Incorporating participants' welfare into sequential multiple assignment randomized trials.

Dynamic treatment regimes (DTRs) are sequences of decision rules that recommend treatments based on patients' time-varying clinical conditions. The sequential, multiple assignment, randomized trial (SMART) is an experimental design that can provide high-quality evidence for constructing optimal DTRs. In a conventional SMART, participants are randomized to available treatments at multiple stages with balanced randomization probabilities. Despite its relative simplicity of implementation and desirable performance in comparing embedded DTRs, the conventional SMART faces inevitable ethical issues, including assigning many participants to the empirically inferior treatment or the treatment they dislike, which might slow down the recruitment procedure and lead to higher attrition rates, ultimately leading to poor internal and external validities of the trial results. In this context, we propose a SMART under the Experiment-as-Market framework (SMART-EXAM), a novel SMART design that holds the potential to improve participants' welfare by incorporating their preferences and predicted treatment effects into the randomization procedure. We describe the steps of conducting a SMART-EXAM and evaluate its performance compared to the conventional SMART. The results indicate that the SMART-EXAM can improve the welfare of the participants enrolled in the trial, while also achieving a desirable ability to construct an optimal DTR when the experimental parameters are suitably specified. We finally illustrate the practical potential of the SMART-EXAM design using data from a SMART for children with attention-deficit/hyperactivity disorder.

Incorporating nonparametric methods for estimating causal excursion effects in mobile health with zero-inflated count outcomes.

In mobile health, tailoring interventions for real-time delivery is of paramount importance. Micro-randomized trials have emerged as the "gold-standard" methodology for developing such interventions. Analyzing data from these trials provides insights into the efficacy of interventions and the potential moderation by specific covariates. The "causal excursion effect," a novel class of causal estimand, addresses these inquiries. Yet, existing research mainly focuses on continuous or binary data, leaving count data largely unexplored. The current work is motivated by the Drink Less micro-randomized trial from the UK, which focuses on a zero-inflated proximal outcome, i.e., the number of screen views in the subsequent hour following the intervention decision point. To be specific, we revisit the concept of causal excursion effect, specifically for zero-inflated count outcomes, and introduce novel estimation approaches that incorporate nonparametric techniques. Bidirectional asymptotics are established for the proposed estimators. Simulation studies are conducted to evaluate the performance of the proposed methods. As an illustration, we also implement these methods to the Drink Less trial data.

Extending the diabetic retinopathy screening intervals in Singapore: methodology and preliminary findings of a cohort study.

BACKGROUND: The Diabetic Retinopathy Extended Screening Study (DRESS) aims to develop and validate a new DR/diabetic macular edema (DME) risk stratification model in patients with Type 2 diabetes (DM) to identify low-risk groups who can be safely assigned to biennial or triennial screening intervals. We describe the study methodology, participants' baseline characteristics, and preliminary DR progression rates at the first annual follow-up. METHODS: DRESS is a 3-year ongoing longitudinal study of patients with T2DM and no or mild non-proliferative DR (NPDR, non-referable) who underwent teleophthalmic screening under the Singapore integrated Diabetic Retinopathy Programme (SiDRP) at four SingHealth Polyclinics. Patients with referable DR/DME (> mild NPDR) or ungradable fundus images were excluded. Sociodemographic, lifestyle, medical and clinical information was obtained from medical records and interviewer-administered questionnaires at baseline. These data are extracted from medical records at 12, 24 and 36 months post-enrollment. Baseline descriptive characteristics stratified by DR severity at baseline and rates of progression to referable DR at 12-month follow-up were calculated. RESULTS: Of 5,840 eligible patients, 78.3% (n = 4,570, median [interquartile range [IQR] age 61.0 [55-67] years; 54.7% male; 68.0% Chinese) completed the baseline assessment. At baseline, 97.4% and 2.6% had none and mild NPDR (worse eye), respectively. Most participants had hypertension (79.2%) and dyslipidemia (92.8%); and almost half were obese (43.4%, BMI ≥ 27.5 kg/m2). Participants without DR (vs mild DR) reported shorter DM duration, and had lower haemoglobin A1c, triglycerides and urine albumin/creatinine ratio (all p < 0.05). To date, we have extracted 41.8% (n = 1909) of the 12-month follow-up data. Of these, 99.7% (n = 1,904) did not progress to referable DR. Those who progressed to referable DR status (0.3%) had no DR at baseline. CONCLUSIONS: In our prospective study of patients with T2DM and non-referable DR attending polyclinics, we found extremely low annual DR progression rates. These preliminary results suggest that extending screening intervals beyond 12 months may be viable and safe for most participants, although our 3-year follow up data are needed to substantiate this claim and develop the risk stratification model to identify low-risk patients with T2DM who can be assigned biennial or triennial screening intervals.

