Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

Assessing fun in serious games: Formative evaluation of games from two diabetes prevention interventions

Purpose. To determine the usability of two video games to prevent type 2 diabetes and obesity among youth through analysis of data collected during alpha-testing. ^ Subjects. Ten children aged 9 to 12 were selected for three 2-hour alpha testing sessions.^ Methods. "Escape from Diab" and "Nanoswarm" were designed to change dietary and physical inactivity behaviors, based on a theoretical framework of mediating variables obtained from social cognitive theory, self-determination theory, elaboration likelihood model, and behavioral inoculation theory. Thirteen mini-games developed by the software company were divided into 3 groups based on completion date. Children tested 4-5 mini-games in each of three sessions. Observed game play was followed by a scripted interview. Results from observation forms and interview transcripts were tabulated and coded to determine usability. Suggestions for game modifications were delivered to the software design firm, and a follow-up table reports rationale for inclusion or exclusion of such modifications.^ Results. Participants were 50% frequent video game players and 20% non game-players. Most (60%) were female. The mean grade (indicating likeability as a subset of usability) across all games given by children was significantly greater than a neutral grade of 80% (89%, p < 0.01), indicating a positive likeability score. The games on average also received positive ratings for fun, helpfulness of instructions and length compared to neutral values (midpoint on likert scales) (all p < 0.01). Observation notes indicated that participants paid attention to the instructions, did not appear to have much difficulty with the games, and were "not frustrated", "not bored", "very engaged", "not fidgety" and "very calm" (all p < 0.01). The primary issues noted in observations and interviews were unclear instructions and unclear purpose of some games. Player suggestions primarily involved ways to make on screen cues more visible or noticeable, instructions more clear, and games more elaborate or difficult.^ Conclusions. The present study highlights the importance of alpha testing video game components for usability prior to completion to enhance usability and likeability. Results indicate that creating clear instructions, making peripheral screen cues more eye-catching or noticeable, and vigorously stating the purpose of the game to improve understandability are important elements. However, future interventions will each present unique materials and user-interfaces and should therefore also be thoroughly alpha-tested. ^

Left, right and interval bivariate censored data: Evaluating screening mammography in the presence of lead -time bias, length bias and over-detection

Of the large clinical trials evaluating screening mammography efficacy, none included women ages 75 and older. Recommendations on an upper age limit at which to discontinue screening are based on indirect evidence and are not consistent. Screening mammography is evaluated using observational data from the SEER-Medicare linked database. Measuring the benefit of screening mammography is difficult due to the impact of lead-time bias, length bias and over-detection. The underlying conceptual model divides the disease into two stages: pre-clinical (T0) and symptomatic (T1) breast cancer. Treating the time in these phases as a pair of dependent bivariate observations, (t0,t1), estimates are derived to describe the distribution of this random vector. To quantify the effect of screening mammography, statistical inference is made about the mammography parameters that correspond to the marginal distribution of the symptomatic phase duration (T1). This shows the hazard ratio of death from breast cancer comparing women with screen-detected tumors to those detected at their symptom onset is 0.36 (0.30, 0.42), indicating a benefit among the screen-detected cases. ^

Analysis of interval -censored events in hypertension studies: Evaluation of treatment of coronary heart disease

Many statistical studies feature data with both exact-time and interval-censored events. While a number of methods currently exist to handle interval-censored events and multivariate exact-time events separately, few techniques exist to deal with their combination. This thesis develops a theoretical framework for analyzing a multivariate endpoint comprised of a single interval-censored event plus an arbitrary number of exact-time events. The approach fuses the exact-time events, modeled using the marginal method of Wei, Lin, and Weissfeld, with a piecewise-exponential interval-censored component. The resulting model incorporates more of the information in the data and also removes some of the biases associated with the exclusion of interval-censored events. A simulation study demonstrates that our approach produces reliable estimates for the model parameters and their variance-covariance matrix. As a real-world data example, we apply this technique to the Systolic Hypertension in the Elderly Program (SHEP) clinical trial, which features three correlated events: clinical non-fatal myocardial infarction, fatal myocardial infarction (two exact-time events), and silent myocardial infarction (one interval-censored event). ^