Pharmacokinetics and pharmacodynamics of the proposed biosimilar denosumab GP2411 and reference denosumab in healthy males.

Background: This Phase I study compared the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of GP2411 proposed denosumab biosimilar to reference denosumab (a monoclonal antibody for specific pro-resorptive conditions).

Research Design And Methods: Healthy males (28-65 years, 50-90 kg) were randomized to a single sub-therapeutic subcutaneous injection of 35 mg GP2411, EU-Xgeva® or US-Xgeva®, and followed for 39 weeks. The primary endpoints were AUC, AUC, and C.

Multi-part strategy for testing differential taxa abundance in sequencing data: A simulation study with an application to a microbiome study.

Comparing the microbiome across study arms is a recurrent goal in many studies. Standard statistical methods are often used for this purpose, however, they do not always represent the best choice in this context given the characteristics of microbiota sequencing data, e.g.

Effect of Multiple Doses of Omeprazole on the Pharmacokinetics, Safety, and Tolerability of Roxadustat in Healthy Subjects.

Background And Objectives: Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat.

Methods: This phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects.

Oral follicle-stimulating hormone agonist tested in healthy young women of reproductive age failed to demonstrate effect on follicular development but affected thyroid function.

Objective: To assess the safety, pharmacokinetics, and pharmacodynamics of MK-8389.

Design: Double-blind, placebo-controlled, parallel-group, ascending dose study.

Setting: Two clinical research organizations.

Lack of a clinically relevant effect of sugammadex on anti-Xa activity or activated partial thromboplastin time following pretreatment with either unfractionated or low-molecular-weight heparin in healthy subjects.

Objective: To investigate the potential effect of sugammadex on anti-Xa anticoagulantactivity of enoxaparin and the activated partial thromboplastin time (APTT) of unfractionated heparin (UFH).

Methods: This two-part, randomized, double-blind, placebocontrolled, four-period cross-over study was performed in healthy males (18 - 45 years). In each period, subjects received 40 mg enoxaparin (in part 1), 5,000 units UFH (in part 2), or placebo followed by 4 or 16 mg/kg sugammadex, or placebo.

No clinically relevant interaction between sugammadex and aspirin on platelet aggregation and coagulation parameters.

Objectives: This study evaluated interaction potential between sugammadex and aspirin on platelet aggregation.

Methods: This was a randomized, double-blind, placebo-controlled, four-period crossover study in 26 healthy adult males. Treatments were i.

Tibolone increases bone mineral density but also relapse in breast cancer survivors: LIBERATE trial bone substudy.

Introduction: The Livial Intervention Following Breast Cancer: Efficacy, Recurrence and Tolerability Endpoints (LIBERATE: Clinical http://Trials.gov number NCT00408863), a randomized, placebo-controlled, double-blind trial that demonstrated that tibolone (Livial), a tissue-selective hormone-replacement therapy (HRT), increased breast cancer (BC) recurrence HR 1.40 (95% CI, 1.

Global tests for linkage.

To test for global linkage along a genome or in a chromosomal region, the maximum over the marker locations of mean alleles shared identical by descent of affected relative pairs, Z(max), can be used. Feingold et al. (1993) derived a Gaussian approximation to the distribution of the Z(max).

Generalizing Terwilliger's likelihood approach: a new score statistic to test for genetic association.

Background: In this paper, we propose a one degree of freedom test for association between a candidate gene and a binary trait. This method is a generalization of Terwilliger's likelihood ratio statistic and is especially powerful for the situation of one associated haplotype. As an alternative to the likelihood ratio statistic, we derive a score statistic, which has a tractable expression.

Genetic variation in the DNA repair genes is predictive of outcome in lung cancer.

To assess whether DNA repair gene variants influence the clinical behaviour of lung cancer we examined the impact of a comprehensive panel of 109 non-synonymous single-nucleotide polymorphisms (nsSNPs) in 50 DNA repair genes on overall survival (OS) in 700 lung cancer patients. Fifteen nsSNPs were associated with OS, significantly greater than that expected (P = 0.04).

Lack of evidence that p53 Arg72Pro influences lung cancer prognosis: an analysis of survival in 619 female patients.

The prognostic significance of the Arg72Pro polymorphism of the p53 tumour suppressor gene in cancer is controversial. To determine whether Arg72Pro is a marker for lung cancer prognosis we genotyped 619 female lung cancer patients with incident disease and examined the relationship between genotype and overall survival (OS). Nonparametric tests provided no evidence for a relationship between SNP genotype and OS (P-values 0.

Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14 704 first-degree relatives.

To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing.

Locally weighted transmission/disequilibrium test for genetic association analysis.

The transmission/disequilibrium test statistic has been used for assessing genetic association in affected-parent trios. In the presence of multiple tightly linked marker loci where local dependency may exist, haplotypes are reconstructed statistically to estimate the joint effects of these markers. In this manuscript, we propose an alternative to the haplotype approach by taking a weighted average of multiple loci, where the weight is proportional to the product of (1-2X recombination fraction) and the linkage disequilibrium between markers.

Methods to test for association between a disease and a multi-allelic marker applied to a candidate region.

We report the analysis results of the Genetic Analysis Workshop 14 simulated microsatellite marker dataset, using replicate 50 from the Danacaa population. We applied several methods for association analysis of multi-allelic markers to case-control data to study the association between Kofendrerd Personality Disorder and multi-allelic markers in a candidate region previously identified by the linkage analysis. Evidence for association was found for marker D03S0127 (p < 0.

Phenotypic subtypes in attention deficit hyperactivity disorder in an isolated population.

We address the use of two informants in genetic studies and whether familial aggregation is similar for the three phenotypic subtypes of ADHD. Lifetime ADHD was diagnosed in a Dutch isolated population using parents and teachers as informants, creating two subgroups (one or two informants), then further divided into three phenotypic categories (inattentive, hyperactive/impulsive, combined). Genealogy was collected for all patients.