Development and validation of a claims-based algorithm to identify moderate exacerbations in patients with asthma treated in the US.

INTRODUCTION: Definitions of moderate asthma exacerbation have been inconsistent, making their economic burden difficult to assess. An algorithm to accurately identify moderate exacerbations from claims data is needed. METHODS: A retrospective cohort study of Reliant Medical Group patients aged ≥18 years, with ≥1 prescription claim for inhaled corticosteroid/long-acting ß2-agonist, and ≥1 medical claim with a diagnosis code for asthma was conducted. The objective was to refine current algorithms to identify moderate exacerbations in claims data and assess the refined algorithm's performance. Positive and negative predictive values (PPV and NPV) were assessed via chart review of 150 moderate exacerbations events and 50 patients without exacerbations. Sensitivity analyses assessed alternative algorithms and compared healthcare resource utilization (HRU) between algorithm-identified patients (claims group) and those confirmed by chart review (confirmed group) to have experienced a moderate exacerbation. RESULTS: Algorithm-identified moderate exacerbations were: visit of ≤1 day with an asthma exacerbation diagnosis OR visit of ≤1 day with selected asthma diagnoses AND ≥1 respiratory pharmacy claim, excluding systemic corticosteroids, within 14 days after the first claim. The algorithm's PPV was 42%; the NPV was 78%. HRU was similar for both groups. CONCLUSION: This algorithm identified potential moderate exacerbations from claims data; however, the modest PPV underscores its limitations in identifying moderate exacerbations, although performance was partially due to identification of previously unidentified severe exacerbations. Application of this algorithm in future claims-based studies may help quantify the economic burden of moderate and severe exacerbations in asthma when an algorithm identifying severe exacerbations is applied first.

Frequency and economic burden of exacerbations in inhaled corticosteroid/long-acting beta-agonist-treated patients with asthma: A retrospective US claims study.

INTRODUCTION: Despite adherence to inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) therapy, many patients with asthma experience moderate exacerbations. Data on the impact of moderate exacerbations on the healthcare system are limited. This study assessed the frequency and economic burden of moderate exacerbations in patients receiving ICS/LABA. METHODS: Retrospective, longitudinal study analyzed data from Optum's de-identified Clinformatics® Data Mart Database recorded between October 1, 2015, and December 31, 2019. Eligibility criteria included patients ≥18 years of age with ≥1 ICS/LABA claim and ≥1 medical claim for asthma in the 12 months pre-index (first ICS/LABA claim). Primary objectives included describing moderate exacerbation frequency, and associated healthcare resource utilization (HRU) and costs. A secondary objective was assessing the relationship between moderate exacerbations and subsequent risk of severe exacerbations. Patients were stratified by moderate exacerbation frequency in the 12 months post index. Moderate exacerbations were identified using a newly developed algorithm. RESULTS: In the first 12 months post index 61.6% of patients experienced ≥1 moderate exacerbation. Mean number of asthma-related visits was 4.1 per person/year and median total asthma-related costs was $3544. HRU and costs increased with increasing exacerbation frequency. Outpatient and inpatient visits accounted for a similar proportion of these costs. Moderate exacerbations were associated with an increased rate and risk of future severe exacerbations (incidence rate ratio, 1.56; hazard ratio, 1.51 [both p < 0.001]). CONCLUSIONS: This study highlighted that a high proportion of patients continue to experience moderate exacerbations despite ICS/LABA therapy and subsequently experience increased economic burden and risk of future severe exacerbations.

Treatment Patterns and Clinical Outcomes Among Patients With Metastatic Prostate Cancer Harboring Homologous Recombination Repair Mutations.

BACKGROUND: There is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations. METHODS: Medical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014. RESULTS: Among 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy. CONCLUSIONS: Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.

Real-world overall survival with abiraterone acetate versus enzalutamide in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

