Training the Next Generation of Data Monitoring Committee Members: An Initiative of the Heart Failure Collaboratory.

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members. The Heart Failure Collaboratory (HFC), a multidisciplinary public-private consortium of academics, trialists, patients, industry representatives, and government agencies, is working to improve the clinical trial ecosystem. The HFC aims to improve clinical trial efficiency and quality by standardizing concepts, and to help meet the demand for experienced individuals on DMCs by creating a standardized approach to training new members. This paper discusses the HFC's training workshop, and an apprenticeship model for new DMC members. It describes opportunities and challenges DMCs face, along with common myths and best practices learned through previous experiences, with an emphasis on data confidentiality and need for quality independent statistical reporting groups.

How Consistently Do 13 Clearinghouses Identify Social and Behavioral Development Programs as "Evidence-Based"?

Clearinghouses develop scientific criteria that they then use to vet existing research studies on a program to reach a verdict about how evidence-based it is. This verdict is then recorded on a website in hopes that stakeholders in science, public policy, the media, and even the general public, will consult it. This paper (1) compares the causal design and analysis preferences of 13 clearinghouses that assess the effectiveness of social and behavioral development programs, (2) estimates how consistently these clearinghouses rank the same program, and then (3) uses case studies to probe why their conclusions differ. Most clearinghouses place their highest value on randomized control trials, but they differ in how they treat program implementation, quasi-experiments, and whether their highest program ratings require effects of a given size that independently replicate or that temporally persist. Of the 2525 social and behavioral development programs sampled over clearinghouses, 82% (n = 2069) were rated by a single clearinghouse. Of the 297 programs rated by two clearinghouses, agreement about program effectiveness was obtained for about 55% (n = 164), but the clearinghouses agreed much more on program ineffectiveness than effectiveness. Most of the inconsistency is due to clearinghouses' differences in requiring independently replicated and/or temporally sustained effects. Without scientific consensus about matters like these, "evidence-based" will remain more of an aspiration than achievement in the social and behavioral sciences.

Primary care providers should prescribe aspirin to prevent cardiovascular disease based on benefit-risk ratio, not age.

Recent guidelines restricted aspirin (ASA) in primary prevention of cardiovascular disease (CVD) to patients <70 years old and more recent guidance to <60.In the most comprehensive prior meta-analysis, the Antithrombotic Trialists Collaboration reported a significant 12% reduction in CVD with similar benefit-risk ratios at older ages. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, four trials were added to an updated meta-analysis.ASA produced a statistically significant 13% reduction in CVD with 95% confidence limits (0.83 to 0.92) with similar benefits at older ages in each of the trials.Primary care providers should make individual decisions whether to prescribe ASA based on benefit-risk ratio, not simply age. When the absolute risk of CVD is >10%, benefits of ASA will generally outweigh risks of significant bleeding. ASA should be considered only after implementation of therapeutic lifestyle changes and other drugs of proven benefit such as statins, which are, at the very least, additive to ASA. Our perspective is that individual clinical judgements by primary care providers about prescription of ASA in primary prevention of CVD should be based on our evidence-based solution of weighing all the absolute benefits and risks rather than age. This strategy would do far more good for far more patients as well as far more good than harm in both developed and developing countries. This new and novel strategy for primary care providers to consider in prescribing ASA in primary prevention of CVD is the same as the general approach suggested by Professor Geoffrey Rose decades ago.

Point of care, bone marrow mononuclear cell therapy in ischemic heart failure patients personalized for cell potency: 12-month feasibility results from CardiAMP heart failure roll-in cohort.

