SMART Binary: New Sample Size Planning Resources for SMART Studies with Binary Outcome Measurements.

Sequential Multiple-Assignment Randomized Trials (SMARTs) play an increasingly important role in psychological and behavioral health research. This experimental approach enables researchers to answer scientific questions about how to sequence and match interventions to the unique, changing needs of individuals. A variety of sample size planning resources for SMART studies have been developed, enabling researchers to plan SMARTs for addressing different types of scientific questions. However, relatively limited attention has been given to planning SMARTs with binary (dichotomous) outcomes, which often require higher sample sizes relative to continuous outcomes. Existing resources for estimating sample size requirements for SMARTs with binary outcomes do not consider the potential to improve power by including a baseline measurement and/or multiple repeated outcome measurements. The current paper addresses this issue by providing sample size planning simulation procedures and approximate formulas for two-wave repeated measures binary outcomes (i.e., two measurement times for the outcome variable, before and after intervention delivery). The simulation results agree well with the formulas. We also discuss how to use simulations to calculate power for studies with more than two outcome measurement occasions. Results show that having at least one repeated measurement of the outcome can substantially improve power under certain conditions.

Design of experiments with sequential randomizations on multiple timescales: the hybrid experimental design.

Psychological interventions, especially those leveraging mobile and wireless technologies, often include multiple components that are delivered and adapted on multiple timescales (e.g., coaching sessions adapted monthly based on clinical progress, combined with motivational messages from a mobile device adapted daily based on the person's daily emotional state). The hybrid experimental design (HED) is a new experimental approach that enables researchers to answer scientific questions about the construction of psychological interventions in which components are delivered and adapted on different timescales. These designs involve sequential randomizations of study participants to intervention components, each at an appropriate timescale (e.g., monthly randomization to different intensities of coaching sessions and daily randomization to different forms of motivational messages). The goal of the current manuscript is twofold. The first is to highlight the flexibility of the HED by conceptualizing this experimental approach as a special form of a factorial design in which different factors are introduced at multiple timescales. We also discuss how the structure of the HED can vary depending on the scientific question(s) motivating the study. The second goal is to explain how data from various types of HEDs can be analyzed to answer a variety of scientific questions about the development of multicomponent psychological interventions. For illustration, we use a completed HED to inform the development of a technology-based weight loss intervention that integrates components that are delivered and adapted on multiple timescales.

Trends in Depressive Symptoms and Associated Factors During Residency, 2007 to 2019 : A Repeated Annual Cohort Study.

BACKGROUND: Efforts to address the high depression rates among training physicians have been implemented at various levels of the U.S. medical education system. The cumulative effect of these efforts is unknown. OBJECTIVE: To assess how the increase in depressive symptoms with residency has shifted over time and to identify parallel trends in factors that have previously been associated with resident physician depression. DESIGN: Repeated annual cohort study. SETTING: U.S. health care organizations. PARTICIPANTS: First-year resident physicians (interns) who started training between 2007 and 2019. MEASUREMENTS: Depressive symptoms (9-item Patient Health Questionnaire [PHQ-9]) assessed at baseline and quarterly throughout internship. RESULTS: Among 16 965 interns, baseline depressive symptoms increased from 2007 to 2019 (PHQ-9 score, 2.3 to 2.9; difference, 0.6 [95% CI, 0.3 to 0.8]). The prevalence of baseline predictors of greater increase in depressive symptoms with internship also increased across cohorts. Despite the higher prevalence of baseline risk factors, the average change in depressive symptoms with internship decreased 24.4% from 2007 to 2019 (change in PHQ-9 score, 4.1 to 3.0; difference, -1.0 [CI, -1.5 to -0.6]). This change across cohorts was greater among women (4.7 to 3.3; difference, -1.4 [CI, -1.9 to -0.9]) than men (3.5 to 2.9; difference, -0.6 [CI, -1.2 to -0.05]) and greater among nonsurgical interns (4.1 to 3.0; difference, -1.1 [CI, -1.6 to -0.6]) than surgical interns (4.0 to 3.2; difference, -0.8 [CI, -1.2 to -0.4]). In parallel to the decrease in depressive symptom change, there were increases in sleep hours, quality of faculty feedback, and use of mental health services and a decrease in work hours across cohorts. The decrease in work hours was greater for nonsurgical than surgical interns. Further, the increase in mental health treatment across cohorts was greater for women than men. LIMITATION: Data are observational and subject to biases due to nonrandom sampling, missing data, and unmeasured confounders, limiting causal conclusions. CONCLUSION: Although depression during physician training remains high, the average increase in depressive symptoms associated with internship decreased between 2007 and 2019. PRIMARY FUNDING SOURCE: National Institute of Mental Health.