BACKGROUND: There are no large head-to-head phase 3 clinical trials comparing overall survival (OS) for abiraterone and enzalutamide. This study used Medicare claims data to compare OS in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) who initiated abiraterone or enzalutamide. METHODS: This retrospective analysis of the Medicare database (2009-2020) included adult men with ≥1 claim for prostate cancer, metastatic diagnosis, and no prior chemotherapy or novel hormone therapy who initiated first-line (1L) abiraterone or enzalutamide in the index period (September 10, 2014 to May 31, 2017). Cox proportional-hazards models with inverse probability treatment-weighting (IPTW) were used to compare OS between abiraterone- and enzalutamide-treated patients, adjusting for baseline characteristics. Subgroup analyses by baseline characteristics were also conducted. RESULTS: Overall, 5506 patients who received 1L abiraterone (n = 2911) or enzalutamide (n = 2595) were included. Median follow-up was comparable in both cohorts (abiraterone, 19.1 months; enzalutamide, 20.3 months). IPTW-adjusted median OS (95% CI) was 20.6 months (19.7‒21.4) for abiraterone and 22.5 months (21.2‒23.8) for enzalutamide, with an IPTW-adjusted hazard ratio (95% CI) of 1.10 (1.04-1.16). Median OS was significantly shorter for abiraterone versus enzalutamide in patients ≥75 years old; White patients; patients with baseline diabetes, cardiovascular disease, both diabetes and cardiovascular disease, and renal disease; and across all socioeconomic strata. CONCLUSIONS: In the Medicare chemotherapy-naïve mCRPC population, 1L abiraterone was associated with worse OS versus enzalutamide in the overall population and among subgroups with older age and comorbidities, supporting findings from previous real-world studies and demonstrating a disparity in outcomes.

Real-World Effectiveness of Sotrovimab for the Early Treatment of COVID-19: Evidence from the US National COVID Cohort Collaborative (N3C).

BACKGROUND AND OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has been an unprecedented healthcare crisis, one that threatened to overwhelm health systems and prompted an urgent need for early treatment options for patients with mild-to-moderate COVID-19 at high risk for progression to severe disease. Randomised clinical trials established the safety and efficacy of monoclonal antibodies (mAbs) early in the pandemic; in vitro data subsequently led to use of the mAbs being discontinued, without clear evidence on how these data were linked to outcomes. In this study, we describe and compare real-world outcomes for patients with mild-to-moderate COVID-19 at high risk for progression to severe COVID-19 treated with sotrovimab versus untreated patients. METHODS: Electronic health records from the National COVID Cohort Collaborative (N3C) were used to identify US patients (aged ≥ 12 years) diagnosed with COVID-19 (positive test or ICD-10: U07.1) in an ambulatory setting (27 September 2021-30 April 2022) who met Emergency Use Authorization (EUA) high-risk criteria. Patients receiving the mAb sotrovimab within 10 days of diagnosis were assigned to the sotrovimab cohort, with the day of infusion as the index date. Untreated patients (no evidence of early mAb treatment, prophylactic mAb or oral antiviral treatment) were assigned to the untreated cohort, with an imputed index date based on the time distribution between diagnosis and sotrovimab infusion in the sotrovimab cohort. The primary endpoint was hospitalisation or death (both all-cause) within 29 days of index, reported as descriptive rate and adjusted [via inverse probability of treatment weighting (IPTW)] odds ratio (OR) and 95% confidence interval (CI). RESULTS: Of nearly 2.9 million patients diagnosed with COVID-19 during the analysis period, 4992 met the criteria for the sotrovimab cohort, and 541,325 were included in the untreated cohort. Before weighting, significant differences were noted between the cohorts; for example, patients in the sotrovimab cohort were older (60 years versus 54 years), were more likely to be white (85% versus 75%) and met more EUA criteria (mean 3.1 versus 2.2) versus the untreated cohort. The proportions of patients with 29-day hospitalisation or death were 3.5% (176/4992) and 4.5% (24,163/541,325) in the sotrovimab and untreated cohorts, respectively (unadjusted OR: 0.78; 95% CI: 0.67, 0.91; p = 0.001). In adjusted analysis, sotrovimab was associated with a 25% reduction in the odds of hospitalisation or death compared with the untreated cohort (IPTW-adjusted OR: 0.75; 95% CI: 0.61, 0.92; p = 0.005). CONCLUSIONS: Sotrovimab demonstrated clinical effectiveness in preventing severe outcomes (hospitalisation, mortality) in the period 27 September 2021-30 April 2022, which included Delta and Omicron BA.1 variants and an early surge of Omicron BA.2 variant.

Cost-Effectiveness Analysis of Pembrolizumab as an Adjuvant Treatment of Resected Stage IIB or IIC Melanoma in the United States.

