTIVE: To characterize health care resource utilization (HCRU), health care costs, and adverse events (AEs) among patients with systemic lupus erythematosus (SLE) initiating oral corticosteroids (OCS) versus patients without OCS use. METHODS: In this retrospective cohort study (GSK Study 213061), eligible patients (aged ≥5 years at first OCS claim) with SLE from the IQVIA Real-World Data Adjudicated Claims-US database (January 2006 to July 2019) had continuous enrollment during the 6-month preindex (baseline) and 12-month postindex (observation) periods and one or more inpatient or emergency department SLE diagnosis codes or two or more outpatient SLE diagnosis codes during baseline. The "OCS-initiator cohort" comprised patients with one or more OCS pharmacy claims during the study period and no evidence of preindex OCS use and was classified into three exposure categories based on the number of 6-month periods of more than 5 mg/day of OCS use (0, 1, 2). The "no-OCS-use cohort" comprised patients without OCS claims, although patients may have received OCS prior to the study period. Clinical and economic outcomes were reported over the observation period. RESULTS: Adjusted health care costs differed significantly ($6542 [95% confidence interval (CI): $5761-$7368], $19,149 [95% CI: $16,954-$21,471], $28,985 [95% CI: $25,546-$32,885]). HCRU incidence rates were significantly greater for all OCS-initiator exposure categories (n = 16,216) versus the no-OCS-use cohort (n = 11,137; adjusted incidence rate ratios [95% CI]: 1.22 [1.19-1.24], 1.39 [1.34-1.43], 1.66 [1.60-1.73]). OCS-related AEs were experienced by 67.1% to 74.1% of patients with OCS initiation, most commonly affecting the immune system. CONCLUSION: Within 12 months of OCS initiation, patients with SLE experienced substantial clinical and economic burden, which may imply a need to minimize OCS use.

Prolonged oral corticosteroid treatment in patients with systemic lupus erythematosus: An evaluation of 12-month economic and clinical burden.

BACKGROUND: Prolonged, high-dose corticosteroid treatment for systemic lupus erythematosus (SLE) is associated with substantial health care costs, health care resource utilization (HCRU), and adverse events (AEs). OBJECTIVE: To compare all-cause health care costs, HCRU, and oral corticosteroid (OCS)-related AEs among patients with prevalent OCS use and patients without OCS use. METHODS: This retrospective, longitudinal cohort study (GSK study 214100) used claims data from the IQVIA Real-World Data Adjudicated Claims - US, IQVIA, Inc, database between January 1, 2006, and July 31, 2019, to identify patients with SLE. Patients with at least 1 OCS pharmacy claim during the study period and continuous OCS use during the 6-month pre-index (baseline) period (index date is the date of the first OCS claim following 6 months' continuous use) formed the "prevalent OCS use cohort." This cohort was subdivided based on the level of OCS exposure during the 12-month observation period, ie, the number of 6-month periods of greater than 5 mg/day OCS use (0, 1, or 2). Patients without OCS claims formed the "no OCS use cohort." All patients had continuous enrollment during the baseline and observation periods, had at least 1 inpatient or at least 2 outpatient SLE diagnosis codes during baseline, and were aged at least 5 years at index. A 2-part model, a generalized linear regression model with a negative binomial distribution, and a multivariate logistic regression model were used to compare health care costs, HCRU, and the odds of developing an OCS-related AE between cohorts, respectively. RESULTS: The no OCS use and prevalent OCS use cohorts included 21,517 and 16,209 patients, respectively. Adjusted health care cost differences (95% CI) were significantly lower for the no OCS use cohort vs all prevalent OCS use exposure categories ($5,439 [$4,537-$6,371] vs $17,856 [$16,368-$19,498]), driven by inpatient stays and outpatient visits; HCRU was also significantly lower (adjusted incidence rate ratios vs no OCS use cohort [95% CI]: 1.20 [1.16-1.23] vs 1.47 [1.41-1.52]). Health care costs and HCRU increased with increasing length of OCS exposure. OCS-related AEs occurred more frequently for all prevalent OCS use exposure categories vs the no OCS use cohort (odds ratio [95% CI]: 1.39 [1.25-1.55] vs 2.32 [2.02-2.68]), driven by hematologic/oncologic and immune system-related AEs. The mean (SD) average daily dose of OCS increased with increasing periods of prevalent OCS use (2.5 [1.3], 6.9 [31.1], and 34.6 [1,717.3] mg/day, respectively, for patients with 0, 1, and 2 periods of OCS use). CONCLUSIONS: Prevalent OCS use incurs a substantial clinical and economic burden, highlighting the need for restricted OCS doses and durations. DISCLOSURES: This study (GSK Study 214100) was funded by GSK. GSK was involved in designing the study, contributing to the collection, analysis, and interpretation of the data, supporting the authors in the development of the manuscript, and funding the medical writing assistance. All authors, including those employed by GSK, approved the content of the submitted manuscript and were involved in the decision to submit the manuscript for publication. Dr DerSarkissian, Dr Duh, and Mr Benson are employees of Analysis Group, which received research funding from GSK to conduct this study. Dr Wang, Ms Gu, and Mr Vu are former employees of Analysis Group. Mr Bell is an employee of GSK and holds stocks and shares in the company. Ms Averell and Dr Huang are former employees of GSK and held stocks and shares in the company at the time of the study.

