Increasing the Precision of Hypertension Treatment Through Personalized Trials: a Pilot Study.

BACKGROUND: There are substantial differences in the effects of blood pressure (BP) medications in individual patients. Yet, the current standard approach to prescribing BP medications is not personalized. OBJECTIVE: To determine the feasibility of individualizing the selection of BP medications through pragmatic personalized (i.e., N-of-1) trials. DESIGN: Series of N-of-1 trials. SETTING: Outpatient. PATIENTS: Hypertensive adults prescribed none or one BP medication. INTERVENTION: Participation in a flexible, open-label personalized trial of two to three BP medications (NCT02744456). MEASUREMENTS: BP was measured twice per day with a validated home BP device. Frequency and severity of side effects were assessed at the end of the day via an electronic questionnaire. Patients' BP medication preference was assessed after reviewing BP lowering and side effect results with a study clinician. Feasibility was assessed by determining the proportion of patients who adhered to self-assessments. Benefit was assessed by asking patients to rate the helpfulness of participation and whether they would recommend personalized trials to other hypertensive patients. KEY RESULTS: Of ten patients enrolled, two dropped out prior to initiation, one discovered white coat hypertension through ambulatory BP monitoring, and seven (mean age 58 years, 71% of women) completed personalized trials. All seven were compliant with home BP monitoring and side effect tracking. All seven recommended personalized trials of BP medications to others. Thiazides were preferred by three patients, renin-angiotensin system-blocking agents by two patients, a combination of thiazide and beta-blocker by one patient, and any of three classes by one patient. CONCLUSIONS: Personalized trials of BP medications were feasible and led to improved treatment precision. Heterogeneity of patient preferences and of therapeutic BP response for first-line BP medications can be determined through a personalized trial approach.

The Influence of Daily Stress on Sedentary Behavior: Group and Person (N of 1) Level Results of a 1-Year Observational Study.

OBJECTIVE: The purpose of this study, which used mobile technologies to continuously collect data for 1 year, was to examine the association of psychological stress with objectively measured sedentary behavior in adults at both the group (e.g., nomothetic approach) and individual (e.g., idiographic approach) level. METHODS: Data were collected in an observational study of healthy adults (n = 79) residing in the New York City metro area who were studied for 365 days from 2014 to 2015. Sedentary behavior was objectively measured via accelerometry. A smartphone-based electronic diary was used to assess level of stress ("Overall, how stressful was your day?" 0-10 scale) and sources of stress. RESULTS: The end-of-day stress rating was not associated with total sedentary time (B = -1.34, p = .767) at the group level. When specific sources of stress were evaluated at the group level, argument-related stress was associated with increased sedentariness, whereas running late- and work-related stress were associated with decreased sedentariness. There was a substantial degree of interindividual variability in the relationship of stress with sedentary behavior. Both the level and sources of stress were associated with increased sedentariness for some, decreased sedentariness for others, and had no effect for many (within-person variance p < .001). CONCLUSIONS: These findings suggest that the influence of stress on sedentary behavior varies by source of stress and from person to person. A precision medicine approach may be warranted to target reductions in sedentary time, although further studies are needed to confirm the observed findings in light of study limitations including a small sample size and enrollment of participants from a single, urban metropolitan area.

Risk factors for bronchial hyperresponsiveness in teenagers differ with sex and atopic status.

BACKGROUND: Sex-related differences in bronchial hyperresponsiveness (BHR) have been reported in adolescents, but the mechanisms remain obscure. OBJECTIVE: To investigate the risk factors for BHR in the Raine Study, a community-based longitudinal birth cohort. METHODS: At 14 years of age, children underwent a respiratory assessment including a questionnaire, lung function testing, methacholine challenge, and determination of atopic status. RESULTS: A total of 1779 children provided data for assessment, with 1510 completing lung function and methacholine challenge testing. Current asthma was present in 152 (10.4%), 762 (50.5%) were atopic, and 277 (18.6%) had BHR. BHR was more common in girls, whereas atopy was more common in boys, with no sex differences in asthma or current wheeze. Independent risk factors for BHR were being female (odds ratio [OR], 3.45; P < .001), atopy at 14 years (OR, 1.27; P = .004), and current asthma (OR, 2.15; P = .005). Better lung function was protective against BHR (forced expiratory flow between 25% and 75% of forced vital capacity/forced vital capacity, OR, 0.09; P < .001). Risk factors differed with sex and atopic status. Early-life factors were generally not independent risk factors for BHR at 14 years of age, with the exception of being smaller at birth in boys (birth length, OR, 6 × 10(-9); P = .017) and maternal asthma in girls (OR, 1.84; P = .041). Current asthma was not a risk for BHR in nonatopic children. CONCLUSION: Bronchial hyperresponsiveness was more common and more severe in girls. These differences could not be explained by differences in lung function or atopic status.

Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis.

INTRODUCTION: Improved nutrition is the major proven benefit of newborn screening programmes for cystic fibrosis (CF) and is associated with better clinical outcomes. It was hypothesised that early pulmonary inflammation and infection in infants with CF is associated with worse nutrition. METHODS: Weight, height and pulmonary inflammation and infection in bronchoalveolar lavage (BAL) were assessed shortly after diagnosis in infants with CF and again at 1, 2 and 3 years of age. Body mass index (BMI) was expressed as z-scores. Inflammatory cells and cytokines (interleukin 1ß (IL-1ß), IL-6, IL-8 and tumour necrosis factor α (TNFα)), free neutrophil elastase activity and myeloperoxidase were measured in BAL. Mixed effects modelling was used to assess longitudinal associations between pulmonary inflammation, pulmonary infection (Staphylococcus aureus and Pseudomonas aeruginosa) and BMI z-score after adjusting for potential confounding factors. RESULTS: Forty-two infants were studied (16 (38%) male; 39 (93%) pancreatic insufficient); 36 were diagnosed by newborn screening (at median age 4 weeks) and six by early clinical diagnosis (meconium ileus). Thirty-one (74%) received antistaphylococcal antibiotics. More than two-thirds were asymptomatic at each assessment. Mean BMI z-scores were -1.5 at diagnosis and 0.5, -0.2 and -0.1 at 1, 2 and 3 years, respectively. Neutrophil elastase and infection with S aureus were associated with lower BMI, whereas age (p=0.01) and antistaphylococcal antibiotics (p=0.013) were associated with increased BMI. On average, each log(10) increase in free neutrophil elastase activity was associated with a 0.43 (95% CI 0.06 to 0.79) reduction in BMI z-score. DISCUSSION: Early nutritional status is associated with the underlying pulmonary pathophysiology in CF, and better understanding of these relationships is required. Studies are required to assess whether interventions can decrease pulmonary inflammation and improve nutrition. Early surveillance will enable such targeted interventions with the aim of improving these important clinical outcomes.

Toward improved prediction of risk for atopy and asthma among preschoolers: a prospective cohort study.

BACKGROUND: Atopy and asthma are commonly initiated during early life, and there is increasing interest in the development of preventive treatments for at-risk children. However, effective methods for assessing the level of risk in individual children are lacking. OBJECTIVE: We sought to identify clinical and laboratory biomarkers in 2-year-olds that are predictive of the risk for persistent atopy and wheeze at age 5 years. METHODS: We prospectively studied 198 atopic family history-positive children to age 5 years. Clinical and laboratory assessments related to asthma history and atopy status were undertaken annually; episodes of acute respiratory illness were assessed and classified throughout and graded by severity. RESULTS: Aeroallergen-specific IgE titers cycled continuously within the low range in nonatopic subjects. Atopic subjects displayed similar cycling in infancy but eventually locked into a stable pattern of upwardly trending antibody production and T(H)2-polarized cellular immunity. The latter was associated with stable expression of IL-4 receptor in allergen-specific T(H)2 memory responses, which was absent from responses during infancy. Risk for persistent wheeze was strongly linked to early sensitization and in turn to early infection. Integration of these data by means of logistic regression revealed that attaining mite-specific IgE titers of greater than 0.20 kU/L by age 2 years was associated with a 12.7% risk of persistent wheeze, increasing progressively to an 87.2% risk with increasing numbers of severe lower respiratory tract illnesses experienced. CONCLUSION: The risk for development of persistent wheeze in children can be quantified by means of integration of measures related to early sensitization and early infections. Follow-up studies along similar lines in larger unselected populations to refine this approach are warranted.

Elucidation of asthma phenotypes in atopic teenagers through parallel immunophenotypic and clinical profiling.