Integrating Intensive Longitudinal Data (ILD) to Inform the Development of Dynamic Theories of Behavior Change and Intervention Design: a Case Study of Scientific and Practical Considerations.

The increasing sophistication of mobile and sensing technology has enabled the collection of intensive longitudinal data (ILD) concerning dynamic changes in an individual's state and context. ILD can be used to develop dynamic theories of behavior change which, in turn, can be used to provide a conceptual framework for the development of just-in-time adaptive interventions (JITAIs) that leverage advances in mobile and sensing technology to determine when and how to intervene. As such, JITAIs hold tremendous potential in addressing major public health concerns such as cigarette smoking, which can recur and arise unexpectedly. In tandem, a growing number of studies have utilized multiple methods to collect data on a particular dynamic construct of interest from the same individual. This approach holds promise in providing investigators with a significantly more detailed view of how a behavior change processes unfold within the same individual than ever before. However, nuanced challenges relating to coarse data, noisy data, and incoherence among data sources are introduced. In this manuscript, we use a mobile health (mHealth) study on smokers motivated to quit (Break Free; R01MD010362) to illustrate these challenges. Practical approaches to integrate multiple data sources are discussed within the greater scientific context of developing dynamic theories of behavior change and JITAIs.

Virtual AppLication-supported Environment To INcrease Exercise (VALENTINE) during cardiac rehabilitation study: Rationale and design.

BACKGROUND: In-person, exercise-based cardiac rehabilitation improves physical activity and reduces morbidity and mortality for patients with cardiovascular disease. However, activity levels may not be optimized and decline over time after patients graduate from cardiac rehabilitation. Scalable interventions through mobile health (mHealth) technologies have the potential to augment activity levels and extend the benefits of cardiac rehabilitation. METHODS: The VALENTINE Study is a prospective, randomized-controlled, remotely-administered trial designed to evaluate an mHealth intervention to supplement cardiac rehabilitation for low- and moderate-risk patients (ClinicalTrials.gov NCT04587882). Participants are randomized to the control or intervention arms of the study. Both groups receive a compatible smartwatch (Fitbit Versa 2 or Apple Watch 4) and usual care. Participants in the intervention arm of the study additionally receive a just-in-time adaptive intervention (JITAI) delivered as contextually tailored notifications promoting low-level physical activity and exercise throughout the day. In addition, they have access to activity tracking and goal setting through the mobile study application and receive weekly activity summaries via email. The primary outcome is change in 6-minute walk distance at 6-months and, secondarily, change in average daily step count. Exploratory analyses will examine the impact of notifications on immediate short-term smartwatch-measured step counts and exercise minutes. CONCLUSIONS: The VALENTINE study leverages innovative techniques in behavioral and cardiovascular disease research and will make a significant contribution to our understanding of how to support patients using mHealth technologies to promote and sustain physical activity.

Optimal diagnostic test allocation strategy during the COVID-19 pandemic and beyond.

Timely diagnostic testing for active SARS-CoV-2 viral infections is key to controlling the spread of the virus and preventing severe disease. A central public health challenge is defining test allocation strategies with limited resources. In this paper, we provide a mathematical framework for defining an optimal strategy for allocating viral diagnostic tests. The framework accounts for imperfect test results, selective testing in certain high-risk patient populations, practical constraints in terms of budget and/or total number of available tests, and the purpose of testing. Our method is not only useful for detecting infections, but can also be used for long-time surveillance to detect new outbreaks. In our proposed approach, tests can be allocated across population strata defined by symptom severity and other patient characteristics, allowing the test allocation plan to prioritize higher risk patient populations. We illustrate our framework using historical data from the initial wave of the COVID-19 outbreak in New York City. We extend our proposed method to address the challenge of allocating two different types of diagnostic tests with different costs and accuracy, for example, the RT-PCR and the rapid antigen test (RAT), under budget constraints. We show how this latter framework can be useful to reopening of college campuses where university administrators are challenged with finite resources for community surveillance. We provide a R Shiny web application allowing users to explore test allocation strategies across a variety of pandemic scenarios. This work can serve as a useful tool for guiding public health decision-making at a community level and adapting testing plans to different stages of an epidemic. The conceptual framework has broader relevance beyond the current COVID-19 pandemic.

