A flexible multi‐domain test with adaptive weights and its application to clinical trials

The design of a clinical trial is often complicated by the multi‐systemic nature of the disease; a single endpoint often cannot capture the spectrum of potential therapeutic benefits. Multi‐domain outcomes which take into account patient heterogeneity of disease presentation through measurements of multiple symptom/functional domains are an attractive alternative to a single endpoint. A multi‐domain test with adaptive weights is proposed to synthesize the evidence of treatment efficacy over numerous disease domains. The test is a weighted sum of domain‐specific test statistics with weights selected adaptively via a data‐driven algorithm. The null distribution of the test statistic is constructed empirically through resampling and does not require estimation of the covariance structure of domain‐specific test statistics. Simulations show that the proposed test controls the type I error rate, and has increased power over other methods such as the O'Brien and Wei‐Lachin tests in scenarios reflective of clinical trial settings. Data from a clinical trial in a rare lysosomal storage disorder were used to illustrate the properties of the proposed test. As a strategy of combining marginal test statistics, the proposed test is flexible and readily applicable to a variety of clinical trial scenarios.     

What matters most? Different stakeholder perspectives on estimands for an invented case study in COPD

In drug development, we ask ourselves which population, endpoint and treatment comparison should be investigated. In this context, we also debate what matters most to the different stakeholders that are involved in clinical drug development, for example, patients, physicians, regulators and payers. With the publication of draft ICH E9 addendum on estimands in 2017, we now have a common framework and language to discuss such questions in an informed and transparent way. This has led to the estimand discussion being a key element in study development, including design, analysis and interpretation of a treatment effect. At an invited session at the 2018 PSI annual conference, PSI hosted a role‐play debate where the aim of the session was to mimic a regulatory and payer scientific advice discussion for a COPD drug. Including role‐play views from an industry sponsor, a patient, a regulator and a payer. This paper presents the invented COPD case‐study design and considerations relating to appropriate estimands are discussed by each of the stakeholders from their differing viewpoints with the additional inclusion of a technical (academic) perspective. The rationale for each perspective on approaches for handling intercurrent events is presented, with a key emphasis on the application of while‐on‐treatment and treatment policy estimands in this context. It is increasingly recognised that the treatment effect estimated by the treatment policy approach may not always be of primary clinical interest and may not appropriately communicate to patients the efficacy they can expect if they take the treatment as directed.     

The Who Concept of Sexual Health Applied to An Urban Poor Community in Mumbai,India

Objectives: The objectives of this study were to describe a scale that operationalizes the World Health Organization concept of sexual health and to assess factors associated with scale variation. Methods: Qualitative in-depth interviews (N = 39), sexual health interviews (N = 21), and survey data (N = 1,128) for this article are drawn from an Indo-U.S. project to reduce the incidence of HIV and sexually transmitted infections among poor urban married women (aged 18–49 years old) in Mumbai, India. Results: Lower sexual health status was significantly associated with gender inequity, marital violence, poorer marital relationships and physical health, and lower empowerment and social support. Conclusions: This work demonstrates the need to view sexual health in the broader context of community and family.     

Immigrant employment and earnings growth in Canada and the USA: evidence from longitudinal data

We study the short-term trajectories of employment, hours worked, and real wages of immigrants in Canada and the USA using nationally representative longitudinal datasets covering 1996–2008. Models with person fixed effects show that, on average, immigrant men in Canada do not experience any relative growth in these three outcomes compared to men born in Canada. Immigrant men in the USA, on the other hand, experience positive annual growth in all three domains relative to US-born men. This difference is largely on account of low-educated immigrant men, who experience faster or longer periods of relative growth in employment and wages in the USA than in Canada. We further compare longitudinal and cross-sectional trajectories and find that the latter over-estimate wage growth of earlier arrivals, presumably reflecting selective return migration.     

Ecometrics: Toward a Science of Assessing Ecological Settings, With Application to the Systematic Social Observation of Neighborhoods

This paper considers the quantitative assessment of ecological settings such as neighborhoods and schools. Available administrative data typically provide useful but limited information on such settings. We demonstrate how more complete information can be reliably obtained from surveys and observational studies. Survey-based assessments are constructed by aggregating over multiple item responses of multiple informants within each setting. Item and rater inconsistency produce uncertainty about the setting being assessed, with definite implications for research design. Observation-based assessments also have a multilevel error structure. The paper describes measures constructed from interviews, direct observations, and videotapes of Chicago neighborhoods and illustrates an "ecometric" analysis—a study of bias and random error in neighborhood assessments. Using the observation data as an illustrative example, we present a three-level hierarchical statistical model that identifies sources of error in aggregating across items within face-blocks and in aggregating across face-blocks to larger geographic units such as census tracts. Convergent and divergent validity are evaluated by studying associations between the observational measures and theoretically related measures obtained from the U.S. Census, and a citywide survey of neighborhood residents.     

A continuously adaptive nonparametric two–sample test

A two–sample test statistic for detecting shifts in location is developed for a broad range of underlying distributions using adaptive techniques. The test statistic is a linear rank statistics which uses a simple modification of the Wilcoxon test; the scores are Winsorized ranks where the upper and lower Winsorinzing proportions are estimated in the first stage of the adaptive procedure using sample the first stage of the adaptive procedure using sample measures of the distribution's skewness and tailweight. An empirical relationship between the Winsorizing proportions and the sample skewness and tailweight allows for a ‘continuous’ adaptation of the test statistic to the data. The test has good asymptotic properties, and the small sample results are compared with other populatr parametric, nonparametric, and two–stage tests using Monte Carlo methods. Based on these results, this proposed test procedure is recommended for moderate and larger sample sizes.     

Reducing Risk Through Real Options in Systems Design: The Case of Architecting a Maritime Domain Protection System

Complex engineering systems are usually designed to last for many years. Such systems will face many uncertainties in the future. Hence the design and deployment of these systems should not be based on a single scenario, but should incorporate flexibility. Flexibility can be incorporated in system architectures in the form of options that can be exercised in the future when new information is available. Incorporating flexibility comes, however, at a cost. To evaluate if this cost is worth the investment a real options analysis can be carried out. This approach is demonstrated through analysis of a case study of a previously developed static system-of-systems for maritime domain protection in the Straits of Malacca. This article presents a framework for dynamic strategic planning of engineering systems using real options analysis and demonstrates that flexibility adds considerable value over a static design. In addition to this it is shown that Monte Carlo analysis and genetic algorithms can be successfully combined to find solutions in a case with a very large number of possible futures and system designs.     

An Examination of Mandated Versus Voluntary Referral as a Determinant of Clinical Outcome

A literature review was undertaken to examine evidence for the effectiveness of psychotherapy with mandated clients. The primary question addressed was whether or not clients mandated to therapy, whether by court order or by order of their employers, show poorer outcomes than clients who enter therapy voluntarily. To this end, research on client resistance and motivational readiness to change was reviewed. This was followed by an examination of research on the effectiveness of mandated treatment. The question of the potential influence of relationship factors such as the therapeutic alliance was also addressed. The literature review was followed by suggestions for future research on the effectiveness of treatment for clients with mandated or voluntary referral status.