INTRODUCTION: Pembrolizumab was approved in the US as adjuvant treatment of patients with stage IIB or IIC melanoma post-complete resection, based on prolonged recurrence-free survival vs. placebo in the Phase 3 KEYNOTE-716 trial. This study aimed to evaluate the cost-effectiveness of pembrolizumab vs. observation as adjuvant treatment of stage IIB or IIC melanoma from a US health sector perspective. METHODS: A Markov cohort model was constructed to simulate patient transitions among recurrence-free, locoregional recurrence, distant metastasis, and death. Transition probabilities from recurrence-free and locoregional recurrence were estimated via multistate parametric modeling based on patient-level data from an interim analysis (data cutoff date: 04-Jan-2022). Transition probabilities from distant metastasis were based on KEYNOTE-006 data and network meta-analysis. Costs were estimated in 2022 US dollars. Utilities were based on applying US value set to EQ-5D-5L data collected in trial and literature. RESULTS: Compared to observation, pembrolizumab increased total costs by $80,423 and provided gains of 1.17 quality-adjusted life years (QALYs) and 1.24 life years (LYs) over lifetime, resulting in incremental cost-effectiveness ratios of $68,736/QALY and $65,059/LY. The higher upfront costs of adjuvant treatment were largely offset by reductions in costs of subsequent treatment, downstream disease management, and terminal care, reflecting the lower risk of recurrence with pembrolizumab. Results were robust in one-way sensitivity and scenario analyses. At a $150,000/QALY threshold, pembrolizumab was cost-effective vs. observation in 73.9% of probabilistic simulations that considered parameter uncertainty. CONCLUSION: As an adjuvant treatment of stage IIB or IIC melanoma, pembrolizumab was estimated to reduce recurrence, extend patients' life and QALYs, and be cost-effective versus observation at a US willingness-to-pay threshold.

Regression discontinuity design to evaluate the effect of statins on myocardial infarction in electronic health records.

Regression discontinuity design (RDD) is a quasi-experimental method intended for causal inference in observational settings. While RDD is gaining popularity in clinical studies, there are limited real-world studies examining the performance on estimating known trial casual effects. The goal of this paper is to estimate the effect of statins on myocardial infarction (MI) using RDD and compare with propensity score matching and Cox regression. For the RDD, we leveraged a 2008 UK guideline that recommends statins if a patient's 10-year cardiovascular disease (CVD) risk score > 20%. We used UK electronic health record data from the Health Improvement Network on 49,242 patients aged 65 + in 2008-2011 (baseline) without a history of CVD and no statin use in the two years prior to the CVD risk score assessment. Both the regression discontinuity (n = 19,432) and the propensity score matched populations (n = 24,814) demonstrated good balance of confounders. Using RDD, the adjusted point estimate for statins on MI was in the protective direction and similar to the statin effect observed in clinical trials, although the confidence interval included the null (HR = 0.8, 95% CI 0.4, 1.4). Conversely, the adjusted estimates using propensity score matching and Cox regression remained in the harmful direction: HR = 2.42 (95% CI 1.96, 2.99) and 2.51 (2.12, 2.97). RDD appeared superior to other methods in replicating the known protective effect of statins with MI, although precision was poor. Our findings suggest that, when used appropriately, RDD can expand the scope of clinical investigations aimed at causal inference by leveraging treatment rules from everyday clinical practice.

Propensity Scores in Health Disparities Research: The Example of Cognitive Aging and the Hispanic Paradox.

BACKGROUND: Individuals of Mexican ancestry in the United States experience substantial socioeconomic disadvantages compared with non-Hispanic white individuals; however, some studies show these groups have similar dementia risk. Evaluating whether migration selection factors (e.g., education) associated with risk of Alzheimer disease and related dementia (ADRD) explain this paradoxical finding presents statistical challenges. Intercorrelation of risk factors, common with social determinants, could make certain covariate patterns very likely or unlikely to occur for particular groups, which complicates their comparison. Propensity score (PS) methods could be leveraged here to diagnose nonoverlap and help balance exposure groups. METHODS: We compare conventional and PS-based methods to examine differences in cognitive trajectories between foreign-born Mexican American, US-born Mexican American, and US-born non-Hispanic white individuals in the Health and Retirement Study (1994-2018). We examined cognition using a global measure. We estimated trajectories of cognitive decline from linear mixed models adjusted for migration selection factors also associated with ADRD risk conventionally or with inverse probability weighting. We also employed PS trimming and match weighting. RESULTS: In the full sample, where PS overlap was poor, unadjusted analyses showed both Mexican ancestry groups had worse baseline cognitive scores but similar or slower rates of decline compared with non-Hispanic white adults; adjusted findings were similar, regardless of method. Focusing analyses on populations where PS overlap was improved (PS trimming and match weighting) did not alter conclusions. CONCLUSIONS: Attempting to equalize groups on migration selection and ADRD risk factors did not explain paradoxical findings for Mexican ancestry groups in our study.

Disease progression rates in ambulatory Duchenne muscular dystrophy by steroid type, patient age and functional status.