AIM: Heart failure following myocardial infarction (MI) is a potentially lethal problem with a staggering incidence. The CardiAMP Heart Failure trial represents the first attempt to personalize marrow-derived cell-based therapy to individuals with cell characteristics associated with beneficial responses in prior trials. Before the initiation of the randomized pivotal trial, an open-label "roll-in cohort" was completed to ensure the feasibility of the protocol's procedures. METHODS: Patients with chronic post-MI heart failure (NYHA class II-III) receiving stable, guideline-directed medical therapy with a left ventricular ejection fraction between 20 and 40% were eligible. Two weeks prior to treatment, a ~ 5 mL bone marrow aspiration was performed to examine "cell potency". On treatment day, a 60 mL bone marrow aspiration, bone marrow mononuclear cell (BM MNC) enrichment and transendocardial injection of 200 million BM MNC's was performed in a single, point of care encounter. Patients were then followed to assess clinical outcomes. RESULTS: The cell potency small volume bone marrow aspirate, the 60 mL bone marrow aspirate, and transendocardial injections were well tolerated in 10 patients enrolled. There were no serious adverse events related to bone marrow aspiration or cell delivery. Improvement in 6-min walk distance was observed at 6 months (+47.8 m, P = 0.01) and trended to improvement at 12 months (+46.4, P = 0.06). Similarly, trends to improved NYHA heart failure functional class, quality of life, left ventricular ejection fraction and recruitment of previously akinetic left ventricular wall segments were observed. CONCLUSION: All CardiAMP HF protocol procedures were feasible and well tolerated. Favorable functional, echo and quality of life trends suggest this approach may offer promise for patients with post MI heart failure. The randomized CardiAMP Heart Failure pivotal trial is underway to confirm the efficacy of this approach. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02438306.

Manifesto for new directions in developmental science.

Although developmental science has always been evolving, these times of fast-paced and profound social and scientific changes easily lead to disorienting fragmentation rather than coherent scientific advances. What directions should developmental science pursue to meaningfully address real-world problems that impact human development throughout the lifespan? What conceptual or policy shifts are needed to steer the field in these directions? The present manifesto is proposed by a group of scholars from various disciplines and perspectives within developmental science to spark conversations and action plans in response to these questions. After highlighting four critical content domains that merit concentrated and often urgent research efforts, two issues regarding "how" we do developmental science and "what for" are outlined. This manifesto concludes with five proposals, calling for integrative, inclusive, transdisciplinary, transparent, and actionable developmental science. Specific recommendations, prospects, pitfalls, and challenges to reach this goal are discussed.

Carotid Plaque Strain Indices Were Correlated With Cognitive Performance in a Cohort With Advanced Atherosclerosis, and Traditional Doppler Measures Showed no Association.

OBJECTIVES: Traditional Doppler measures have been used to predict cognitive performance in patients with carotid atherosclerosis. Novel measures, such as carotid plaque strain indices (CPSIs), have shown associations with cognitive performance. We hypothesized that lower mean middle cerebral artery (MCA) velocities, higher bulb-internal carotid artery (ICA) velocities, the MCA pulsatility index (PI), and CPSIs would be associated with poorer cognitive performance in individuals with advanced atherosclerosis. METHODS: Neurocognitive testing, carotid ultrasound imaging, transcranial Doppler imaging, and carotid strain imaging were performed on 40 patients scheduled for carotid endarterectomy. Kendall tau correlations were used to examine relationships between cognitive tests and the surgical-side maximum peak systolic velocity (PSV; from the bulb, proximal, mid, or distal ICA), mean MCA velocity and PI, and maximum CPSIs (axial, lateral, and shear strain indices used to characterize plaque deformations with arterial pulsation). Cognitive measures included age-adjusted indices of verbal fluency, verbal and visual learning/memory, psychomotor speed, auditory attention/working memory, visuospatial construction, and mental flexibility. RESULTS: Participants had a median age of 71.0 (interquartile range, 9.75) years; 26 were male (65%), and 14 were female (35%). Traditional Doppler parameters, PSV, mean MCA velocity, and MCA PI did not predict cognitive performance (all P > .05). Maximum CPSIs were significantly associated with cognitive performance (P < .05). CONCLUSIONS: Traditional velocity measurements of the maximum bulb-ICA PSV, mean MCA velocity, and PI were not associated with cognitive performance in patients with advanced atherosclerotic disease; however, maximum CPSIs were associated with cognitive performance. These findings suggest that cognition may be associated with unstable plaque rather than blood flow.

Attenuation Coefficient Parameter Computations for Tissue Composition Assessment of Carotid Atherosclerotic Plaque in Vivo.