The Sequential Multiple Assignment Randomized Trial for Controlling Infectious Diseases: A Review of Recent Developments.

Infectious diseases have posed severe threats to public health across the world. Effective prevention and control of infectious diseases in the long term requires adapting interventions based on epidemiological evidence. The sequential multiple assignment randomized trial (SMART) is a multistage randomized trial that can provide valid evidence of when and how to adapt interventions for controlling infectious diseases based on evolving epidemiological evidence. We review recent developments in SMARTs to bring wider attention to the potential benefits of employing SMARTs in constructing effective adaptive interventions for controlling infectious diseases and other threats to public health. We discuss 2 example SMARTs for infectious diseases and summarize recent developments in SMARTs from the varied aspects of design, analysis, cost, and ethics. Public health investigators are encouraged to familiarize themselves with the related materials we discuss and collaborate with experts in SMARTs to translate the methodological developments into preeminent public health research. (Am J Public Health. 2023;113(1):49-59. https://doi.org/10.2105/AJPH.2022.307135).

Microrandomized Trials: Developing Just-in-Time Adaptive Interventions for Better Public Health.

Just-in-time adaptive interventions (JITAIs) represent an intervention design that adapts the provision and type of support over time to an individual's changing status and contexts, intending to deliver the right support on the right occasion. As a novel strategy for delivering mobile health interventions, JITAIs have the potential to improve access to quality care in underserved communities and, thus, alleviate health disparities, a significant public health concern. Valid experimental designs and analysis methods are required to inform the development of JITAIs. Here, we briefly review the cutting-edge design of microrandomized trials (MRTs), covering both the classical MRT design and its outcome-adaptive counterpart. Associated statistical challenges related to the design and analysis of MRTs are also discussed. Two case studies are provided to illustrate the aforementioned concepts and designs throughout the article. We hope our work leads to better design and application of JITAIs, advancing public health research and practice. (Am J Public Health. 2023;113(1):60-69. https://doi.org/10.2105/AJPH.2022.307150).

A novel approach to assess dynamic treatment regimes embedded in a SMART with an ordinal outcome.

Sequential multiple assignment randomized trials (SMARTs) are used to construct data-driven optimal intervention strategies for subjects based on their intervention and covariate histories in different branches of health and behavioral sciences where a sequence of interventions is given to a participant. Sequential intervention strategies are often called dynamic treatment regimes (DTR). In the existing literature, the majority of the analysis methodologies for SMART data assume a continuous primary outcome. However, ordinal outcomes are also quite common in clinical practice. In this work, first, we introduce the notion of generalized odds ratio ( G O R $$ GOR $$ ) to compare two DTRs embedded in a SMART with an ordinal outcome and discuss some combinatorial properties of this measure. Next, we propose a likelihood-based approach to estimate G O R $$ GOR $$ from SMART data, and derive the asymptotic properties of its estimate. We discuss alternative ways to estimate G O R $$ GOR $$ using concordant-discordant pairs and two-sample U $$ U $$ -statistic. We derive the required sample size formula for designing SMARTs with ordinal outcomes based on G O R $$ GOR $$ . A simulation study shows the performance of the estimated G O R $$ GOR $$ in terms of the estimated power corresponding to the derived sample size. The methodology is applied to analyze data from the SMART+ study, conducted in the UK, to improve carbohydrate periodization behavior in athletes using a menu planner mobile application, Hexis Performance. A freely available Shiny web app using R is provided to make the proposed methodology accessible to other researchers and practitioners.

FedScore: A privacy-preserving framework for federated scoring system development.

