RESUMO
Human tumor xenograft studies are the primary means to evaluate the biological activity of anticancer agents in late-stage preclinical drug discovery. The variability in the growth rate of human tumors established in mice and the small sample sizes make rigorous statistical analysis critical. The most commonly used summary of antitumor activity for these studies is the T/C ratio. However, alternative methods based on growth rate modeling can be used. Here, we describe a summary metric called the rate-based T/C, derived by fitting each animal's tumor growth to a simple exponential model. The rate-based T/C uses all of the data, in contrast with the traditional T/C, which only uses a single measurement. We compare the rate-based T/C with the traditional T/C and assess their performance through a bootstrap analysis of 219 tumor xenograft studies. We find that the rate-based T/C requires fewer animals to achieve the same power as the traditional T/C. We also compare 14-day studies with 21-day studies and find that 14-day studies are more cost efficient. Finally, we perform a power analysis to determine an appropriate sample size.
RESUMO
MS-based proteomics characterizes protein contents of biological samples. The most common approach is to first match observed MS/MS peptide spectra against theoretical spectra from a protein sequence database and then to score these matches. The false discovery rate (FDR) can be estimated as a function of the score by searching together the protein sequence database and its randomized version and comparing the score distributions of the randomized versus nonrandomized matches. This work introduces a straightforward isotonic regression-based method to estimate the cumulative FDRs and local FDRs (LFDRs) of peptide identification. Our isotonic method not only performed as well as other methods used for comparison, but also has the advantages of being: (i) monotonic in the score, (ii) computationally simple, and (iii) not dependent on assumptions about score distributions. We demonstrate the flexibility of our approach by using it to estimate FDRs and LFDRs for protein identification using summaries of the peptide spectra scores. We reconfirmed that several of these methods were superior to a two-peptide rule. Finally, by estimating both the FDRs and LFDRs, we showed for both peptide and protein identification, moderate FDR values (5%) corresponded to large LFDR values (53 and 60%).
Assuntos
Biologia Computacional , Bases de Dados de Proteínas , Peptídeos/análise , Proteínas/análiseRESUMO
We identify three properties of the standard oncology Phase I trial design or 3 + 3 design. We show that the standard design implicitly uses isotonic regression to estimate a maximum tolerated dose. We next illustrate the relationship between the standard design and a Bayesian design proposed by Ji et al. (2007). A slight modification to this Bayesian design, under a particular model specification, would assign treatments in a manner identical to the standard design. We finally present calculations revealing the behavior of the standard design in a worst case scenario and compare its behavior with other 3 + 3-like designs.