Prediction of tumour pathological subtype from genomic profile using sparse logistic regression with random effects

The purpose of this study is to highlight the application of sparse logistic regression models in dealing with prediction of tumour pathological subtypes based on lung cancer patients'' genomic information. We consider sparse logistic regression models to deal with the high dimensionality and correlation between genomic regions. In a hierarchical likelihood (HL) method, it is assumed that the random effects follow a normal distribution and its variance is assumed to follow a gamma distribution. This formulation considers ridge and lasso penalties as special cases. We extend the HL penalty to include a ridge penalty (called ‘HLnet’) in a similar principle of the elastic net penalty, which is constructed from lasso penalty. The results indicate that the HL penalty creates more sparse estimates than lasso penalty with comparable prediction performance, while HLnet and elastic net penalties have the best prediction performance in real data. We illustrate the methods in a lung cancer study.     

The assessment of tumour response to treatment

Summary.  A parsimonious model for treated tumours is developed as a continuation of our previous work on regrowth curve theory. The statistical model belongs to the family of marginal non-linear models since the only linear parameters of the model are tumour specific and random facilitating parameter estimation. An important feature of the model is that it enables the estimation of the fraction of cancer cells surviving the treatment in vivo having easy-to-obtain longitudinal measurements of tumour volume. We compare several methods of estimation, including Lindstrom–Bates, iterated reweighted least squares and maximum likelihood. The last two methods are computed via the total estimating equations approach and variance least squares. The theory is illustrated with a photodynamic tumour therapy example.     

单细胞结构与功能的原子力显微镜研究

首先强调了研究单细胞的生物学意义;介绍了原子力显微镜作为一种显微探测和操纵工具的主要特点及其在生命科学特别是在单细胞研究中的巨大优势。回顾了国内外有关AFM在单细胞表面形态与结构、活细胞的力学响应和生理过程的监控、细胞间粘附力的测量和肿瘤的科学诊断等研究中的应用情况;并结合自己在肿瘤细胞形态研究中的经验和体会对AFM在细胞研究中的深入研究进行了探讨。     

Bayesian incidence analysis of animal tumorigenicity data

Statistical inference about tumorigenesis should focus on the tumour incidence rate. Unfortunately, in most animal carcinogenicity experiments, tumours are not observable in live animals and censoring of the tumour onset times is informative. In this paper, we propose a Bayesian method for analysing data from such studies. Our approach focuses on the incidence of tumours and accommodates occult tumours and censored onset times without restricting tumour lethality, relying on cause-of-death data, or requiring interim sacrifices. We represent the underlying state of nature by a multistate stochastic process and assume general probit models for the time-specific transition rates. These models allow the incorporation of covariates, historical control data and subjective prior information. The inherent flexibility of this approach facilitates the interpretation of results, particularly when the sample size is small or the data are sparse. We use a Gibbs sampler to estimate the relevant posterior distributions. The methods proposed are applied to data from a US National Toxicology Program carcinogenicity study.     

Assessing Poisson variation of intestinal tumour multiplicity in mice carrying a Robertsonian translocation

Summary.  Tumour multiplicity is a frequently measured phenotype in animal studies of cancer biology. Poisson variation of this measurement represents a biological and statistical reference point that is usually violated, even in highly controlled experiments, owing to sources of variation in the stochastic process of tumour formation. A recent experiment on murine intestinal tumours presented conditions which seem to generate Poisson-distributed tumour counts. If valid, this would support a claim about mechanisms by which the adenomatous polyposis coli gene is inactivated during tumour initiation. In considering hypothesis testing strategies, model choice and Bayesian approaches, we quantify the positive evidence favouring Poisson variation in this experiment. Statistical techniques used include likelihood ratio testing, the Bayes and Akaike information criteria, negative binomial modelling, reversible jump Markov chain Monte Carlo methods and posterior predictive checking. The posterior approximation that is based on the Bayes information criterion is found to be quite accurate in this small n case-study.     

A survival-adjusted quantal response test for comparing tumour incidence rates

Summary.  The paper presents a case-study of skin fibromas among male rats in the 2-year cancer bioassay of methyleugenol that was conducted by the US National Toxicology Program (NTP). In animal carcinogenicity experiments such as this one, tumour rates are often compared with the Cochran–Armitage (CA) trend test. The operating characteristics of the CA test, however, can be adversely affected by survival differences across groups and by the assumed dose metric. Survival-adjusted generalizations of the CA test have been proposed, but they are still sensitive to the choice of scores that are assigned to the dose groups. We present an alternative test, which outperforms the survival-adjusted CA test which is currently used by the NTP to compare incidence rates. Simulated data from a wide range of realistic situations show that the operating characteristics of the test proposed are superior to those of the NTP's survival-adjusted CA test, especially for rare tumours and wide logarithmic spacings of the dose metric.     

The validation of surrogate end points by using data from randomized clinical trials: a case-study in advanced colorectal cancer

Summary.  In many therapeutic areas, the identification and validation of surrogate end points is of prime interest to reduce the duration and/or size of clinical trials. Buyse and co-workers and Burzykowski and co-workers have proposed a validation strategy for end points that are either normally distributed or (possibly censored) failure times. In this paper, we address the problem of validating an ordinal categorical or binary end point as a surrogate for a failure time true end point. In particular, we investigate the validity of tumour response as a surrogate for survival time in evaluating fluoropyrimidine-based experimental therapies for advanced colorectal cancer. Our analysis is performed on data from 28 randomized trials in advanced colorectal cancer, which are available through the Meta-Analysis Group in Cancer.     

Discrete Scale Models for Survival–Sacrifice Experiments

Analyses of carcinogenicity experiments involving occult (hidden) tumours are usually based on cause-of-death information or the results of many interim sacrifices. A simple compartmental model is described that does not involve the cause of death. The method of analysis requires only one interim sacrifice, in addition to the usual terminal kill, to ensure that the tumour incidence rates can be estimated. One advantage of the approach is demonstrated in the analysis of glomerulosclerosis following exposure to ionizing radiation. Although the semiparametric model involves fewer parameters, estimates of key functions derived in this analysis are similar to those obtained previously by using a nonparametric method that involves many more parameters.     

Flexible estimates of tumour incidence for intermediately lethal tumours in a typical long-term animal bioassay

The estimation of the incidence of tumours in an animal carcinogenicity study is complicated by the occult nature of the tumours involved (i.e. tumours are not observable before an animal's death). Also, the lethality of tumours is generally unknown, making the tumour incidence function non-identifiable without interim sacrifices, cause-of-death data or modelling assumptions. Although Kaplan–Meier curves for overall survival are typically displayed, obtaining analogous plots for tumour incidence generally requires fairly elaborate model fitting. We present a case-study of tetrafluoroethylene to illustrate a simple method for estimating the incidence of tumours as a function of more easily estimable components. One of the components, tumour prevalence, is modelled by using a generalized additive model, which leads to estimates that are more flexible than those derived under the usual parametric models. A multiplicative assumption for tumour lethality allows for the incorporation of concomitant information, such as the size of tumours. Our approach requires only terminal sacrifice data although additional sacrifice data are easily accommodated. Simulations are used to illustrate the estimator proposed and to evaluate its properties. The method also yields a simple summary measure of tumour lethality, which can be helpful in interpreting the results of a study.