Quantitative ultrasound has been used to assess carotid plaque tissue composition. Here, we compute the attenuation coefficient (AC) in vivo with the optimum power spectral shift estimator (OPSSE) and reference phantom method (RPM), extract AC parameters and form parametric maps. Differences between OPSSE and RPM AC parameters are computed. Relationships between AC parameters, surgical scores and histopathology assessments are examined. Kendall's τ correlations between OPSSE AC and surgical scores are significant, including those between cholesterol and Standard Deviation (adjusted p = 0.038); thrombus and Minimum (adjusted p = 0.002), Maximum (adjusted p = 0.021) and Standard Deviation (adjusted p = 0.001); ulceration and Average (adjusted p = 0.033), Median (unadjusted p = 0.013), Maximum (unadjusted p = 0.039) and Mode (adjusted p = 0.009). The strongest correlations with histopathology are percentage cholesterol and Median OPSSE (unadjusted p = 0.007); percentage hemorrhage and Minimum OPSSE (adjusted p < 0.001); hemosiderin score and Median OPSSE (adjusted p = 0.010); and percentage calcium and Percentage Non-physical RPM Pixels (unadjusted p = 0.014). Kruskal-Wallis H and Dunn's post hoc tests have the ability to distinguish between groups (p < 0.05). Results suggest AC parameters may assist in vivo evaluation of carotid plaque vulnerability.

How much bias results if a quasi-experimental design combines local comparison groups, a pretest outcome measure and other covariates?: A within study comparison of preschool effects.

This study uses a within study comparison design (WSC) to conduct a novel test of how much causal bias results when researchers use a nonequivalent comparison group design type (NECGD) that combines: (a) a comparison group local to the treatment group; (b) a pretest measure of the study outcome; and (c) a rich set of 19 other multidimensional covariates. Most prior WSCs have dealt with the bias consequences of only 1 of these, revealing that each routinely reduces bias but does not necessarily eliminate it. Thus, a need exists to identify NECGDs that more robustly eliminate bias. This study is the first to examine how combining the 3 bias-control mechanisms above affects bias. The intervention we examine is a prekindergarten mathematics curriculum, for which a randomized control trial (RCT) produces a positive 1-year math effect. Final bias in the NECGD is assessed as the difference between its impact and that of the RCT when each design has the same intervention, outcome, and estimand. Over the many specifications we explore, NECGD bias is less than .10 standard deviations, indicating that minimal bias results when an NECGD combines all 3 design elements. The factorial design we use in this study also tests the bias associated with seven other NECGD types. Comparing the total pattern of results shows that the minimal bias when all 3 elements are combined is uniquely attributable to the locally chosen comparison group and not the availability of a pretest or other covariates. In actual research practice, it is impossible to predict in advance which design elements will affect bias by how much in any given application. So further research is needed to probe whether the simultaneous use of all three design elements achieves minimal bias dependably across diverse applications and not just in the preschool math context examined here. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The Set of Assumptions Randomized Control Trials Make and Their Implications for the Role of Such Experiments in Evidence-Based Child and Adolescent Development Research.

This chapter highlights the key assumptions underlying Randomized Control Trials (RCTs) and illustrates them with regard to the practice of RCTs in the realm of child and adolescent development. Given the prominence of RCTs in policy research, we analyze the possible ways in which these assumptions might not be met by single randomized experiments, thereby making it difficult to draw valid causal inference from single studies. We frame this discussion within the categories of internal validity, statistical conclusion validity, construct validity, and external validity and address the debate about the "gold standard" status accorded to RCTs.

The selection of comparators for randomized controlled trials of health-related behavioral interventions: recommendations of an NIH expert panel.

OBJECTIVES: To provide recommendations for the selection of comparators for randomized controlled trials of health-related behavioral interventions. STUDY DESIGN AND SETTING: The National Institutes of Health Office of Behavioral and Social Science Research convened an expert panel to critically review the literature on control or comparison groups for behavioral trials and to develop strategies for improving comparator choices and for resolving controversies and disagreements about comparators. RESULTS: The panel developed a Pragmatic Model for Comparator Selection in Health-Related Behavioral Trials. The model indicates that the optimal comparator is the one that best serves the primary purpose of the trial but that the optimal comparator's limitations and barriers to its use must also be taken into account. CONCLUSION: We developed best practice recommendations for the selection of comparators for health-related behavioral trials. Use of the Pragmatic Model for Comparator Selection in Health-Related Behavioral Trials can improve the comparator selection process and help resolve disagreements about comparator choices.

