A computational framework for complex disease stratification from multiple large-scale datasets.

BACKGROUND: Multilevel data integration is becoming a major area of research in systems biology. Within this area, multi-'omics datasets on complex diseases are becoming more readily available and there is a need to set standards and good practices for integrated analysis of biological, clinical and environmental data. We present a framework to plan and generate single and multi-'omics signatures of disease states. METHODS: The framework is divided into four major steps: dataset subsetting, feature filtering, 'omics-based clustering and biomarker identification. RESULTS: We illustrate the usefulness of this framework by identifying potential patient clusters based on integrated multi-'omics signatures in a publicly available ovarian cystadenocarcinoma dataset. The analysis generated a higher number of stable and clinically relevant clusters than previously reported, and enabled the generation of predictive models of patient outcomes. CONCLUSIONS: This framework will help health researchers plan and perform multi-'omics big data analyses to generate hypotheses and make sense of their rich, diverse and ever growing datasets, to enable implementation of translational P4 medicine.

Effects of tadalafil on myocardial blood flow in patients with coronary artery disease.

OBJECTIVE: Erectile dysfunction and coronary artery disease share similar risk factors. Although phosphodiesterase-5 inhibitors used to treat erectile dysfunction do not adversely affect hemodynamic parameters in patients with coronary artery disease, their effects on myocardial blood flow are unknown. METHODS: In a randomized, double-blind, crossover study we examined the effects of tadalafil, 20 mg, compared with placebo on myocardial blood flow in patients with stable coronary artery disease (n=7, 52-73 years old). After tadalafil or placebo, myocardial blood flow was measured with positron emission tomography (nine-segment model) at rest, during maximal coronary hyperemia with adenosine, and during increased myocardial work with dobutamine. Abnormal flow was defined as myocardial blood flow <75% of maximum perfusion during adenosine plus placebo (46 normal/17 abnormal segments dentified). RESULTS: Compared with placebo, tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Similarly, in normal and abnormal segments, tadalafil versus placebo had no significant effect on resting myocardial blood flow or on adenosine-induced increases in myocardial blood flow. In normal segments, myocardial blood flow with dobutamine plus tadalafil was greater than that with dobutamine plus placebo (1.79+/-0.56 versus 1.56+/-0.37 ml/g per min, P<0.01), and in abnormal segments, there was a trend for tadalafil compared with placebo to increase myocardial blood flow during dobutamine infusion (1.46+/-0.44 versus 1.36+/-0.36 ml/g per min, P=0.7). CONCLUSIONS: Tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Compared with placebo, tadalafil significantly augmented myocardial blood flow during increased workload in normal regions, with a trend toward improving myocardial blood flow in poorly perfused regions.

Tadalafil pharmacokinetics in healthy subjects.

AIMS: To characterize tadalafil plasma pharmacokinetics in healthy subjects following single and multiple doses. METHODS: Noncompartmental parameters were calculated for healthy subjects receiving a single 2.5-20-mg tadalafil dose in 13 clinical pharmacology studies. An integrated statistical analysis of results in 237 subjects provided global averages and an assessment of effects of body mass index (BMI), age, gender and smoking status. Diurnal variation, food effects and proportionality of exposure to dose were analysed in three studies. Multiple-dose pharmacokinetics were evaluated in a separate study in which parallel groups of 15 subjects received 10 or 20 mg tadalafil once daily for 10 days. RESULTS: Tadalafil was absorbed rapidly with mean Cmax (378 microg l-1 for 20 mg) observed at 2 h; thereafter, concentrations declined nearly monoexponentially with a mean (5th, 95th percentiles) t1/2 of 17.5 (11.5, 29.6) hours. Mean oral clearance (CL/F) was 2.48 (1.35, 4.35) l h-1 and apparent volume of distribution (Vz/F) was 62.6 (39.5, 92.1) l. No clinically meaningful effect of BMI, age, gender or smoking was identified. Exposure was not substantially affected by time of dosing. Food had negligible effects on bioavailability as assessed by 90% confidence intervals for Cmax and AUC mean ratios. Parameters were proportional to dose, indicating that doubling the dose doubled exposure. Steady state was attained by day 5 following once-daily administration, and accumulation (1.6-fold) was consistent with the t1/2. CONCLUSIONS: Tadalafil pharmacokinetics are linear with respect to dose and time, and are not affected by food. Systemic clearance is low relative to other phosphodiesterase 5 inhibitors.