OBJECTIVE: We propose FedScore, a privacy-preserving federated learning framework for scoring system generation across multiple sites to facilitate cross-institutional collaborations. MATERIALS AND METHODS: The FedScore framework includes five modules: federated variable ranking, federated variable transformation, federated score derivation, federated model selection and federated model evaluation. To illustrate usage and assess FedScore's performance, we built a hypothetical global scoring system for mortality prediction within 30 days after a visit to an emergency department using 10 simulated sites divided from a tertiary hospital in Singapore. We employed a pre-existing score generator to construct 10 local scoring systems independently at each site and we also developed a scoring system using centralized data for comparison. RESULTS: We compared the acquired FedScore model's performance with that of other scoring models using the receiver operating characteristic (ROC) analysis. The FedScore model achieved an average area under the curve (AUC) value of 0.763 across all sites, with a standard deviation (SD) of 0.020. We also calculated the average AUC values and SDs for each local model, and the FedScore model showed promising accuracy and stability with a high average AUC value which was closest to the one of the pooled model and SD which was lower than that of most local models. CONCLUSION: This study demonstrates that FedScore is a privacy-preserving scoring system generator with potentially good generalizability.

Estimating the optimal linear combination of predictors using spherically constrained optimization.

BACKGROUND: In the context of a binary classification problem, the optimal linear combination of continuous predictors can be estimated by maximizing the area under the receiver operating characteristic curve. For ordinal responses, the optimal predictor combination can similarly be obtained by maximization of the hypervolume under the manifold (HUM). Since the empirical HUM is discontinuous, non-differentiable, and possibly multi-modal, solving this maximization problem requires a global optimization technique. Estimation of the optimal coefficient vector using existing global optimization techniques is computationally expensive, becoming prohibitive as the number of predictors and the number of outcome categories increases. RESULTS: We propose an efficient derivative-free black-box optimization technique based on pattern search to solve this problem, which we refer to as Spherically Constrained Optimization Routine (SCOR). Through extensive simulation studies, we demonstrate that the proposed method achieves better performance than existing methods including the step-down algorithm. Finally, we illustrate the proposed method to predict the severity of swallowing difficulty after radiation therapy for oropharyngeal cancer based on radiation dose to various structures in the head and neck. CONCLUSIONS: Our proposed method addresses an important challenge in combining multiple biomarkers to predict an ordinal outcome. This problem is particularly relevant to medical research, where it may be of interest to diagnose a disease with various stages of progression or a toxicity with multiple grades of severity. We provide the implementation of our proposed SCOR method as an R package, available online at https://CRAN.R-project.org/package=SCOR .

Evaluation of Combinations of Nudging, Pricing, and Labeling Strategies to Improve Diet Quality: A Virtual Grocery Store Experiment Employing a Multiphase Optimization Strategy.

BACKGROUND: Several intervention strategies have been shown to improve diet quality. However, there is limited evidence on the increase in effectiveness that may be achieved through select combinations of these strategies. PURPOSE: This study aimed to identify an effective multicomponent intervention to improve diet quality of a grocery basket by applying a Multiphase Optimization Strategy framework and testing various combinations of four promising strategies using a fully functional web-based grocery store: (i) front-of-pack food labels and real-time feedback of the healthiness of the shoppers' grocery basket, (ii) a tax, (iii) ordering products by a nutritional quality score, and (iv) healthier substitute offers. METHODS: We conducted a hypothetical shopping study (N = 756) with a randomized full factorial design (16 conditions) to estimate main and interaction effects of the four interventions. RESULTS: The "food labels & real-time feedback" and "ordering" strategies had significantly positive main effects on overall diet quality of the shopping basket (both at p < .001). We found no effects on diet quality for the "tax" and "healthier substitute offers." None of the two-way interaction effects for different strategies on overall diet quality and nutrients were significant. CONCLUSIONS: Having "food labels & real-time feedback" and "ordering" simultaneously seemed to be more effective at improving diet quality, compared to having only one of these interventions. These results suggest that a combination of food labels with real-time feedback and ordering interventions can be part of a promising multicomponent strategy to improve diet quality in online shopping platforms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04632212.

Daily Motivational Text Messages to Promote Physical Activity in University Students: Results From a Microrandomized Trial.