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein.

Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebral artery occlusion. Decreased miR-7 expression was observed in both young and aged rats of both sexes after cerebral ischemia. Pre- or postischemic treatment with miR-7 mimic decreased the lesion volume in both sexes and ages studied. Furthermore, systemic injection of miR-7 mimic into mice at 30 min (but not 2 hours) after cerebral ischemia substantially decreased the lesion volume and improved motor and cognitive functional recovery with minimal peripheral toxicity. The miR-7 mimic treatment substantially reduced the postischemic induction of α-synuclein (α-Syn), a protein that induces mitochondrial fragmentation, oxidative stress, and autophagy that promote neuronal cell death. Deletion of the gene encoding α-Syn abolished miR-7 mimic-dependent neuroprotection and functional recovery in young male mice. Further analysis confirmed that the transcript encoding α-Syn was bound and repressed by miR-7. Our findings suggest that miR-7 mimics may therapeutically minimize stroke-induced brain damage and disability.

The Sequential Scale-Up of an Evidence-Based Intervention: A Case Study.

Policy makers face dilemmas when choosing a policy, program, or practice to implement. Researchers in education, public health, and other fields have proposed a sequential approach to identifying interventions worthy of broader adoption, involving pilot, efficacy, effectiveness, and scale-up studies. In this article, we examine a scale-up of an early math intervention to the state level, using a cluster randomized controlled trial. The intervention, Pre-K Mathematics, has produced robust positive effects on children's math ability in prior pilot, efficacy, and effectiveness studies. In the current study, we ask if it remains effective at a larger scale in a heterogeneous collection of pre-K programs that plausibly represent all low-income families with a child of pre-K age who live in California. We find that Pre-K Mathematics remains effective at the state level, with positive and statistically significant effects (effect size on the Early Childhood Longitudinal Study, Birth Cohort Mathematics Assessment = .30, p < .01). In addition, we develop a framework of the dimensions of scale-up to explain why effect sizes might decrease as scale increases. Using this framework, we compare the causal estimates from the present study to those from earlier, smaller studies. Consistent with our framework, we find that effect sizes have decreased over time. We conclude with a discussion of the implications of our study for how we think about the external validity of causal relationships.

Comparative Regression Discontinuity: A Stress Test With Small Samples.

Compared to the randomized experiment (RE), the regression discontinuity design (RDD) has three main limitations: (1) In expectation, its results are unbiased only at the treatment cutoff and not for the entire study population; (2) it is less efficient than the RE and so requires more cases for the same statistical power; and (3) it requires correctly specifying the functional form that relates the assignment and outcome variables. One way to overcome these limitations might be to add a no-treatment functional form to the basic RDD and including it in the outcome analysis as a comparison function rather than as a covariate to increase power. Doing this creates a comparative regression discontinuity design (CRD). It has three untreated regression lines. Two are in the untreated segment of the RDD-the usual RDD one and the added untreated comparison function-while the third is in the treated RDD segment. Also observed is the treated regression line in the treated segment. Recent studies comparing RE, RDD, and CRD causal estimates have found that CRD reduces imprecision compared to RDD and also produces valid causal estimates at the treatment cutoff and also along all the rest of the assignment variable. The present study seeks to replicate these results, but with considerably smaller sample sizes. The power difference between RDD and CRD is replicated, but not the bias results either at the treatment cutoff or away from it. We conclude that CRD without large samples can be dangerous.

Statistical Power for the Comparative Regression Discontinuity Design With a Pretest No-Treatment Control Function: Theory and Evidence From the National Head Start Impact Study.

The basic regression discontinuity design (RDD) has less statistical power than a randomized control trial (RCT) with the same sample size. Adding a no-treatment comparison function to the basic RDD creates a comparative RDD (CRD); and when this function comes from the pretest value of the study outcome, a CRD-Pre design results. We use a within-study comparison (WSC) to examine the power of CRD-Pre relative to both basic RDD and RCT. We first build the theoretical foundation for power in CRD-Pre, then derive the relevant variance formulae, and finally compare them to the theoretical RCT variance. We conclude from this theoretical part of this article that (1) CRD-Pre's power gain depends on the partial correlation between the pretest and posttest measures after conditioning on the assignment variable, (2) CRD-Pre is less responsive than basic RDD to how the assignment variable is distributed and where the cutoff is located, and (3) under a variety of conditions, the efficiency of CRD-Pre is very close to that of the RCT. Data from the National Head Start Impact Study are then used to construct RCT, RDD, and CRD-Pre designs and to compare their power. The empirical results indicate (1) a high level of correspondence between the predicted and obtained power results for RDD and CRD-Pre relative to the RCT, and (2) power levels in CRD-Pre and RCT that are very close. The study is unique among WSCs for its focus on the correspondence between RCT and observational study standard errors rather than means.