BACKGROUND: Current treatment strategies for asthma in teenagers derive primarily from information on chronic disease in adults. More detailed understanding of risk factors related to teenage asthma might aid in the development of improved preventive and treatment strategies for this age group. OBJECTIVE: We sought to identify biomarkers associated with asthma phenotypes in teenagers, particularly atopic asthma, and to identify markers that aid in discriminating between atopic subjects at high versus low risk of asthma. METHODS: We studied 1380 unselected 14-year-olds and collected data on clinical history, allergic sensitization, and respiratory and immunoinflammatory function. The latter comprised measurements of circulating inflammatory markers and in vitro innate and adaptive immune functions, including house dust mite T-cell responses. We integrated the data into regression models to identify variables most strongly associated with asthma risk and severity among atopic subjects. RESULTS: Eight hundred twenty-seven subjects were atopic, 140 subjects were asthmatic, and 81% of asthmatic subjects were also atopic. We identified asthma risk variables related to atopy intensity, including specific IgE and eosinophil levels, plus an additional series external to the T(H)2 cascade but that modified risk only in atopic subjects, including IFN-gamma, IL-10, and IL-12 responses and neutrophil numbers in blood. Moreover, bronchial hyperresponsiveness was associated strongly with atopic but not nonatopic asthma, and the bronchial hyperresponsiveness risk profile was itself dominated by atopy-associated variables. CONCLUSIONS: Asthma in teenagers is predominantly driven by atopy acting in concert with a second tier of T(H)2-independent immunoinflammatory mechanisms, which contribute to pathogenesis only against the background of pre-existing inhalant allergy.

Effect of Depression Screening After Acute Coronary Syndromes on Quality of Life: The CODIACS-QoL Randomized Clinical Trial.

Importance: Patients with acute coronary syndrome (ACS) and elevated depressive symptoms are at increased risk for recurrent cardiovascular events and mortality, worse quality of life, and higher health care costs. These observational findings prompted multiple scientific panels to advise universal depression screening in survivors of ACS prior to evidence from randomized screening trials. Objective: To determine whether systematically screening for depression in survivors of ACS improves quality of life and depression compared with usual care. Design, Setting, and Participants: A 3-group multisite randomized trial enrolled 1500 patients with ACS from 4 health care systems between November 1, 2013, and March 31, 2017, with follow-up ending July 31, 2018. Patients were eligible if they had been hospitalized for ACS in the previous 2 to 12 months and had no prior history of depression. All analyses were performed on an intention-to-treat basis. Interventions: Patients with ACS were randomly assigned 1:1:1 to receive (1) systematic depression screening using the 8-item Patient Health Questionnaire, with notification of primary care clinicians and provision of centralized, patient-preference, stepped depression care for those with positive screening results (8-item Patient Health Questionnaire score ≥10; screen, notify, and treat, n = 499); (2) systematic depression screening, with notification of primary care clinicians for those with positive screening results (screen and notify, n = 501); and (3) usual care (no screening, n = 500). Main Outcomes and Measures: The primary outcome was change in quality-adjusted life-years. The secondary outcome was depression-free days. Adverse effects and mortality were assessed by patient interview and hospital records. Results: A total of 1500 patients (424 women and 1076 men; mean [SD] age, 65.9 [11.5] years) were randomized in the 18-month trial. Only 71 of 1000 eligible survivors of ACS (7.1%) had elevated 8-item Patient Health Questionnaire scores indicating depressive symptoms at screening. There were no differences in mean (SD) change in quality-adjusted life-years (screen, notify and treat, -0.06 [0.20]; screen and notify, -0.06 [0.20]; no screen, -0.06 [0.18]; P = .98) or cumulative mean (SD) depression-free days (screen, notify and treat, 343.1 [179.0] days; screen and notify, 351.3 [175.0] days; no screen, 339.0 [176.6] days; P = .63). Harms including death, bleeding, or sleep difficulties did not differ among groups. Conclusions and Relevance: In patients with ACS without a history of depression, systematic depression screening with or without providing depression treatment did not alter quality-adjusted life-years, depression-free days, or harms. Trial Registration: ClinicalTrials.gov identifier: NCT01993017.

Behavioral economics implementation: Regret lottery improves mHealth patient study adherence.