BACKGROUND: Low physical activity is an important risk factor for common physical and mental disorders. Physical activity interventions delivered via smartphones can help users maintain and increase physical activity, but outcomes have been mixed. PURPOSE: Here we assessed the effects of sending daily motivational and feedback text messages in a microrandomized clinical trial on changes in physical activity from one day to the next in a student population. METHODS: We included 93 participants who used a physical activity app, "DIAMANTE" for a period of 6 weeks. Every day, their phone pedometer passively tracked participants' steps. They were microrandomized to receive different types of motivational messages, based on a cognitive-behavioral framework, and feedback on their steps. We used generalized estimation equation models to test the effectiveness of feedback and motivational messages on changes in steps from one day to the next. RESULTS: Sending any versus no text message initially resulted in an increase in daily steps (729 steps, p = .012), but this effect decreased over time. A multivariate analysis evaluating each text message category separately showed that the initial positive effect was driven by the motivational messages though the effect was small and trend-wise significant (717 steps; p = .083), but not the feedback messages (-276 steps, p = .4). CONCLUSION: Sending motivational physical activity text messages based on a cognitive-behavioral framework may have a positive effect on increasing steps, but this decreases with time. Further work is needed to examine using personalization and contextualization to improve the efficacy of text-messaging interventions on physical activity outcomes. CLINICALTRIALS.GOV IDENTIFIER: NCT04440553.

AutoScore-Ordinal: an interpretable machine learning framework for generating scoring models for ordinal outcomes.

BACKGROUND: Risk prediction models are useful tools in clinical decision-making which help with risk stratification and resource allocations and may lead to a better health care for patients. AutoScore is a machine learning-based automatic clinical score generator for binary outcomes. This study aims to expand the AutoScore framework to provide a tool for interpretable risk prediction for ordinal outcomes. METHODS: The AutoScore-Ordinal framework is generated using the same 6 modules of the original AutoScore algorithm including variable ranking, variable transformation, score derivation (from proportional odds models), model selection, score fine-tuning, and model evaluation. To illustrate the AutoScore-Ordinal performance, the method was conducted on electronic health records data from the emergency department at Singapore General Hospital over 2008 to 2017. The model was trained on 70% of the data, validated on 10% and tested on the remaining 20%. RESULTS: This study included 445,989 inpatient cases, where the distribution of the ordinal outcome was 80.7% alive without 30-day readmission, 12.5% alive with 30-day readmission, and 6.8% died inpatient or by day 30 post discharge. Two point-based risk prediction models were developed using two sets of 8 predictor variables identified by the flexible variable selection procedure. The two models indicated reasonably good performance measured by mean area under the receiver operating characteristic curve (0.758 and 0.793) and generalized c-index (0.737 and 0.760), which were comparable to alternative models. CONCLUSION: AutoScore-Ordinal provides an automated and easy-to-use framework for development and validation of risk prediction models for ordinal outcomes, which can systematically identify potential predictors from high-dimensional data.

AutoScore-Survival: Developing interpretable machine learning-based time-to-event scores with right-censored survival data.

BACKGROUND: Scoring systems are highly interpretable and widely used to evaluate time-to-event outcomes in healthcare research. However, existing time-to-event scores are predominantly created ad-hoc using a few manually selected variables based on clinician's knowledge, suggesting an unmet need for a robust and efficient generic score-generating method. METHODS: AutoScore was previously developed as an interpretable machine learning score generator, integrating both machine learning and point-based scores in the strong discriminability and accessibility. We have further extended it to the time-to-event outcomes and developed AutoScore-Survival, for generating time-to-event scores with right-censored survival data. Random survival forest provided an efficient solution for selecting variables, and Cox regression was used for score weighting. We implemented our proposed method as an R package. We illustrated our method in a study of 90-day survival prediction for patients in intensive care units and compared its performance with other survival models, the random survival forest, and two traditional clinical scores. RESULTS: The AutoScore-Survival-derived scoring system was more parsimonious than survival models built using traditional variable selection methods (e.g., penalized likelihood approach and stepwise variable selection), and its performance was comparable to survival models using the same set of variables. Although AutoScore-Survival achieved a comparable integrated area under the curve of 0.782 (95% CI: 0.767-0.794), the integer-valued time-to-event scores generated are favorable in clinical applications because they are easier to compute and interpret. CONCLUSIONS: Our proposed AutoScore-Survival provides a robust and easy-to-use machine learning-based clinical score generator to studies of time-to-event outcomes. It gives a systematic guideline to facilitate the future development of time-to-event scores for clinical applications.

Deep learning for temporal data representation in electronic health records: A systematic review of challenges and methodologies.

