Effect of Quantitative Nuclear Image Features on Recurrence of Ductal Carcinoma In Situ (DCIS) of the Breast

BACKGROUND: Nuclear grade has been associated with breast DCIS recurrence and progression to invasive carcinoma; however, our previous study of a cohort of patients with breast DCIS did not find such an association with outcome. Fifty percent of patients had heterogeneous DCIS with more than one nuclear grade. The aim of the current study was to investigate the effect of quantitative nuclear features assessed with digital image analysis on ipsilateral DCIS recurrence.CONCLUSION: Analysis of nuclear features measured by image cytometry may contribute to the classification and prognosis of breast DCIS patients with more than one nuclear grade.Author manuscript. Published in final edited form as: Cancer Informatics 2008:4 99–109.The final published version of this article is located at: http://la-press.com/article.php?article_id=583NIH U56 CA113004; to David E. AxelrodThis work was funded by the New Jersey Commission for Cancer Research 1076-CCRS0, the National Institutes of Health U56 CA113004, the Hyde and Watson Foundation, the Busch Memorial Fund, and the E.B. Fish Research Fund.NJ Commission on Cancer Research 1076-CCR-SO; to David E. Axelro

Ductal carcinoma in situ of the breast (DCIS) with heterogeneity of nuclear grade: prognostic effects of quantitative nuclear assessment

<p>Abstract</p> <p>Background</p> <p>Previously, 50% of patients with breast ductal carcinoma <it>in situ (</it>DCIS) had more than one nuclear grade, and neither worst nor predominant nuclear grade was significantly associated with development of invasive carcinoma. Here, we used image analysis in addition to histologic evaluation to determine if quantification of nuclear features could provide additional prognostic information and hence impact prognostic assessments.</p> <p>Methods</p> <p>Nuclear image features were extracted from about 200 nuclei of each of 80 patients with DCIS who underwent lumpectomy alone, and received no adjuvant systemic therapy. Nuclear images were obtained from 20 representative nuclei per duct, from each of a group of 5 ducts, in two separate fields, for 10 ducts. Reproducibility of image analysis features was determined, as was the ability of features to discriminate between nuclear grades. Patient information was available about clinical factors (age and method of DCIS detection), pathologic factors (DCIS size, nuclear grade, margin size, and amount of parenchymal involvement), and 39 image features (morphology, densitometry, and texture). The prognostic effects of these factors and features on the development of invasive breast cancer were examined with Cox step-wise multivariate regression.</p> <p>Results</p> <p>Duplicate measurements were similar for 89.7% to 97.4% of assessed image features. For the pooled assessment with ~200 nuclei per patient, a discriminant function with one densitometric and two texture features was significantly (p < 0.001) associated with nuclear grading, and provided 78.8% correct jackknifed classification of a patient's nuclear grade. In multivariate assessments, image analysis nuclear features had significant prognostic associations (p ≤ 0.05) with the development of invasive breast cancer. Texture (difference entropy, p < 0.001; contrast, p < 0.001; peak transition probability, p = 0.01), densitometry (range density, p = 0.004), and measured margin (p = 0.05) were associated with development of invasive disease for the pooled data across all ducts.</p> <p>Conclusion</p> <p>Image analysis provided reproducible assessments of nuclear features which quantitated differences in nuclear grading for patients. Quantitative nuclear image features indicated prognostically significant differences in DCIS, and may contribute additional information to prognostic assessments of which patients are likely to develop invasive disease.</p

Adjusted Empirical Likelihood Method in the Presence of Nuisance Parameters with Application to the Sharpe Ratio

The Sharpe ratio is a widely used risk-adjusted performance measurement in economics and finance. Most of the known statistical inferential methods devoted to the Sharpe ratio are based on the assumption that the data are normally distributed. In this article, without making any distributional assumption on the data, we develop the adjusted empirical likelihood method to obtain inference for a parameter of interest in the presence of nuisance parameters. We show that the log adjusted empirical likelihood ratio statistic is asymptotically distributed as the chi-square distribution. The proposed method is applied to obtain inference for the Sharpe ratio. Simulation results illustrate that the proposed method is comparable to Jobson and Korkie&rsquo;s method (1981) and outperforms the empirical likelihood method when the data are from a symmetric distribution. In addition, when the data are from a skewed distribution, the proposed method significantly outperforms all other existing methods. A real-data example is analyzed to exemplify the application of the proposed method

