Maier, C. | bioRxiv Science

bioRxiv2018

T vector velocity: A new ECG biomarker for identifying drug effects on cardiac ventricular repolarization

We present a new family TrX of ECG biomarkers based on the T vector velocity (TVV) for assessing drug effects on ventricular repolarization. Assuming a link between the TVV and the instantaneous change of the cellular action potentials, drugs accelerating repolarization by blocking inward (depolarizing) ion currents cause a relative increase of the TVV, while drugs delaying repolarization by blocking outward ion currents cause a relative decrease of the TVV.\n\nEvaluating the published data from two FDA funded studies, the TrX effect profiles indicate increasingly delayed electrical activity over the entire repolarization process for drugs solely reducing outward potassium current (dofetilide, moxifloxacin). For drugs eliciting block of the inward sodium or calcium currents (mexiletine, lidocaine), the TrX effect profiles were consistent with accelerated electrical activity in the initial repolarization phase. For multichannel blocking drugs (ranolazine) or drug combinations blocking multiple ion currents (dofetilide + mexiletine, dofetilide + lidocaine), the overall TrX effect profiles indicate a superposition of the individual TrX effect profiles.\n\nThe parameter Tr40c allows separating pure potassium channel blocking drugs from multichannel blocking drugs with an area under the ROC curve (AUC) value of 0.90, CI = [0.88 to 0.92]. This is significantly larger than the performance of J-Tpeakc (0.81, CI = [0.78 to 0.84]) using the published data from the second FDA study. Further performance improvement was achieved by combining the ten parameters Tr10c to Tr100c in a logistic regression model, resulting in an AUC value of 0.94.\n\nThe TVV based approach substantially improves assessment of drug effects on cardiac repolarization, providing a plausible and improved mechanistic link between drug effects on ionic currents and overall ventricular repolarization reflected in the body surface ECG. TVV may contribute to a better assessment of the proarrhythmic risk of drugs beyond QTc prolongation and JTpeakc.

pharmacology and toxicology↗

bioRxiv2016

A genetic risk score to guide age-specific, personalized prostate cancer screening

BackgroundProstate-specific-antigen (PSA) screening resulted in reduced prostate cancer (PCa) mortality in a large clinical trial, but due to a high false-positive rate, among other concerns, many guidelines do not endorse universal screening and instead recommend an individualized decision based on each patients risk. Genetic risk may provide key information to guide the decisions of whether and at what age to screen an individual man for PCa.\n\nMethodsGenotype, PCa status, and age from 34,444 men of European ancestry from the PRACTICAL consortium database were analyzed to select single-nucleotide polymorphisms (SNPs) associated with prostate cancer diagnosis. These SNPs were then incorporated into a survival analysis to estimate their effects on age at PCa diagnosis. The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was validated in an independent dataset comprised of 6,417 men with screening PSA and genotype data. PHS was calculated for these men to test for prediction of PCa-free survival. PHS was also combined with age-specific PCa incidence data from the U.S. population to generate a PCa-Risk (PCaR) age that relates a given mans risk to that of the population average. PHS and PCaR age were evaluated for prediction of positive predictive value (PPV) of PSA screening.\n\nFindingsPHS calculated from 54 SNPs was very highly predictive of age at PCa diagnosis for men in the validation set (p =10-53). PPV of PSA screening varied from 0.18 to 0.52 for men with low and high genetic risk, respectively. PHS modulates PCa-free survival curves by an estimated 20 years between men in the 1st or 99th percentiles of genetic risk.\n\nInterpretationPolygenic hazard scores give personalized genetic risk estimates and can inform the decisions of whether and at what age to screen a man for PCa.\n\nFundingDepartment of Defense #W81XWH-13-1-0391

genetics↗