Addressing Posttreatment Selection Bias in Comparative Effectiveness Research, Using Real-World Data and Simulation.

To examine methodologies that address imbalanced treatment switching and censoring, 6 different analytical approaches were evaluated under a comparative effectiveness framework: intention-to-treat, as-treated, intention-to-treat with censor-weighting, as-treated with censor-weighting, time-varying exposure, and time-varying exposure with censor-weighting. Marginal structural models were employed to address time-varying exposure, confounding, and possibly informative censoring in an administrative data set of adult patients who were hospitalized with acute coronary syndrome and treated with either clopidogrel or ticagrelor. The effectiveness endpoint included first occurrence of death, myocardial infarction, or stroke. These methodologies were then applied across simulated data sets with varying frequencies of treatment switching and censoring to compare the effect estimate of each analysis. The findings suggest that implementing different analytical approaches has an impact on the point estimate and interpretation of analyses, especially when censoring is highly unbalanced.

Diagnostic accuracy and prediction increment of markers of epithelial-mesenchymal transition to assess cancer cell detachment from primary tumors.

BACKGROUND: Metastases play a role in about 90% of cancer deaths. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells might provide diagnostic information about the likelihood that cancer cells have detached from the primary tumor. Used together with established diagnostic tests of detachment-lymph node evaluation and radiologic imaging-EMT marker measurements might improve the ability of clinicians to assess the patient's risk of metastatic disease. Translation of EMT markers to clinical use has been hampered by a lack of valid analyses of clinically-informative parameters. Here, we demonstrate a rigorous approach to estimating the sensitivity, specificity, and prediction increment of an EMT marker to assess cancer cell detachment from primary tumors. METHODS: We illustrate the approach using immunohistochemical measurements of the EMT marker E-cadherin in a set of colorectal primary tumors from a population-based prospective cohort in North Carolina. Bayesian latent class analysis was used to estimate sensitivity and specificity in a setting of multiple imperfect diagnostic tests and no gold standard. Risk reclassification analysis was used to assess the extent to which addition of the marker to the panel of established diagnostic tests would improve mortality prediction. We explored how changing the latent class conditional dependence assumptions and definition of marker positivity would impact the results. RESULTS: All diagnostic accuracy and prediction increment statistics varied with the choice of cut point to define marker positivity. When comparing different definitions of marker positivity to each other, numerous trade-offs were observed in terms of sensitivity, specificity, predictive discrimination, and prediction model calibration. We then discussed several implementation considerations and the plausibility of analytic assumptions. CONCLUSIONS: The approaches presented here can be extended to any EMT marker, to most forms of cancer, and to different kinds of EMT marker measurements, such as RNA or gene methylation data. These methods provide valid, clinically-informative assessment of whether and how to use a given EMT marker to refine tumor staging and consequent treatment decisions.

Interrelationships between stress, eating attitudes, and metabolism in endurance athletes across a competitive season.

A competitive sport season represents a multidimensional stressor where physical and psychological stress may render an athlete susceptible to energy deficiency (ED). Downstream effects of ED can include a reduction in measured-to-predicted resting metabolic rate (RMRratio), indicating metabolic compensation. A pathway linking stress, eating attitudes, and metabolic compensation has not been explored. To test if sport-specific stress is associated with eating attitudes and metabolism in endurance athletes (18-22 years) at different phases of a competitive season, we assessed two groups of athletes: 26 swimmers (15 female and 11 male) during peak season (PEAK), and 26 runners (female) across pre- (PRE) and off-season (OFF). Stress (RESTQ-52), eating attitudes (cognitive restraint (CR), drive for muscularity (DM), and body dissatisfaction), and metabolism (RMRratio) were assessed. In PRE, sport-specific stress and CR were negatively correlated with RMRratio (R = -0.58; p < 0.05, and R = -0.57; p < 0.05, respectively). In PEAK, sport-specific stress and DM were negatively correlated with RMRratio (R = -0.64; p < 0.05; R = -0.40; p < 0.05, respectively). DM was positively related to sport-specific stress (R = 0.55; p < 0.05). During OFF, there was no relation between RMRratio and sport-specific stress. In runners, there was a change in stress from PRE-to-OFF with highest reported stress during PRE (p < 0.05) versus OFF. Regression analyses revealed that sport-specific stress and CR were significant predictors of RMRratio during PRE and PEAK (p < 0.05), but not OFF (p > 0.05). Associations between stress, eating attitudes, and metabolic compensation in endurance athletes during PRE and PEAK season suggest that during heavier training, metabolic compensation may be linked to upstream eating attitudes associated with sport-stressors.