OBJECTIVE: Temporal electronic health records (EHRs) contain a wealth of information for secondary uses, such as clinical events prediction and chronic disease management. However, challenges exist for temporal data representation. We therefore sought to identify these challenges and evaluate novel methodologies for addressing them through a systematic examination of deep learning solutions. METHODS: We searched five databases (PubMed, Embase, the Institute of Electrical and Electronics Engineers [IEEE] Xplore Digital Library, the Association for Computing Machinery [ACM] Digital Library, and Web of Science) complemented with hand-searching in several prestigious computer science conference proceedings. We sought articles that reported deep learning methodologies on temporal data representation in structured EHR data from January 1, 2010, to August 30, 2020. We summarized and analyzed the selected articles from three perspectives: nature of time series, methodology, and model implementation. RESULTS: We included 98 articles related to temporal data representation using deep learning. Four major challenges were identified, including data irregularity, heterogeneity, sparsity, and model opacity. We then studied how deep learning techniques were applied to address these challenges. Finally, we discuss some open challenges arising from deep learning. CONCLUSION: Temporal EHR data present several major challenges for clinical prediction modeling and data utilization. To some extent, current deep learning solutions can address these challenges. Future studies may consider designing comprehensive and integrated solutions. Moreover, researchers should incorporate clinical domain knowledge into study designs and enhance model interpretability to facilitate clinical implementation.

AutoScore-Imbalance: An interpretable machine learning tool for development of clinical scores with rare events data.

BACKGROUND: Medical decision-making impacts both individual and public health. Clinical scores are commonly used among various decision-making models to determine the degree of disease deterioration at the bedside. AutoScore was proposed as a useful clinical score generator based on machine learning and a generalized linear model. However, its current framework still leaves room for improvement when addressing unbalanced data of rare events. METHODS: Using machine intelligence approaches, we developed AutoScore-Imbalance, which comprises three components: training dataset optimization, sample weight optimization, and adjusted AutoScore. Baseline techniques for performance comparison included the original AutoScore, full logistic regression, stepwise logistic regression, least absolute shrinkage and selection operator (LASSO), full random forest, and random forest with a reduced number of variables. These models were evaluated based on their area under the curve (AUC) in the receiver operating characteristic analysis and balanced accuracy (i.e., mean value of sensitivity and specificity). By utilizing a publicly accessible dataset from Beth Israel Deaconess Medical Center, we assessed the proposed model and baseline approaches to predict inpatient mortality. RESULTS: AutoScore-Imbalance outperformed baselines in terms of AUC and balanced accuracy. The nine-variable AutoScore-Imbalance sub-model achieved the highest AUC of 0.786 (0.732-0.839), while the eleven-variable original AutoScore obtained an AUC of 0.723 (0.663-0.783), and the logistic regression with 21 variables obtained an AUC of 0.743 (0.685-0.801). The AutoScore-Imbalance sub-model (using a down-sampling algorithm) yielded an AUC of 0.771 (0.718-0.823) with only five variables, demonstrating a good balance between performance and variable sparsity. Furthermore, AutoScore-Imbalance obtained the highest balanced accuracy of 0.757 (0.702-0.805), compared to 0.698 (0.643-0.753) by the original AutoScore and the maximum of 0.720 (0.664-0.769) by other baseline models. CONCLUSIONS: We have developed an interpretable tool to handle clinical data imbalance, presented its structure, and demonstrated its superiority over baselines. The AutoScore-Imbalance tool can be applied to highly unbalanced datasets to gain further insight into rare medical events and facilitate real-world clinical decision-making.

Protocol for a multi-site randomized controlled trial of a stepped-care intervention for emergency department patients with panic-related anxiety.

BACKGROUND: Approximately 40% of Emergency Department (ED) patients with chest pain meet diagnostic criteria for panic-related anxiety, but only 1-2% are correctly diagnosed and appropriately managed in the ED. A stepped-care model, which focuses on providing evidence-based interventions in a resource-efficient manner, is the state-of-the art for treating panic disorder patients in medical settings such as primary care. Stepped-care has yet to be tested in the ED setting, which is the first point of contact with the healthcare system for most patients with panic symptoms. METHODS: This multi-site randomized controlled trial (RCT) aims to evaluate the clinical, patient-centred, and economic effectiveness of a stepped-care intervention in a sample of 212 patients with panic-related anxiety presenting to the ED of Singapore's largest public healthcare group. Participants will be randomly assigned to either: 1) an enhanced care arm consisting of a stepped-care intervention for panic-related anxiety; or 2) a control arm consisting of screening for panic attacks and panic disorder. Screening will be followed by baseline assessments and blocked randomization in a 1:1 ratio. Masked follow-up assessments will be conducted at 1, 3, 6, and 12 months. Clinical outcomes will be panic symptom severity and rates of panic disorder. Patient-centred outcomes will be health-related quality of life, daily functioning, psychiatric comorbidity, and health services utilization. Economic effectiveness outcomes will be the incremental cost-effectiveness ratio of the stepped-care intervention relative to screening alone. DISCUSSION: This trial will examine the impact of early intervention for patients with panic-related anxiety in the ED setting. The results will be used to propose a clinically-meaningful and cost-effective model of care for ED patients with panic-related anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT03632356. Retrospectively registered 15 August 2018.