BACKGROUND: Nonadherence to study protocols reduces the generalizability, validity, and statistical power of longitudinal studies. PURPOSE: To determine whether an automated electronically-delivered regret lottery would improve adherence to an intensive mHealth self-monitoring protocol as part of a longitudinal observational study. METHODS: We enrolled 77 adults into a 52-week study requiring five daily ecologic momentary assessments (EMA) of stress and daily accelerometer use. We performed a pre/post single-arm study to evaluate the efficacy of a lottery intervention in improving adherence to this protocol. Midway through the study, participants were invited to enter a weekly regret lottery ($50 prize, expected value <$1) in which prize collection was contingent upon meeting adherence thresholds for the prior week. Study protocol adherence before and after lottery initiation were compared using mixed models repeated measures analysis of variance. RESULTS: 62 participants consented to lottery participation. In the 12 weeks prior to lottery initiation, weekly adherence was declining (slope -1.4%/week). The weekly per-participant probability of adherence was higher after lottery initiation when comparing the 4-week (32% pre-lottery vs 50% post-lottery, p < 0.001), 8-week (37% vs 49%, p < 0.001), and 12-week periods (39% vs 45%, p = 0.001) before and after lottery initiation. However, the rate of decline in adherence over time was unchanged. CONCLUSION: The implementation of an automated, electronically-delivered weekly regret lottery improved adherence with an intensive self-monitoring study protocol. Regret lotteries may represent a cost-effective tool to improve adherence and reduce bias caused by dropout or nonadherence.

Clinical Usefulness of Bright White Light Therapy for Depressive Symptoms in Cancer Survivors: Results from a Series of Personalized (N-of-1) Trials.

Purpose: Little is known about the effectiveness of bright white light therapy (BWL) for depressive symptoms in cancer survivors, many of whom prefer non-pharmacological treatments. The purpose of this study was to compare the effectiveness of BWL versus dim red light therapy (DRL) on depressive symptoms within individual cancer survivors using personalized (N-of-1) trials. Methods: Cancer survivors with at least mild depressive symptoms were randomized to one of two treatment sequences consisting of counterbalanced crossover comparisons of three-weeks of lightbox-delivered BWL (intervention) or DRL (sham) for 30 min each morning across 12 weeks. A smartphone application guided cancer survivors through the treatment sequence and facilitated data collection. Cancer survivors tracked end-of-day depressive symptoms (primary outcome) and fatigue using visual analog scales. Within-patient effects of BWL were assessed using an autoregressive model with adjustment for linear time trends. Results: Eight of nine cancer survivors completed the 12-week protocol. Two survivors reported significantly (i.e., p < 0.05) lower depressive symptoms (-1.3 ± 0.5 and -1.30 ± 0.9 points on a 10-point scale), five reported no difference in depressive symptoms, and one reported higher depressive symptoms (+1.7 ± 0.6 points) with BWL versus DRL. Eight of nine cancer survivors recommended personalized trials of BWL to others. Conclusions: There were heterogeneous effects of three-week BWL on self-reported depressive symptoms among cancer survivors, with some finding a benefit but others finding no benefit or even harm. Implications for Cancer Survivors: Personalized trials can help cancer survivors learn if BWL is helpful for improving their depressive symptoms.

Rationale, design, and baseline data for a multicenter randomized clinical trial comparing depression screening strategies after acute coronary syndrome: The comparison of depression identification after acute Coronary Syndromes-Quality of Life and Cost Outcomes (CODIACS-QOL) trial.

BACKGROUND: Elevated depressive symptoms among survivors of acute coronary syndromes (ACS) confer recurrent cardiovascular events and mortality, worse quality of life, and higher healthcare costs. While multiple scientific groups advise routine depression screening for ACS survivors, no randomized trials exist to inform this screening recommendation. We aimed to assess the effect of screening for depression on change in quality of life over 18 months among ACS patients. METHODS: The Comparison of Depression Identification after Acute Coronary Syndrome on Quality of Life and Cost Outcomes (CODIACS-QoL) trial is a pragmatic, 3-arm trial that randomized ACS patients to 1) systematic depression screening using the 8-item Patient Health Questionnaire (PHQ-8) and if positive screen (PHQ-8 ≥ 10), notification of primary care providers (PCPs) and invitation to participate in centralized, patient-preference, stepped depression care (Screen, Notify, and Treat, N = 499); 2) systematic depression screening and PCP notification only (Screen and Notify, N = 501); and 3) usual care (No Screen, N = 500). Adults hospitalized for ACS in the previous 2-12 months without prior history of depression were eligible for participation. Key outcomes will be quality-adjusted life years (primary), cost of health care utilization, and depression-free days across 18 months. RESULTS: A total of 1500 patients were randomized in the CODIACS-QOL trial (28.3% women; 16.3% Hispanic; mean age 65.9 (11.5) years). Only 7% of ACS survivors had elevated depressive symptoms. CONCLUSIONS: Using a novel randomization schema and pragmatic design principles, the CODIACS-QoL trial achieved its enrollment target. Eventual results of this trial will inform future depression screening recommendations in cardiac patients. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01993017).