Health Care Costs With Sustained Oral Corticosteroid Use in Systemic Lupus Erythematosus.

PURPOSE: The goal of this study was to compare health care costs, health care resource utilization, and adverse events associated with sustained oral corticosteroid (OCS) use versus no OCS use in systemic lupus erythematosus. METHODS: This retrospective cohort study used claims data (January 1, 2006-July 31, 2019) from patients with systemic lupus erythematosus aged ≥5 years with ≥24 months of continuous enrollment. Health care costs, health care resource utilization, and OCS-related adverse events were assessed. The sustained OCS cohort (defined as ≥12 months of continuous OCS use) was divided into exposure categories based on the number of 6-month classification periods with >5 mg/d OCS (0, 1-2, or 3-4). FINDINGS: Of the 6234 patients in the sustained OCS use cohort, there were 1587 (25.5%) patients with 0 periods of >5 mg/d OCS use, 2087 (33.5%) patients with 1 to 2 periods of >5 mg/d OCS use, and 2560 (41.1%) patients with 3 to 4 periods of >5 mg/d OCS use; the no OCS use cohort included 7828 patients. Adjusted health care cost differences (95% CIs) were significantly greater for patients with 0, 1 to 2, and 3 to 4 periods of OCS use >5 mg/d versus the no OCS use cohort ($7774 [5426-10,223], $21,738 [18,898-25,321], and $30,119 [26,492-33,774], respectively). A higher proportion of patients in all OCS exposure categories required health care resource utilization (≥99.7% vs 93.4%) and experienced OCS-related adverse events (94.3%-96.8% vs 82.6%) versus the no OCS use cohort, with more periods of OCS use >5 mg/d associated with increased health care resource utilization and adverse events. IMPLICATIONS: Sustained OCS use in systemic lupus erythematosus was associated with high economic burden, health care resource utilization, and OCS-related adverse events. These data highlight the need for health care providers to carefully consider OCS use in systemic lupus erythematosus.

Re-sequencing of ankyrin 3 exon 48 and case-control association analysis of rare variants in bipolar disorder type I.

OBJECTIVES: Genome-wide association studies (GWAS) recently identified ankyrin 3 (ANK3) as a candidate gene for bipolar disorder type I (BPD-I). Because the GWAS suggested multiple common haplotypes associated with BPD-I (with odds ratio ~1.3), we hypothesized that rare variants within these common haplotypes might increase risk for BPD-I. METHODS: We undertook a project in which the serine-rich domain-tail domain (SRD-TD)-encoding exon of ANK3 was amplified from genomic DNA (gDNA) of 384 BPD-I patients and re-sequenced by next generation sequencing (NGS; SOLiD™). RESULTS: We confirmed 18 novel mis-sense rare variants and one novel insertion/deletion variant within the SRD-TD exon, many of which change amino acid residues with extremely high evolutionary conservation. We genotyped most of these mis-sense variants in ≥ 1000 BPD-I and ≥ 1000 control individuals. We found no statistically significant association of any of the rare variants detected with BPD-I. CONCLUSIONS: Thus, we conclude that rare variants within the re-sequenced structural domains of ANK3 exon 48 do not contribute to BPD-I.

Patient Preferences for Attributes of Biologic Treatments in Moderate to Severe Asthma: A Discrete Choice Experiment Study.

