Dose-finding Experiments with Mixed Continuous and Discrete Responses
Valerii Fedorov, Yuehui Wu and Rongmei Zhang
Published as GSK DDS Technical Report 2010-02
Abstract: In dose-finding clinical studies, it is common that multiple endpoints are of interest. For instance, in phase I/II studies efficacy and toxicity are often the primary endpoints which are observed simultaneously and need to be evaluated together. Motivated by this, we confine ourselves to bivariate responses and focus on the most analytically difficult case: a mixture of continuous and categorical responses. We adopt the bivariate probit dose-response model and quantify our goal by a utility function. Locally optimal designs, two-stage optimal designs, and fully adaptive designs are studied under different ethical and cost constraints in the experiments. We assess the performance of two-stage designs and fully adaptive designs
via simulations. Our simulations suggest that the two-stage designs are as efficient as and may be more efficient than the fully adaptive designs if there is a moderate sample size in the initial stage. In addition, two-stage designs are easier to construct and implement, and thus can be a useful approach in practice.
CagA C-terminal variations in Helicobacter pylori strains from Colombian patients with gastric precancerous lesions
L Sicinshci, P Correa, R Peek, M Camargo, M Piazuelo, Robertino Mera
Published in Clinical Microbiology and Infection, 2010, Vol 16, Issue 4
Abstract: The C-terminus of the Helicobacter pylori CagA protein is polymorphic, bearing different EPIYA sequences (EPIYA-A, B, C or D), and one or more CagA multimerization (CM) motifs. The number of EPIYA-C motifs is associated with precancerous lesions and gastric cancer (GC). The relationship between EPIYA, CM motifs and gastric lesions was examined in H. pylori-infected Colombian patients from areas of high and low risk for GC. Genomic DNA was extracted from H. pylori strains cultured from gastric biopsies from 80 adults with dyspeptic symptoms. Sixty-seven (83.8%) of 80 strains were cagA positive. The 3¢ region of cagA was sequenced, and EPIYA and CM motifs were identified. CagA proteins contained one (64.2%), two (34.3%) or three EPIYA-C motifs (1.5%), all with Western type CagA-specific sequences. Strains with one EPIYA-C motif were associated with less severe gastric lesions (non-atrophic and multifocal atrophic gastritis), whereas strains with multiple EPIYA-C motifs were associated with more severe lesions (intestinal metaplasia and dysplasia) (p <0.001). In 54 strains, the CM motifs were identical to those common in Western strains. Thirteen strains from the low-risk area contained two different CM motifs: one of Western type located within the EPIYA-C segment and another following the EPIYA-C segment and resembling the CM motif found in East Asian strains. These strains induced significantly shorter projections in AGS cells and an attenuated reduction in levels of CagA upon immunodepletion of SHP-2 than strains possessing Western/Western motifs. This novel finding may partially explain the difference in GC incidence in these populations.
Semi-automated Risk Estimation using large databases: Quinolones and Clostridium difficile associated diarrhea
Robertino Mera, K Beach, G Powell, E Pattishal
Published in Pharmacoepidemiology and Drug SafetyPublished Online in advance of print: Apr 29 2010.DOI: 10.1002/pds.1968
Abstract:
Purpose: The availability of large databases with person time information and appropriate statistical methods allow for relatively rapid pharmacovigilance analyses. A semi-automated method was used to investigate the effect of fluoroquinolones on the incidence of C. difficile associated diarrhea (CDAD).
Methods: Two US databases, an electronic medical record (EMR) and a large medical claims database for the period 2006–2007 were evaluated using a semi-automated methodology. The raw EMR and claims datasets were subject to a normalization procedure that aligns the drug exposures and conditions using ontologies; Snowmed for medications and MedDRA for conditions. A retrospective cohort design was used together with matching by means of the propensity score. The association between exposure and outcome was evaluated using a Poisson regression model after taking into account potential confounders.
Results: A comparison between quinolones as the target cohort and macrolides as the comparison cohort produced a total of 564 797 subjects exposed to a quinolone in the claims data and 233 090 subjects in the EMR. They were matched with replacement within six strata of the propensity score. Among the matched cohorts there were a total of 488 and 158 outcomes in the claims and the EMR respectively. Quinolones were found to be twice more likely to be significantly associated with CDAD than macrolides adjusting for risk factors (IRR 2.75, 95%CI 2.18–3.48).
Conclusions: Use of a semi-automated method was successfully applied to two observational databases and was able to rapidly identify a potential for increased risk of developing CDAD with quinolones.
Quantifying Combination Drug Synergy
John Peterson
Presented at Midwest Biopharmaceutical Statistics Workshop, Muncie, IN May 25, 2010
