Michael P. Meredith

Improving the Sensitivity of in Vitro Skin Penetration Experiments

The institution of a readily-implemented sample screening and data handling procedure for in vitro skin penetration studies yields substantial improvements in sensitivity for distinguishing between formulations, treatments, penetrants, etc. The procedure involves four steps: 1) prescreen the tissue samples to determine their intrinsic permeability; 2) apply treatments using a randomized complete block (RGB) design, with blocking by tissue permeability; 3) apply a variance-stabilizing transformation to the penetration data, followed by outlier testing; and 4) analyze the transformed data according to an RGB analysis of variance, using tissue permeability as the blocking variable. For penetration studies in which high sample variability is a concern, the above procedure commonly yields a sensitivity advantage of several-fold versus alternative methods of comparison.

Vertebral fracture risk reduction with risedronate in post-menopausal women with osteoporosis: a meta-analysis of individual patient data

Background and aims: The effect of risedronate, a potent pyridinyl bisphosphonate, on vertebral fractures in post-menopausal women was evaluated in randomized, placebo-controlled clinical trials. These trials included two large vertebral fracture studies that used time-to-event methods to evaluate the effects of treatment on fracture risk, thereby allowing both the occurrence and the timing of fractures to be considered. Methods: We used individual patient data (IPD) and time-to-event methods to perform a meta-analysis of the anti-fracture efficacy of risedronate (2.5 or 5 mg daily) in osteoporotic women enrolled in five double-blind, placebo-controlled clinical trials. Women were included in the analysis if, at baseline, they had either at least one prevalent vertebral fracture or a femoral neck bone mineral density (BMD) T-score of less than −2.5, were at least 1 year post-menopausal, and had had vertebral fracture assessments (N=3331). Results: Risedronate 5 mg daily reduced the risk of radiographically defined vertebral fracture by 64% (95% CI, 46 to 76%, p<0.001) in the first year of treatment and 45% (95% CI, 31 to 57%, p<0.001) in 3 years. The numbers of patients who needed to be treated with risedronate 5 mg to prevent one new vertebral fracture over 1 and 3 years were 21 and 13, respectively. Comparable findings were observed in sub-populations defined on the basis of either prevalent vertebral fracture without regard to femoral neck BMD, or femoral neck BMD without regard to vertebral fracture status. Risedronate significantly reduced the incidence of clinical (symptomatic) vertebral fractures in the first 6 months of treatment (p<0.001). Conclusions: This meta-analysis, based upon five trials and using IPD and time-to-event statistical methods, provides a more precise estimate of the effect of risedronate in reducing vertebral fracture risk in post-menopausal osteoporotic women than a meta-analysis using summary statistics from the literature.

Interspecies Scaling of Tebufelone Pharmacokinetic Data and Application to Preclinical Toxicology

AbstractPurpose. Retrospective application of allometric scaling techniques to tebufelone, a nonsteroidal antiinflammatory agent, in order to better understand the systemic exposure relationships between the doses administered to the species used in toxicology studies and the doses given to human subjects and patients in clinical studies. Methods. Non-compartmental estimates of tebufelones total body volume of distribution during the terminal phase (Vz) and clearance (CL) obtained from intravenous dosing to rat, monkey, dog, and human were allometrically scaled to body weight, and body weight and brain weight, respectively. AUCs determined from single or multiple dose pharmacokinetic studies and from preclinical toxicology studies were plotted versus dose adjusted for bioavailability and divided by allometrically scaled clearance to produce an allometric relationship suggesting a non-linear increase in AUC with dose across the four species. Results. Segmental linear regression analysis of this relationship indicates a change point associated with an AUC of approximately 2,300 ng-hr/mL. Elevations in serum levels of various liver enzymes or associated signs of hepatic toxicity occur in some, but not all of the animals exposed for more than three weeks in repeat dosing studies at the actual dose that this represents. Conclusions. The analysis suggests that doses producing tebufelone plasma levels above a certain threshold AUC and duration of exposure to parent tebufelone are associated with increased risks of hepatic effects. Whether this is because metabolic shifts occur at these doses cannot be determined from these data.

