Analyzing left-truncated right-censored data with uncertain onset time with parametric models

Prevalent sampling is an efficient and focused approach to the study of the natural history of disease. Right-censored time-to-event data observed from prospective prevalent cohort studies are often subject to left-truncated sampling. Left-truncated samples are not randomly selected from the population of interest and have a selection bias. Extensive studies have focused on estimating the unbiased distribution given left-truncated samples. However, in many applications, the exact date of disease onset was not observed. For example, in an HIV infection study, the exact HIV infection time is not observable. However, it is known that the HIV infection date occurred between two observable dates. Meeting these challenges motivated our study. We propose parametric models to estimate the unbiased distribution of left-truncated, right-censored time-to-event data with uncertain onset times. We first consider data from a length-biased sampling, a specific case in left-truncated samplings. Then we extend the proposed method to general left-truncated sampling. With a parametric model, we construct the full likelihood, given a biased sample with unobservable onset of disease. The parameters are estimated through the maximization of the constructed likelihood by adjusting the selection bias and unobservable exact onset. Simulations are conducted to evaluate the finite sample performance of the proposed methods. We apply the proposed method to an HIV infection study, estimating the unbiased survival function and covariance coefficients. ^

Genetic analysis of Pitx2 in left -right asymmetry and cardiovascular development

Pitx2, a paired-related homeobox gene that is mutated in human Rieger Syndrome, plays a key role in transferring the early asymmetric signals to individual organs. Pitx2 encodes three isoforms, Pitx2a, Pitx2b and Pitx2c. I found that Pitx2c was the Pitx2 isoform for regulating left-right asymmetry in heart, lung and the predominant isoform in guts. Previous studies suggested that the generation of left-right asymmetry within individual organs is an all or none, random event. Phenotypic analysis of various Pitx2 allelic combinations, that encode graded levels of Pitx2c, reveals an organ-intrinsic mechanism for regulating left-right asymmetric morphogenesis based on differential response to Pitx2c levels. The heart needs low Pitx2c levels, while the lungs and duodenum require higher doses of Pitx2c. In addition, the duodenal rotation is under strict control of Pitx2c activity. Left-right asymmetry development for aortic arch arteries involves complex vascular remodeling. Left-sided expression of Pitx2c in these developing vessels implied its potential function in this process. In order to determine if Pitx2c also can regulate the left-right asymmetry of the aortic arch arteries, a Pitx2c-specific loss of function mutation is generated. Although in wild type mice, the direction of the aortic arch is always oriented toward the left side, the directions of the aortic arches in the mutants were randomized, showing that Pitx2c also determined the left-right asymmetry of these vessels. I have further showed that the cardiac neural crest wasn't involved in this vascular remodeling process. In addition, all mutant embryos had Double Outlet Right Ventricle (DORV), a common congenital heart disease. This study provided insight into the mechanism of Pitx2c-mediated late stages of left-right asymmetry development and identified the roles of Pitx2c in regulation of aortic arch remodeling and heart development. ^

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. ^

The 2015 Swiss elections: A landslide win for the right, despite limited changes in vote share

Switzerland held federal elections on 18 October, with the conservative Swiss People’s Party winning the largest share of the votes. Daniel Bochsler, Marlène Gerber and David Zumbach write that while the increase in vote share for the Swiss People’s Party was relatively limited, the party managed to significantly increase the number of seats it holds in Switzerland’s lower house of parliament, the National Council. Nevertheless, the party is unlikely to make substantial gains in the country’s upper house, the Senate, as it traditionally struggles under the two-round electoral system used in Senate elections.