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Determination of sample sizes for demonstrating efficacy of radiation countermeasures.

ABSTRACT: In response to the ever increasing threat of radiological and nuclear terrorism, active development of nontoxic new drugs and other countermeasures to protect against and/or mitigate adverse health effects of radiation is ongoing. Although the classical LD(50) study used for many decades as a first step in preclinical toxicity testing of new drugs has been largely replaced by experiments that use fewer animals, the need to evaluate the radioprotective efficacy of new drugs necessitates the conduct of traditional LD(50) comparative studies (FDA, 2002, Federal Register 67, 37988-37998). There is, however, no readily available method to determine the number of animals needed for establishing efficacy in these comparative potency studies. This article presents a sample-size formula based on Student's t for comparative potency testing. It is motivated by the U.S. Food and Drug Administration's (FDA's) requirements for robust efficacy data in the testing of response modifiers in total body irradiation experiments where human studies are not ethical or feasible. Monte Carlo simulation demonstrated the formula's performance for Student's t, Wald, and likelihood ratio tests in both logistic and probit models. Importantly, the results showed clear potential for justifying the use of substantially fewer animals than are customarily used in these studies. The present article may thus initiate a dialogue among researchers who use animals for radioprotection survival studies, institutional animal care and use committees, and drug regulatory bodies to reach a consensus on the number of animals needed to achieve statistically robust results for demonstrating efficacy of radioprotective drugs.

SUBMITTER: Kodell RL

PROVIDER: S-EPMC3036987 | biostudies-other | 2010 Mar

REPOSITORIES: biostudies-other

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Determination of sample sizes for demonstrating efficacy of radiation countermeasures.

Kodell Ralph L RL Lensing Shelly Y SY Landes Reid D RD Kumar K Sree KS Hauer-Jensen Martin M

Biometrics 20090507 1

In response to the ever increasing threat of radiological and nuclear terrorism, active development of nontoxic new drugs and other countermeasures to protect against and/or mitigate adverse health effects of radiation is ongoing. Although the classical LD(50) study used for many decades as a first step in preclinical toxicity testing of new drugs has been largely replaced by experiments that use fewer animals, the need to evaluate the radioprotective efficacy of new drugs necessitates the condu ...[more]

PMID: 19432769

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Project description:Limited sample sizes can lead to spurious modeling findings in biomedical research. The objective of this work is to present a new method to generate synthetic populations (SPs) from limited samples using matched case-control data (n = 180 pairs), considered as two separate limited samples. SPs were generated with multivariate kernel density estimations (KDEs) with unconstrained bandwidth matrices. We included four continuous variables and one categorical variable for each individual. Bandwidth matrices were determined with Differential Evolution (DE) optimization by covariance comparisons. Four synthetic samples (n = 180) were derived from their respective SPs. Similarity between observed samples with synthetic samples was compared assuming their empirical probability density functions (EPDFs) were similar. EPDFs were compared with the maximum mean discrepancy (MMD) test statistic based on the Kernel Two-Sample Test. To evaluate similarity within a modeling context, EPDFs derived from the Principal Component Analysis (PCA) scores and residuals were summarized with the distance to the model in X-space (DModX) as additional comparisons. Four SPs were generated from each sample. The probability of selecting a replicate when randomly constructing synthetic samples (n = 180) was infinitesimally small. MMD tests indicated that the observed sample EPDFs were similar to the respective synthetic EPDFs. For the samples, PCA scores and residuals did not deviate significantly when compared with their respective synthetic samples. The feasibility of this approach was demonstrated by producing synthetic data at the individual level, statistically similar to the observed samples. The methodology coupled KDE with DE optimization and deployed novel similarity metrics derived from PCA. This approach could be used to generate larger-sized synthetic samples. To develop this approach into a research tool for data exploration purposes, additional evaluation with increased dimensionality is required. Moreover, given a fully specified population, the degree to which individuals can be discarded while synthesizing the respective population accurately will be investigated. When these objectives are addressed, comparisons with other techniques such as bootstrapping will be required for a complete evaluation.

Project description:Nuclear factor (NF)-?B is a transcription factor that plays significant role in immunity, cellular survival and inhibition of apoptosis, through the induction of genetic networks. Depending on the stimulus and the cell type, the members of NF-?B related family (RelA, c-Rel, RelB, p50, and p52), forms different combinations of homo and hetero-dimers. The activated complexes (Es) translocate into the nucleus and bind to the 10bp ?B site of promoter region of target genes in stimulus specific manner. In response to radiation, NF-?B is known to reduce cell death by promoting the expression of anti-apoptotic proteins and activation of cellular antioxidant defense system. Constitutive activation of NF-?B associated genes in tumour cells are known to enhance radiation resistance, whereas deletion in mice results in hypersensitivity to IR-induced GI damage. NF-?B is also known to regulate the production of a wide variety of cytokines and chemokines, which contribute in enhancing cell proliferation and tissue regeneration in various organs, such as the GI crypts stem cells, bone marrow etc., following exposure to IR. Several other cytokines are also known to exert potent pro-inflammatory effects that may contribute to the increase of tissue damage following exposure to ionizing radiation. Till date there are a series of molecules or group of compounds that have been evaluated for their radio-protective potential, and very few have reached clinical trials. The failure or less success of identified agents in humans could be due to their reduced radiation protection efficacy. In this review we have considered activation of NF-?B as a potential marker in screening of radiation countermeasure agents (RCAs) and cellular radiation responses. Moreover, we have also focused on associated mechanisms of activation of NF-?B signaling and their specified family member activation with respect to stimuli. Furthermore, we have categorized their regulated gene expressions and their function in radiation response or modulation. In addition, we have discussed some recently developed radiation countermeasures in relation to NF-?B activation.

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Determination of sample sizes for demonstrating efficacy of radiation countermeasures.

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Determination of sample sizes for demonstrating efficacy of radiation countermeasures.

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