Semiparametric Regression Analysis of Multiple Right- and Interval-Censored Events

<p>Health sciences research often involves both right- and interval-censored events because the occurrence of a symptomatic disease can only be observed up to the end of follow-up, while the occurrence of an asymptomatic disease can only be detected through periodic examinations. We formulate the effects of potentially time-dependent covariates on the joint distribution of multiple right- and interval-censored events through semiparametric proportional hazards models with random effects that capture the dependence both within and between the two types of events. We consider nonparametric maximum likelihood estimation and develop a simple and stable EM algorithm for computation. We show that the resulting estimators are consistent and the parametric components are asymptotically normal and efficient with a covariance matrix that can be consistently estimated by profile likelihood or nonparametric bootstrap. In addition, we leverage the joint modelling to provide dynamic prediction of disease incidence based on the evolving event history. Furthermore, we assess the performance of the proposed methods through extensive simulation studies. Finally, we provide an application to a major epidemiological cohort study. Supplementary materials for this article are available online.</p

Genes whose expression levels are associated with rs1859023.

<p>Genes whose expression levels are associated with rs1859023.</p

Influence of relative humidity on fracture toughness of rock: Implications for subcritical crack growth

<p>* <b>Top row: values adjusted for age, smoking, BMI, diabetes, and hypertension and bottom row (shaded): values adjusted for</b> environmental factors as in top row, but also for VWF</p><p>Geometric Mean (95% CI) of FVIII Activity (%) in A Blood Groups^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132626#t004fn001" target="_blank">*</a>}.</p

Regional plot (ARIC) of rs1859023 association with incident CHD and LD in the region arround rs1859023 (YRI) [<b>22]</b>, [23<b> </b>].

<p>Regional plot (ARIC) of rs1859023 association with incident CHD and LD in the region arround rs1859023 (YRI) <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002199#pgen.1002199-Pruim1" target="_blank">[<b>22]</b></a>, <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002199#pgen.1002199-Johnson1" target="_blank">[23<b> </b>]</a>.</p

Association of Single Nucleotide Polymorphisms in the <i>ST3GAL4</i> Gene with VWF Antigen and Factor VIII Activity

<div><p>VWF is extensively glycosylated with biantennary core fucosylated glycans. Most N-linked and O-linked glycans on VWF are sialylated. FVIII is also glycosylated, with a glycan structure similar to that of VWF. ST3GAL sialyltransferases catalyze the transfer of sialic acids in the α2,3 linkage to termini of N- and O-glycans. This sialic acid modification is critical for VWF synthesis and activity. We analyzed genetic and phenotypic data from the Atherosclerosis Risk in Communities (ARIC) study for the association of single nucleotide polymorphisms (SNPs) in the <i>ST3GAL4</i> gene with plasma VWF levels and FVIII activity in 12,117 subjects. We also analyzed <i>ST3GAL4</i> SNPs found in 2,535 subjects of 26 ethnicities from the 1000 Genomes (1000G) project for ethnic diversity, SNP imputation, and <i>ST3GAL4</i> haplotypes. We identified 14 and 1,714 <i>ST3GAL4</i> variants in the ARIC GWAS and 1000G databases respectively, with 46% being ethnically diverse in their allele frequencies. Among the 14 <i>ST3GAL4</i> SNPs found in ARIC GWAS, the intronic rs2186717, rs7928391, and rs11220465 were associated with VWF levels and with FVIII activity after adjustment for age, BMI, hypertension, diabetes, ever-smoking status, and ABO. This study illustrates the power of next-generation sequencing in the discovery of new genetic variants and a significant ethnic diversity in the <i>ST3GAL4</i> gene. We discuss potential mechanisms through which these intronic SNPs regulate ST3GAL4 biosynthesis and the activity that affects VWF and FVIII.</p></div

Baseline characteristics of the ARIC sample.

<p>Baseline characteristics of the ARIC sample.</p

Association of <i>ST3GAL4</i> SNPs with FVIII activity (%) in ARIC^*.

<p>Association of <i>ST3GAL4</i> SNPs with FVIII activity (%) in ARIC^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160757#t005fn001" target="_blank">*</a>}.</p

Association of <i>ST3GAL4</i> SNPs with VWF antigen (%) in ARIC^*.

<p>Association of <i>ST3GAL4</i> SNPs with VWF antigen (%) in ARIC^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160757#t004fn001" target="_blank">*</a>}.</p

Allelic additive effects of the <i>ST3GAL4</i> SNPs for VWF and FVIII^*.

<p>Allelic additive effects of the <i>ST3GAL4</i> SNPs for VWF and FVIII^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160757#t006fn001" target="_blank">*</a>}.</p

Position^* and Allele frequency of <i>ST3GAL4</i> SNPs in ARIC-GWAS.

<p>Position^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0160757#t002fn001" target="_blank">*</a>} and Allele frequency of <i>ST3GAL4</i> SNPs in ARIC-GWAS.</p