Reflecting on "A Statistician in Medicine" in 2020.

In this commentary, we revisit Sir Austin Bradford Hill's seminal Alfred Watson Memorial Lecture in 1962 through the eyes of two practicing biostatisticians of the current era. We summarize some eternal takeaway messages from Hill's lecture regarding observations and experiments translated through the modern lexicon of causal inference. Finally, we pose a series of questions that we would have liked to pose to Sir Austin Bradford Hill if he were to deliver the lecture in 2020.

Exchangeable Markov multi-state survival processes.

We consider exchangeable Markov multi-state survival processes, which are temporal processes taking values over a state-space S , with at least one absorbing failure state b ∈ S that satisfy the natural invariance properties of exchangeability and consistency under subsampling. The set of processes contains many well-known examples from health and epidemiology including survival, illness-death, competing risk, and comorbidity processes. Here, an extension leads to recurrent event processes. We characterize exchangeable Markov multi-state survival processes in both discrete and continuous time. Statistical considerations impose natural constraints on the space of models appropriate for applied work. In particular, we describe constraints arising from the notion of composable systems. We end with an application to irregularly sampled and potentially censored multi-state survival data, developing a Markov chain Monte Carlo algorithm for inference.

Survival models and health sequences.

Survival studies often generate not only a survival time for each patient but also a sequence of health measurements at annual or semi-annual check-ups while the patient remains alive. Such a sequence of random length accompanied by a survival time is called a survival process. Robust health is ordinarily associated with longer survival, so the two parts of a survival process cannot be assumed independent. This paper is concerned with a general technique-reverse alignment-for constructing statistical models for survival processes, here termed revival models. A revival model is a regression model in the sense that it incorporates covariate and treatment effects into both the distribution of survival times and the joint distribution of health outcomes. The revival model also determines a conditional survival distribution given the observed history, which describes how the subsequent survival distribution is determined by the observed progression of health outcomes.

Response to discussants of "survival models and health sequences".

Survival studies often generate not only a survival time for each patient but also a sequence of health measurements at annual or semi-annual check-ups while the patient remains alive. Such a sequence of random length accompanied by a survival time is called a survival process. Robust health is ordinarily associated with longer survival, so the two parts of a survival process cannot be assumed independent. This paper is concerned with a general technique-reverse alignment-for constructing statistical models for survival processes, here termed revival models. A revival model is a regression model in the sense that it incorporates covariate and treatment effects into both the distribution of survival times and the joint distribution of health outcomes. The revival model also determines a conditional survival distribution given the observed history, which describes how the subsequent survival distribution is determined by the observed progression of health outcomes.

Recurrent event analysis in the presence of real-time high frequency data via random subsampling.

Digital monitoring studies collect real-time high frequency data via mobile sensors in the subjects' natural environment. This data can be used to model the impact of changes in physiology on recurrent event outcomes such as smoking, drug use, alcohol use, or self-identified moments of suicide ideation. Likelihood calculations for the recurrent event analysis, however, become computationally prohibitive in this setting. Motivated by this, a random subsampling framework is proposed for computationally efficient, approximate likelihood-based estimation. A subsampling-unbiased estimator for the derivative of the cumulative hazard enters into an approximation of log-likelihood. The estimator has two sources of variation: the first due to the recurrent event model and the second due to subsampling. The latter can be reduced by increasing the sampling rate; however, this leads to increased computational costs. The approximate score equations are equivalent to logistic regression score equations, allowing for standard, "off-the-shelf" software to be used in fitting these models. Simulations demonstrate the method and efficiency-computation trade-off. We end by illustrating our approach using data from a digital monitoring study of suicidal ideation.