Testing Homogeneity in a Semiparametric Two-Sample Problem

We study a two-sample homogeneity testing problem, in which one sample comes from a population with density f(x) and the other is from a mixture population with mixture density (1−λ)f(x)+λg(x). This problem arises naturally from many statistical applications such as test for partial differential gene expression in microarray study or genetic studies for gene mutation. Under the semiparametric assumption g(x)=f(x)eα+βx, a penalized empirical likelihood ratio test could be constructed, but its implementation is hindered by the fact that there is neither feasible algorithm for computing the test statistic nor available research results on its theoretical properties. To circumvent these difficulties, we propose an EM test based on the penalized empirical likelihood. We prove that the EM test has a simple chi-square limiting distribution, and we also demonstrate its competitive testing performances by simulations. A real-data example is used to illustrate the proposed methodology

Two-Sample Tests Based on Data Depth

In this paper, we focus on the homogeneity test that evaluates whether two multivariate samples come from the same distribution. This problem arises naturally in various applications, and there are many methods available in the literature. Based on data depth, several tests have been proposed for this problem but they may not be very powerful. In light of the recent development of data depth as an important measure in quality assurance, we propose two new test statistics for the multivariate two-sample homogeneity test. The proposed test statistics have the same χ2(1) asymptotic null distribution. The generalization of the proposed tests into the multivariate multisample situation is discussed as well. Simulations studies demonstrate the superior performance of the proposed tests. The test procedure is illustrated through two real data examples

Modified likelihood ratio test for homogeneity in a mixture of von Mises distributions

SUMMARY. Directional data are often collected in applications such as in genetics, geology and astrolomy. One particular statistical problem of interest is whether the data are from a mixture of two von Mises distributions or a single von Mises distribution. Motivating examples including a DNA microarray experiment where it is suggested that a proportion of circadian genes have systematically different phase/peak expressions in two different tissues. We study the use of modified likelihood ratio test (MLRT) to this class of problems. The MLRT statistic is shown to have a simple χ 2 1 null limiting distribution. The result is extended to general parametric kernels. The simulation study gives additional insight into the finite-sample performance of the test. For illustration, two real data examples are also given

Group sequential testing of homogeneity in genetic linkage analysis

Human genetic linkage studies have the objective of testing whether disease genes are linked to genetic markers based on family genetic data. Sometimes, these studies require many years of recruiting informative families and large amount of funds. One way to reduce the required sample size for such studies is to use sequential testing procedures. In this paper, we investigate two group sequential tests for homogeneity in binomial mixture models that are commonly used in genetic linkage analysis. We conduct Monte Carlo simulations to examine the performance of the group sequential procedures. The results show that the proposed group sequential procedures can save, on average, substantial sample size and detect linkage with almost the same power as their nonsequential counterparts.

Robust joint score tests in the application of DNA methylation data analysis

Background: Recently differential variability has been showed to be valuable in evaluating the association of DNA methylation to the risks of complex human diseases. The statistical tests based on both differential methylation level and differential variability can be more powerful than those based only on differential methylation level. Anh and Wang (2013) proposed a joint score test (AW) to simultaneously detect for differential methylation and differential variability. However, AW’s method seems to be quite conservative and has not been fully compared with existing joint tests. Results: We proposed three improved joint score tests, namely iAW.Lev, iAW.BF, and iAW.TM, and have made extensive comparisons with the joint likelihood ratio test (jointLRT), the Kolmogorov-Smirnov (KS) test, and the AW test. Systematic simulation studies showed that: 1) the three improved tests performed better (i.e., having larger power, while keeping nominal Type I error rates) than the other three tests for data with outliers and having different variances between cases and controls; 2) for data from normal distributions, the three improved tests had slightly lower power than jointLRT and AW. The analyses of two Illumina HumanMethylation27 data sets GSE37020 and GSE20080 and one Illumina Infinium MethylationEPIC data set GSE107080 demonstrated that three improved tests had higher true validation rates than those from jointLRT, KS, and AW. Conclusions: The three proposed joint score tests are robust against the violation of normality assumption and presence of outlying observations in comparison with other three existing tests. Among the three proposed tests, iAW.BF seems to be the most robust and effective one for all simulated scenarios and also in real data analyses. Electronic supplementary material The online version of this article (10.1186/s12859-018-2185-3) contains supplementary material, which is available to authorized users

TESTING FOR HOMOGENEITY IN GENETIC LINKAGE ANALYSIS

Abstract: We apply the modified likelihood ratio test to two binomial mixture models arising in genetic linkage analysis. The limiting distribution of the test statistic for both models is shown to be a mixture of chi-squared distributions. A consideration of random family sizes for both models gives similar results. We also explore the power properties under local alternatives. Simulation studies show that the modified likelihood ratio test is more powerful than other methods under a variety of model specifications. Key words and phrases: Genetic linkage analysis, hypothesis testing, local asymptotic power, mixture models, modified likelihood, random family sizes, recombinant. 1