Purpose: Multiple biologics are available for moderate to severe asthma. Given the important relationship between patient engagement in healthcare decision-making and health outcomes, patient preference is an increasingly important consideration. This study elicited patients' preferences for attributes of biologic therapies for moderate to severe asthma. Patient and Methods: A discrete choice experiment (DCE) questionnaire was designed to collect data from an existing survey panel of adults with moderate to severe asthma in the United States. Patients were asked to select their preferred hypothetical treatment from profiles with varying attributes related to efficacy, safety, and administration convenience. Conditional logit regression models were used to quantify patient preferences. Results: Of 301 eligible patients who completed the survey, the mean age was 46.7±15.1 years and 71.8% were female. Patients had asthma for 22.5±16.3 years on average, and most (97.3%) had experienced ≥1 asthma attack in the past 12 months. Among treatment attributes examined, patients most valued the absence of a black box warning for the risk of a life-threatening allergic reaction, effectiveness of reducing severe asthma exacerbations, and improvement in lung function (all p < 0.001). Home administration setting for subcutaneous injections (vs doctor's office/clinic) (p = 0.009) and ability of a biologic to treat additional chronic condition(s) (p < 0.05) were also considered important. Dosing frequency and type of injection device were not significant factors. Conclusion: Patients with moderate to severe asthma valued efficacy and safety over convenience attributes when selecting biologic treatments. Awareness of these preferences can facilitate patient-physician shared decision-making when managing moderate to severe asthma in clinical practice.

Chronic obstructive pulmonary disease is associated with an increased risk of herpes zoster: A retrospective United States claims database analysis.

Chronic obstructive pulmonary disease (COPD) has been reported as a potential risk factor for developing herpes zoster (HZ). We aimed at comparing incidence rates of HZ between people with versus without COPD in the US. This retrospective cohort study used data from Optum's de-identified Clinformatics Data Mart database from 1/1/2013 through 12/31/2018. We identified two cohorts of people ≥40 years without prior HZ, HZ vaccination, postherpetic neuralgia (PHN) or HZ ophthalmicus: those with (COPD+) and those without (COPD-) a COPD diagnosis. Adjusted incidence rate ratios (aIRRs) of HZ and PHN were calculated using generalized linear models, controlling for the propensity score of being diagnosed with COPD and relevant demographic and clinical characteristics. People in the COPD+ cohort (n = 161 970) were considerably older, had more comorbidities and were more likely to use corticosteroids than those in the COPD- cohort (n = 9 643 522). The incidence rate of HZ was 5.7-fold higher in the COPD+ versus COPD- cohorts (13.0 vs. 2.3 per 1000 person-years [PY]; aIRR, 2.77; 95% confidence interval [CI], 2.69 to 2.85; P < 0.001). The unadjusted incidence rate of PHN was 1.7-fold higher in the COPD+/HZ+ versus COPD-/HZ+ cohort (64.8 vs. 37.1 per 1000 PY), but not after adjustment (aIRR, 1.07; 95% CI, 0.79 to 1.45). HZ and PHN incidence rates increased with age. After adjustment, COPD+ adults had a 2.8-fold increased risk of developing HZ. These results may help to increase awareness about potential risk factors for HZ and highlight the need for vaccination among those at increased risk.

Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression.

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yet been explored in humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n = 807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n = 31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE) by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n = 6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified a statistical interaction between caregiver physical or emotional abuse during ages 1-5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiology through a sensitive period lens.

Increased Health Care Resource Utilization and Costs Associated with Herpes Zoster Among Patients Aged ≥50 Years with Chronic Obstructive Pulmonary Disease in the United States.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are potentially at increased risk of herpes zoster (HZ). Little is known about the impact of an HZ episode on health care resource utilization (HRU) and costs among patients with COPD. METHODS: This retrospective cohort study of individuals aged ≥50 years in the United States (US) used administrative claims data from Optum's de-identified Clinformatics Data Mart Database for commercially insured and Medicare Advantage members (2013-2018). Two cohorts of patients with COPD, with HZ (COPD+/HZ+) and without HZ (COPD+/HZ-), were identified. All-cause and COPD-related HRU rates and costs (2018 US dollars) were compared between cohorts for up to 12 months of follow-up. Comparisons were controlled for baseline differences through propensity score adjustment. RESULTS: A total of 3415 COPD+/HZ+ and 35,360 COPD+/HZ- patients (mean ages 73.2 ± 9.0 and 72.4 ± 9.4 years, respectively) were identified. Patients in the COPD+/HZ+ versus COPD+/HZ- cohort had increased use of all-cause (adjusted incidence rate ratio [aIRR] 1.17; 95% confidence interval [CI] 1.14, 1.21) and COPD-related (aIRR 1.27; 95% CI 1.21, 1.34) medical services (both P<0.001) and higher mean total all-cause ($4140 versus $3749 per person per month [PPPM]; adjusted cost difference +$313 PPPM) and COPD-related ($1541 versus $1231 PPPM; +$152 PPPM) costs (both P<0.004) in the year after HZ. CONCLUSIONS: HRU and cost burden is higher in patients with COPD with vs without HZ. These results could help to estimate the potential cost benefits of HZ vaccination among patients with COPD.