Exploring the Big Data Paradox for various estimands using vaccination data from the global COVID-19 Trends and Impact Survey (CTIS).

Selection bias poses a substantial challenge to valid statistical inference in nonprobability samples. This study compared estimates of the first-dose COVID-19 vaccination rates among Indian adults in 2021 from a large nonprobability sample, the COVID-19 Trends and Impact Survey (CTIS), and a small probability survey, the Center for Voting Options and Trends in Election Research (CVoter), against national benchmark data from the COVID Vaccine Intelligence Network. Notably, CTIS exhibits a larger estimation error on average (0.37) compared to CVoter (0.14). Additionally, we explored the accuracy (regarding mean squared error) of CTIS in estimating successive differences (over time) and subgroup differences (for females versus males) in mean vaccine uptakes. Compared to the overall vaccination rates, targeting these alternative estimands comparing differences or relative differences in two means increased the effective sample size. These results suggest that the Big Data Paradox can manifest in countries beyond the United States and may not apply equally to every estimand of interest.

Text Messages to Promote Physical Activity in Patients With Cardiovascular Disease: A Micro-Randomized Trial of a Just-In-Time Adaptive Intervention.

BACKGROUND: Text messages may enhance physical activity levels in patients with cardiovascular disease, including those enrolled in cardiac rehabilitation. However, the independent and long-term effects of text messages remain uncertain. METHODS: The VALENTINE study (Virtual Application-supported Environment to Increase Exercise) was a micro-randomized trial that delivered text messages through a smartwatch (Apple Watch or Fitbit Versa) to participants initiating cardiac rehabilitation. Participants were randomized 4× per day over 6-months to receive no text message or a message encouraging low-level physical activity. Text messages were tailored on contextual factors (eg, weather). Our primary outcome was step count 60 minutes following a text message, and we used a centered and weighted least squares mean method to estimate causal effects. Given potential measurement differences between devices determined a priori, data were assessed separately for Apple Watch and Fitbit Versa users over 3 time periods corresponding to the initiation (0-30 days), maintenance (31-120 days), and completion (121-182 days) of cardiac rehabilitation. RESULTS: One hundred eight participants were included with 70 552 randomizations over 6 months; mean age was 59.5 (SD, 10.7) years with 36 (32.4%) female and 68 (63.0%) Apple Watch participants. For Apple Watch participants, text messages led to a trend in increased step count by 10% in the 60-minutes following a message during days 1 to 30 (95% CI, -1% to +20%), with no effect from days 31 to 120 (+1% [95% CI, -4% to +5%]), and a significant 6% increase during days 121 to 182 (95% CI, +0% to +11%). For Fitbit users, text messages significantly increased step count by 17% (95% CI, +7% to +28%) in the 60-minutes following a message in the first 30 days of the study with no effect subsequently. CONCLUSIONS: In patients undergoing cardiac rehabilitation, contextually tailored text messages may increase physical activity, but this effect varies over time and by device. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04587882.

ADDRESSING SELECTION BIAS AND MEASUREMENT ERROR IN COVID-19 CASE COUNT DATA USING AUXILIARY INFORMATION.

Coronavirus case-count data has influenced government policies and drives most epidemiological forecasts. Limited testing is cited as the key driver behind minimal information on the COVID-19 pandemic. While expanded testing is laudable, measurement error and selection bias are the two greatest problems limiting our understanding of the COVID-19 pandemic; neither can be fully addressed by increased testing capacity. In this paper, we demonstrate their impact on estimation of point prevalence and the effective reproduction number. We show that estimates based on the millions of molecular tests in the US has the same mean square error as a small simple random sample. To address this, a procedure is presented that combines case-count data and random samples over time to estimate selection propensities based on key covariate information. We then combine these selection propensities with epidemiological forecast models to construct a doubly robust estimation method that accounts for both measurement-error and selection bias. This method is then applied to estimate Indiana's active infection prevalence using case-count, hospitalization, and death data with demographic information, a statewide random molecular sample collected from April 25-29th, and Delphi's COVID-19 Trends and Impact Survey. We end with a series of recommendations based on the proposed methodology.