Aim: To examine benefits of corticosteroids for Duchenne muscular dystrophy (DMD) by age and disease progression. Methods: Data from daily steroid users (placebo-treated) were pooled from four phase 2b/3 trials in DMD. Outcomes assessed overall and among subgroups included changes from baseline to 48 weeks in six-minute walk distance (6MWD), timed function tests and North Star Ambulatory Assessment total score. Results: Among 231 patients receiving deflazacort (n = 127) or prednisone (n = 104), observed differences in 6MWD favoring deflazacort over prednisone were significant for patients with relatively older age (≥8-years-old), greater disease progression (baseline timed stand from supine ≥5 s), or longer corticosteroid use (>3 years). Conclusion: Daily deflazacort had greater benefits than daily prednisone particularly among older/more progressed patients.

Depressive symptoms mediate the relationship between sustained food insecurity and cognition: a causal mediation analysis.

PURPOSE: This study aimed to investigate the association of change in food insecurity over time with cognitive function in midlife, and whether depressive symptoms mediated that relationship. METHODS: We used longitudinal data from the Coronary Artery Risk Development in Young Adults study. Change in food insecurity in 2000-2005 was coded as "persistently food-secure," "persistently food-insecure," "became food-insecure," and "became food-secure." Depressive symptoms were measured in 2010, and cognitive function was measured in 2015. Multivariable linear regression controlled for sociodemographic and cardiovascular health factors was used. We also conducted causal mediation analysis. RESULTS: Our study population included 2448 participants (57.23% female and 43.18% Black, mean age = 40.31 in 2000). Compared with persistent food security, persistently and became food-insecure were associated with worse cognition, particularly with processing speed (ßpersistent = -0.20 standard unit, 95% CI = -0.36, -0.04; ßbecame = -0.17, 95% CI = -0.31, -0.03), and these associations appeared mediated by depressive symptoms (proportion-mediated = 14% for persistently food-insecure and 18% for became food-insecure). CONCLUSIONS: Persistent and transition to food insecurity were associated with worse cognition, both directly and indirectly through increasing depressive symptoms. Targeting food insecurity or depressive symptoms among persistently or became food-insecure individuals may have the potential to slow premature cognitive aging.

Functional and Clinical Outcomes Associated with Steroid Treatment among Non-ambulatory Patients with Duchenne Muscular Dystrophy1.

BACKGROUND: Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited. OBJECTIVE: Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD. METHODS: Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 [PUL] and Egen Klassifikation Scale Version 2 [EK] scale) and by cardiac and pulmonary function (left ventricular ejection fraction [LVEF], forced vital capacity [FVC] % -predicted, cough peak flow [CPF]). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and body composition metrics were analyzed descriptively and in multivariate models. RESULTS: This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n = 40 [deflazacort], n = 29 [prednisone], n = 17 [no steroids]). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p < 0.05). Both steroids were associated with significantly slower average declines in LVEF, improvement in CPF, and slower declines in total PUL score and EK total score vs. no steroids; deflazacort was associated with slower declines in total PUL score vs. prednisone (all p < 0.05). Both steroids also preserved functional abilities considered especially important to quality of life, including the abilities to perform hand-to-mouth function and to turn in bed at night unaided (all p < 0.05 vs. no steroids). CONCLUSIONS: Steroid use after loss of ambulation in DMD was associated with delayed progression of important pulmonary, cardiac, and upper extremity functional deficits, suggesting some benefits of deflazacort over prednisone.

Association of Low Hourly Wages in Middle Age With Faster Memory Decline in Older Age: Evidence From the Health and Retirement Study.

Little research has investigated the long-term relationship between low wages and memory decline, despite the growing share of low-wage workers in the US labor market. Here, we examined whether cumulative exposure to low wages over 12 years in midlife is associated with memory decline in later life. Using 1992-2016 data from the Health and Retirement Study, we analyzed data from 2,879 individuals born in 1936-1941 using confounder-adjusted linear mixed-effects models. Low-wage work was defined as an hourly wage lower than two-thirds of the federal median wage for the corresponding year and was categorized into "never," "intermittent," and "sustained" based on wages earned from 1992 to 2004. Memory function was measured at each study visit from 2004 to 2016 via a memory composite score. The confounder-adjusted annual rate of memory decline among "never" low-wage earners was -0.12 standard units (95% confidence interval: -0.13, -0.10). Compared with this, memory decline among workers with sustained earning of low midlife wages was significantly faster (ßtime×sustained = -0.014, 95% confidence interval: -0.02, -0.01), corresponding to an annual rate of -0.13 standard units for this group. Sustained low-wage earning in midlife was significantly associated with a downward trajectory of memory performance in older age. Enhancing social policies to protect low-wage workers may be especially beneficial for their cognitive health.