The CardiAMP Heart Failure trial: A randomized controlled pivotal trial of high-dose autologous bone marrow mononuclear cells using the CardiAMP cell therapy system in patients with post-myocardial infarction heart failure: Trial rationale and study design.

BACKGROUND: Heart failure following myocardial infarction is a common, disabling, and deadly condition. Direct injection of autologous bone marrow mononuclear cells into the myocardium may result in improved functional recovery, relieve symptoms, and improve other cardiovascular outcomes. METHODS: CardiAMP-HF is a randomized, double-blind, sham-controlled, pivotal trial designed to investigate the safety and efficacy of autologous bone marrow mononuclear cells treatment for patients with medically refractory and symptomatic ischemic cardiomyopathy. The primary end point is change in 6-minute walk distance adjusted for major adverse cardiovascular events at 12 months following treatment. Particularly novel aspects of this trial include a cell potency assay to screen subjects who have bone marrow cell characteristics that suggest a favorable response to treatment, a point-of-care treatment method, a high target dose of 200 million cells, and an efficient transcatheter intramyocardial delivery method that is associated with high cell retention. CONCLUSIONS: This novel approach may lead to a new treatment for those with ischemic heart disease suffering from medically refractory heart failure.

Statistical power for the comparative regression discontinuity design with a nonequivalent comparison group.

In the "sharp" regression discontinuity design (RD), all units scoring on one side of a designated score on an assignment variable receive treatment, whereas those scoring on the other side become controls. Thus the continuous assignment variable and binary treatment indicator are measured on the same scale. Because each must be in the impact model, the resulting multi-collinearity reduces the efficiency of the RD design. However, untreated comparison data can be added along the assignment variable, and a comparative regression discontinuity design (CRD) is then created. When the untreated data come from a non-equivalent comparison group, we call this CRD-CG. Assuming linear functional forms, we show that power in CRD-CG is (a) greater than in basic RD; (b) less sensitive to the location of the cutoff and the distribution of the assignment variable; and that (c) fewer treated units are needed in the basic RD component within the CRD-CG so that savings can result from having fewer treated cases. The theory we develop is used to make numerical predictions about the efficiency of basic RD and CRD-CG relative to each other and to a randomized control trial. Data from the National Head Start Impact study are used to test these predictions. The obtained estimates are closer to the predicted parameters for CRD-CG than for basic RD and are generally quite close to the parameter predictions, supporting the emerging argument that CRD should be the design of choice in many applications for which basic RD is now used. (PsycINFO Database Record

Pretest Measures of the Study Outcome and the Elimination of Selection Bias: Evidence from Three Within Study Comparisons.

This paper examines how pretest measures of a study outcome reduce selection bias in observational studies in education. The theoretical rationale for privileging pretests in bias control is that they are often highly correlated with the outcome, and in many contexts, they are also highly correlated with the selection process. To examine the pretest's role in bias reduction, we use the data from two within study comparisons and an especially strong quasi-experiment, each with an educational intervention that seeks to improve achievement. In each study, the pretest measures are consistently highly correlated with post-intervention measures of themselves, but the studies vary the correlation between the pretest and the process of selection into treatment. Across the three datasets with two outcomes each, there are three cases where this correlation is low and three where it is high. A single wave of pretest always reduces bias across the six instances examined, and it eliminates bias in three of them. Adding a second pretest wave eliminates bias in two more instances. However, the pattern of bias elimination does not follow the predicted pattern-that more bias reduction ensues as a function of how highly the pretest is correlated with selection. The findings show that bias is more complexly related to the pretest's correlation with selection than we hypothesized, and we seek to explain why.