ASSESSING TIME-VARYING CAUSAL EFFECT MODERATION IN THE PRESENCE OF CLUSTER-LEVEL TREATMENT EFFECT HETEROGENEITY AND INTERFERENCE.

The micro-randomized trial (MRT) is a sequential randomized experimental design to empirically evaluate the effectiveness of mobile health (mHealth) intervention components that may be delivered at hundreds or thousands of decision points. MRTs have motivated a new class of causal estimands, termed "causal excursion effects", for which semiparametric inference can be conducted via a weighted, centered least squares criterion (Boruvka et al., 2018). Existing methods assume between-subject independence and non-interference. Deviations from these assumptions often occur. In this paper, causal excursion effects are revisited under potential cluster-level treatment effect heterogeneity and interference, where the treatment effect of interest may depend on cluster-level moderators. Utility of the proposed methods is shown by analyzing data from a multi-institution cohort of first year medical residents in the United States.

A Text Messaging Intervention for Priming the Affective Rewards of Exercise in Adults: Protocol for a Microrandomized Trial.

BACKGROUND: Physical activity is a critical target for health interventions, but effective interventions remain elusive. A growing body of work suggests that interventions targeting affective attitudes toward physical activity may be more effective for sustaining activity long term than those that rely on cognitive constructs alone, such as goal setting and self-monitoring. Anticipated affective response in particular is a promising target for intervention. OBJECTIVE: We will evaluate the efficacy of an SMS text messaging intervention that manipulates anticipated affective response to exercise to promote physical activity. We hypothesize that reminding users of a positive postexercise affective state before their planned exercise sessions will increase their calories burned during this exercise session. We will deploy 2 forms of affective SMS text messages to explore the design space: low-reflection messages written by participants for themselves and high-reflection prompts that require users to reflect and respond. We will also explore the effect of the intervention on affective attitudes toward exercise. METHODS: A total of 120 individuals will be enrolled in a 9-week microrandomized trial testing affective messages that remind users about feeling good after exercise (40% probability), control reminders (30% probability), or no message (30% probability). Two types of affective SMS text messages will be deployed: one requiring a response and the other in a read-only format. Participants will write the read-only messages themselves to ensure that the messages accurately reflect the participants' anticipated postexercise affective state. Affective attitudes toward exercise and intrinsic motivation for exercise will be measured at the beginning and end of the study. The weighted and centered least squares method will be used to analyze the effect of delivering the intervention versus not on calories burned over 4 hours around the time of the planned activity, measured by the Apple Watch. Secondary analyses will include the effect of the intervention on step count and active minutes, as well as an investigation of the effects of the intervention on affective attitudes toward exercise and intrinsic motivation for exercise. Participants will be interviewed to gain qualitative insights into intervention impact and acceptability. RESULTS: Enrollment began in May 2023, with 57 participants enrolled at the end of July 2023. We anticipate enrolling 120 participants. CONCLUSIONS: This study will provide early evidence about the effect of a repeated manipulation of anticipated affective response to exercise. The use of 2 different types of messages will yield insight into optimal design strategies for improving affective attitudes toward exercise. TRIAL REGISTRATION: ClinicalTrials.gov NCT05582369; https://classic.clinicaltrials.gov/ct2/show/NCT05582369. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/46560.

Effectiveness of gamified team competition as mHealth intervention for medical interns: a cluster micro-randomized trial.

Gamification, the application of gaming elements to increase enjoyment and engagement, has the potential to improve the effectiveness of digital health interventions, while the effectiveness of competition gamification components remains poorly understood on residency. To address this gap, we evaluate the effect of smartphone-based gamified team competition intervention on daily step count and sleep duration via a micro-randomized trial on medical interns. Our aim is to assess potential improvements in the factors (namely step count and sleep) that may help interns cope with stress and improve well-being. In 1779 interns, team competition intervention significantly increases the mean daily step count by 105.8 steps (SE 35.8, p = 0.03) relative to the no competition arm, while does not significantly affect the mean daily sleep minutes (p = 0.76). Moderator analyses indicate that the causal effects of competition on daily step count and sleep minutes decreased by 14.5 steps (SE 10.2, p = 0.16) and 1.9 minutes (SE 0.6, p = 0.003) for each additional week-in-study, respectively. Intra-institutional competition negatively moderates the causal effect of competition upon daily step count by -90.3 steps (SE 86.5, p = 0.30). Our results show that gamified team competition delivered via mobile app significantly increases daily physical activity which suggests that team competition can function as a mobile health intervention tool to increase short-term physical activity levels for medical interns. Future improvements in strategies of forming competition opponents and introducing occasional competition breaks may improve the overall effectiveness.