Incident HIV Infection Among Young Men Associated With Female Sexual Partner Types Identified Through Latent Class Analysis, Rakai, Uganda.

BACKGROUND: Sexual partner characteristics are important determinants of HIV acquisition, but little is known about partner types of young men in sub-Saharan Africa. METHODS: Sexually active men aged 15-24 years from 5 rounds (2005-2013) of the Rakai Community Cohort Study in Uganda reported characteristics of up to 4 past-year female partners. Partner types were identified using latent class analysis. HIV incidence rates (IRs) were calculated by partner-type combinations, and individual-level risk adjusted IR ratios (aIRRs) relative to the lowest incidence type were estimated using the Poisson regression with generalized estimating equations. RESULTS: Young men (N = 1771) reported 4539 past-year female sexual partners. Three partner types were identified: type A: noncohabiting, student, medium duration partnerships; type B: cohabiting, nonstudent, longer duration partnerships; and type C: noncohabiting, nonstudent shorter duration partnerships. Type C partners engaged in the most HIV-related risk behaviors. Many men (29%) had more than 1 partner type/round. IR overall was 9.8/1000 person-years [95% confidence interval (CI): 4.7 to 20.6]. IR was 4.0 (95% CI: 1.2 to 12.7) for men with type A partners alone (41% of men). Relative to them, IR for those with type B partners alone (25%) was not significantly different. Men with type C partners alone (5%) had higher risk (aIRR = 3.2; 95% CI: 1.0 to 9.9), as did men with >1 partner type, including men with both type A and type B partners (12%; aIRR = 6.3; 95% CI: 2.5 to 15.9) and men with type C and other partner types (17%; aIRR = 4.3; 95% CI: 1.7 to 10.8). CONCLUSIONS: Partner-type combination was strongly associated with HIV incidence; type C partners and having more than 1 partner type were the riskiest patterns.

Body mass index in early adulthood and dementia in late life: Findings from a pooled cohort.

INTRODUCTION: To examine the independent association of body mass index (BMI) in early adulthood with dementia incidence among men and women. METHODS: We studied 5104 older adults from the Cardiovascular Health Study (CHS) and the Health, Aging, and Body Composition (Health ABC) study. We imputed early adulthood and midlife BMI using a pooled parent cohort with complete adult lifespan coverage and previously established methods. Dementia was ascertained using criteria such as neuropsychological test battery, medical records, and dementia-related drug use. Pooled logistic regression (PLR) models were used. RESULTS: Compared to women with normal BMI in early adulthood, the odds of dementia were higher among both overweight (odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.31 to 2.54) and obese (OR = 2.45; 95% CI = 1.47 to 4.06) women, independent of mid- and late-life BMI. Similar relationship was observed in men. CONCLUSIONS: With the growing obesity epidemic among US adults, efforts aimed at reducing dementia may need to begin obesity prevention and treatment early in the life course.

Adolescent Gastric Banding: a 5-Year Longitudinal Study.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is used to treat obesity in adults. Less is known about long-term results of the procedure in adolescents. OBJECTIVES: To evaluate LAGB 5-year outcomes in teenagers with severe obesity. SETTING: Children's hospital, USA. METHODS: Adolescents (14-18 years) underwent LAGB in an FDA-approved observational clinical trial. Outcomes including anthropometric measurements, comorbid conditions, complications, and band retention were collected through 60 months. RESULTS: One hundred thirty-seven subjects underwent LAGB (94 female, 43 male; 43% white, 37% Hispanic, 17% black; 4% other). Mean age and body mass index (BMI) pre-operatively were 17.0 + 1.2 years and 48.3 + 8.2 kg/m2, respectively. Comorbidities were present in 71%. Maximum weight loss occurred by 36 months (mean % excess weight loss (EWL) 40.6 + 35.2, mean % excess BMI loss (EBMIL) 41.6 + 34.9) and was maintained through 5 years for most subjects. There were no significant differences in weight loss by gender. Twenty-three (18%) of 127 adolescents reporting at 60 months achieved 50% excess weight loss. Postoperative heartburn and emesis occurred in 70% and 32%, respectively. Complications requiring additional surgery occurred 80 times in 63 patients. Thirty-three (26%) of 127 subjects contacted at 5 years had undergone band removal. CONCLUSION: In this study, fewer than 20% of adolescents with severe obesity lost > 50% of their excess weight following LAGB. Nearly 50% of patients required additional surgery. With reports of success following sleeve gastrectomy and gastric bypass, we believe that LAGB is not a preferred choice to treat adolescents with obesity.