Incentives for Uptake of and Adherence to Outpatient Stroke Rehabilitation Services: A 3-Arm Randomized Controlled Trial.

OBJECTIVE: To determine if rehabilitation uptake and adherence can be increased by providing coordinated transportation (increased convenience) and eliminating out-of-pocket costs (reduced expense). DESIGN: Three-arm randomized controlled trial. SETTING: Stroke units of 2 Singapore tertiary hospitals. PARTICIPANTS: Singaporeans or permanent residents 21 years or older who were diagnosed as having stroke and were discharged home with physician's recommendation to continue outpatient rehabilitation (N=266). INTERVENTIONS: A Transportation Incentives arm (T), which provides free transportation services, a Transportation & Sessions Incentives arm (T&S), offering free transportation and prescribed stroke rehabilitation sessions, and a control arm, Education (E), consisting of a stroke rehabilitation educational program. MAIN OUTCOME MEASURES: The primary study outcome was uptake of outpatient rehabilitation services (ORS) among patients poststroke and key predefined secondary outcomes being number of sessions attended and adherence to prescribed sessions. RESULTS: Uptake rate of ORS was 73.0% for E (confidence interval [CI], 63.8%-82.3%), 81.8% for T (CI, 73.8%-89.8%), and 84.3% for T&S (CI, 76.7%-91.8%). Differences of T and T&S vs E were not statistically significant (P=.22 and P=.10, respectively). However, average number of rehabilitation sessions attended were significantly higher in both intervention arms: 5.50±7.65 for T and 7.51±9.52 for T&S vs 3.26±4.22 for control arm (E) (T vs E: P=.017; T&S vs E: P<.001). Kaplan-Meier analysis indicated that persistence was higher for T&S compared with E (P=.029). CONCLUSIONS: This study has demonstrated a possibility in increasing the uptake of and persistence to stroke ORS with free transportation and sessions. Incentivizing survivors of stroke to take up ORS is a new strategy worthy of further exploration for future policy change in financing ORS or other long-term care services.

Sequential Multiple Assignment Randomized Trial (SMART) to identify optimal sequences of telemedicine interventions for improving initiation of insulin therapy: A simulation study.

BACKGROUND: To examine the value of a Sequential Multiple Assignment Randomized Trial (SMART) design compared to a conventional randomized control trial (RCT) for telemedicine strategies to support titration of insulin therapy for Type 2 Diabetes Mellitus (T2DM) patients new to insulin. METHODS: Microsimulation models were created in R using a synthetic sample based on primary data from 63 subjects enrolled in a pilot study of a smartphone application (App), Diabetes Pal compared to a nurse-based telemedicine strategy (Nurse). For comparability, the SMART and an RCT design were constructed to allow comparison of four (embedded) adaptive interventions (AIs). RESULTS: In the base case scenario, the SMART has similar overall mean expected HbA1c and cost per subject compared with RCT, for sample size of n = 100 over 10,000 simulations. SMART has lower (better) standard deviations of the mean expected HbA1c per AI, and higher efficiency of choosing the correct AI across various sample sizes. The differences between SMART and RCT become apparent as sample size decreases. For both trial designs, the threshold value at which a subject was deemed to have been responsive at an intermediate point in the trial had an optimal choice (i.e., the sensitivity curve had a U-shape). SMART design dominates the RCT, in the overall mean HbA1c (lower value) when the threshold value is close to optimal. CONCLUSIONS: SMART is suited to evaluating the efficacy of different sequences of treatment options, in addition to the advantage of providing information on optimal treatment sequences.

A scoping review of studies using observational data to optimise dynamic treatment regimens.