A randomized trial of a mobile health intervention to augment cardiac rehabilitation.

Mobile health (mHealth) interventions may enhance positive health behaviors, but randomized trials evaluating their efficacy are uncommon. Our goal was to determine if a mHealth intervention augmented and extended benefits of center-based cardiac rehabilitation (CR) for physical activity levels at 6-months. We delivered a randomized clinical trial to low and moderate risk patients with a compatible smartphone enrolled in CR at two health systems. All participants received a compatible smartwatch and usual CR care. Intervention participants received a mHealth intervention that included a just-in-time-adaptive intervention (JITAI) as text messages. The primary outcome was change in remote 6-minute walk distance at 6-months stratified by device type. Here we report the results for 220 participants enrolled in the study (mean [SD]: age 59.6 [10.6] years; 67 [30.5%] women). For our primary outcome at 6 months, there is no significant difference in the change in 6 min walk distance across smartwatch types (Intervention versus control: +31.1 meters Apple Watch, -7.4 meters Fitbit; p = 0.28). Secondary outcomes show no difference in mean step counts between the first and final weeks of the study, but a change in 6 min walk distance at 3 months for Fitbit users. Amongst patients enrolled in center-based CR, a mHealth intervention did not improve 6-month outcomes but suggested differences at 3 months in some users.

Hierarchical network models for exchangeable structured interaction processes.

Network data often arises via a series of structured interactions among a population of constituent elements. E-mail exchanges, for example, have a single sender followed by potentially multiple receivers. Scientific articles, on the other hand, may have multiple subject areas and multiple authors. We introduce a statistical model, termed the Pitman-Yor hierarchical vertex components model (PY-HVCM), that is well suited for structured interaction data. The proposed PY-HVCM effectively models complex relational data by partial pooling of local information via a latent, shared population-level distribution. The PY-HCVM is a canonical example of hierarchical vertex components models - a subfamily of models for exchangeable structured interaction-labeled networks, i.e., networks invariant to interaction relabeling. Theoretical analysis and supporting simulations provide clear model interpretation, and establish global sparsity and power law degree distribution. A computationally tractable Gibbs sampling algorithm is derived for inferring sparsity and power law properties of complex networks. We demonstrate the model on both the Enron e-mail dataset and an ArXiv dataset, showing goodness of fit of the model via posterior predictive validation.

Hybrid Experimental Designs for Intervention Development: What, Why, and How.

Advances in mobile and wireless technologies offer tremendous opportunities for extending the reach and impact of psychological interventions and for adapting interventions to the unique and changing needs of individuals. However, insufficient engagement remains a critical barrier to the effectiveness of digital interventions. Human delivery of interventions (e.g., by clinical staff) can be more engaging but potentially more expensive and burdensome. Hence, the integration of digital and human-delivered components is critical to building effective and scalable psychological interventions. Existing experimental designs can be used to answer questions either about human-delivered components that are typically sequenced and adapted at relatively slow timescales (e.g., monthly) or about digital components that are typically sequenced and adapted at much faster timescales (e.g., daily). However, these methodologies do not accommodate sequencing and adaptation of components at multiple timescales and hence cannot be used to empirically inform the joint sequencing and adaptation of human-delivered and digital components. Here, we introduce the hybrid experimental design (HED)-a new experimental approach that can be used to answer scientific questions about building psychological interventions in which human-delivered and digital components are integrated and adapted at multiple timescales. We describe the key characteristics of HEDs (i.e., what they are), explain their scientific rationale (i.e., why they are needed), and provide guidelines for their design and corresponding data analysis (i.e., how can data arising from HEDs be used to inform effective and scalable psychological interventions).