Exploring the Relationship Between Surrogates and Clinical Outcomes: Analysis of Individual Patient Data vs. Meta-regression on Group-Level Summary Statistics

Abstract There has been an increasing interest in exploring the relationship between a surrogate and a clinical outcome. Two different statistical approaches have been taken by researchers to quantify the treatment effect on the clinical outcome explained by the surrogate endpoint: 1) analysis based on individual patient data (IPD), and 2) meta-regression based on summary statistics from published literature. An analysis based on IPD models the associations between the surrogate and clinical outcome for patients directly and is able to adjust for patient-level covariates. A meta-regression models the trial-level associations using group-level summary statistics and trial-level covariates. The results from these two approaches can be quite disparate and researchers may reach different conclusions on scientific questions that they wish to answer. We demonstrate that the typical summary statistics, such as group means and event counts, do not provide a set of sufficient statistics for estimating the underlying relationship between the surrogate and clinical outcome for patients. Consequently, the associations derived from meta-regression do not necessarily reflect the causal relationship for patients and should be interpreted with caution. A meta-analysis of antiresorptive agents for osteoporosis serves to illustrate the magnitude of differences between the two approaches.

Covariance Analysis for Split-Plot and Split-Block Designs

Abstract Commentaries are informative essays dealing with viewpoints of statistical practice, statistical education, and other topics considered to be of general interest to the broad readership of The American Statistician. Commentaries are similar in spirit to Letters to the Editor, but they involve longer discussions of background, issues, and perspectives. All commentaries will be refereed for their merit and compatibility with these criteria. Proper methodology for the analysis of covariance for experiments designed in a split-plot or split-block design is not found in the statistical literature. Analyses for these designs are often performed incompletely or even incorrectly. This is especially true when popular statistical computer software packages are used for the analysis of these designs. This article provides several appropriate models, ANOVA tables, and standard errors for comparisons from experiments arranged in a standard split-plot, split–split-plot, or split-block design where a covariate ...

Acclimatization to hypoxia alters cerebral convective and diffusive O2 delivery

Ventilatory acclimatization (VA) to hypoxia alters cerebrovascular responses to arterial blood gas perturbations. For example, after VA, cerebral blood flow (CBF) is elevated, at a given arterial CO2 tension (PaCO2), compared to CBF before VA. This experiment examined the effects of VA to 72 h of normobaric hypoxia [arterial O2 tension (PaO2) approx. 40 mmHg, O2 saturation in arterial blood approx. 50%] on total and regional cerebrovascular resistance (CVR and rCVR) and cerebral O2 extraction fraction (OEF) in 32 conscious sheep. Four different O2-CO2 gas combinations were sequentially administered to each sheep before and after VA. CVR and rCVR were calculated from CBF (radiolabeled microspheres) and arterial and cerebral downstream pressures; OEF was calculated from arterial and cerebral venous O2 contents. After VA, during hyperoxia, CVR and rCVR tended to be lower during both hypocapnia and hypercapnia. During hypoxia, although CVR and rCVR were slightly less during hypocapnia, CVR and rCVR during hypercapnia were surprisingly increased. The post-VA increases in mean CVR and mean rCVR during hypoxic gas combinations differed from the post-VA decreases during hyperoxic gas combinations (0.04 less than or equal to P less than or equal to 0.11). In contrast, although VA decreased OEF during three of four gas combinations (P less than or equal to 0.003), there was a greater mean post-VA decrease in OEF during hypercapnic gas combinations than during hypocapnic gas combinations (P = 0.025); decreases in OEF were correlated with decreases in cerebral O2 consumption. The post-VA CVR responses may reflect altered neurocirculatory control by the arterial chemoreflex; the OEF responses suggest relative cerebral hyperperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)