BACKGROUND: Dynamic treatment regimens (DTRs) formalise the multi-stage and dynamic decision problems that clinicians often face when treating chronic or progressive medical conditions. Compared to randomised controlled trials, using observational data to optimise DTRs may allow a wider range of treatments to be evaluated at a lower cost. This review aimed to provide an overview of how DTRs are optimised with observational data in practice. METHODS: Using the PubMed database, a scoping review of studies in which DTRs were optimised using observational data was performed in October 2020. Data extracted from eligible articles included target medical condition, source and type of data, statistical methods, and translational relevance of the included studies. RESULTS: From 209 PubMed abstracts, 37 full-text articles were identified, and a further 26 were screened from the reference lists, totalling 63 articles for inclusion in a narrative data synthesis. Observational DTR models are a recent development and their application has been concentrated in a few medical areas, primarily HIV/AIDS (27, 43%), followed by cancer (8, 13%), and diabetes (6, 10%). There was substantial variation in the scope, intent, complexity, and quality between the included studies. Statistical methods that were used included inverse-probability weighting (26, 41%), the parametric G-formula (16, 25%), Q-learning (10, 16%), G-estimation (4, 6%), targeted maximum likelihood/minimum loss-based estimation (4, 6%), regret regression (3, 5%), and other less common approaches (10, 16%). Notably, studies that were primarily intended to address real-world clinical questions (18, 29%) tended to use inverse-probability weighting and the parametric G-formula, relatively well-established methods, along with a large amount of data. Studies focused on methodological developments (45, 71%) tended to be more complicated and included a demonstrative real-world application only. CONCLUSIONS: As chronic and progressive conditions become more common, the need will grow for personalised treatments and methods to estimate the effects of DTRs. Observational DTR studies will be necessary, but so far their use to inform clinical practice has been limited. Focusing on simple DTRs, collecting large and rich clinical datasets, and fostering tight partnerships between content experts and data analysts may result in more clinically relevant observational DTR studies.

Sample size calculation based on precision for pilot sequential multiple assignment randomized trial (SMART).

The sequential multiple assignment randomized trial (SMART) is a design used to develop dynamic treatment regimes (DTRs). Given that DTRs are generally less well researched, pilot SMART studies are often necessary. One challenge in pilot SMART is to determine the sample size such that it is small yet meaningfully informative for future full-fledged SMART. Here, we develop a precision-based approach, where the calculated sample size confines the marginal mean outcome of a DTR within a prespecified margin of error. The sample size calculations will be presented for two-stage SMARTs, and for various common outcome types.

Heart rate n-variability (HRnV) and its application to risk stratification of chest pain patients in the emergency department.

BACKGROUND: Chest pain is one of the most common complaints among patients presenting to the emergency department (ED). Causes of chest pain can be benign or life threatening, making accurate risk stratification a critical issue in the ED. In addition to the use of established clinical scores, prior studies have attempted to create predictive models with heart rate variability (HRV). In this study, we proposed heart rate n-variability (HRnV), an alternative representation of beat-to-beat variation in electrocardiogram (ECG), and investigated its association with major adverse cardiac events (MACE) in ED patients with chest pain. METHODS: We conducted a retrospective analysis of data collected from the ED of a tertiary hospital in Singapore between September 2010 and July 2015. Patients > 20 years old who presented to the ED with chief complaint of chest pain were conveniently recruited. Five to six-minute single-lead ECGs, demographics, medical history, troponin, and other required variables were collected. We developed the HRnV-Calc software to calculate HRnV parameters. The primary outcome was 30-day MACE, which included all-cause death, acute myocardial infarction, and revascularization. Univariable and multivariable logistic regression analyses were conducted to investigate the association between individual risk factors and the outcome. Receiver operating characteristic (ROC) analysis was performed to compare the HRnV model (based on leave-one-out cross-validation) against other clinical scores in predicting 30-day MACE. RESULTS: A total of 795 patients were included in the analysis, of which 247 (31%) had MACE within 30 days. The MACE group was older, with a higher proportion being male patients. Twenty-one conventional HRV and 115 HRnV parameters were calculated. In univariable analysis, eleven HRV and 48 HRnV parameters were significantly associated with 30-day MACE. The multivariable stepwise logistic regression identified 16 predictors that were strongly associated with MACE outcome; these predictors consisted of one HRV, seven HRnV parameters, troponin, ST segment changes, and several other factors. The HRnV model outperformed several clinical scores in the ROC analysis. CONCLUSIONS: The novel HRnV representation demonstrated its value of augmenting HRV and traditional risk factors in designing a robust risk stratification tool for patients with chest pain in the ED.