Gene Selection using a High-Dimensional Regression Model with Microarrays in Cancer Prognostic Studies

Mining of gene expression data to identify genes associated with patient survival is an ongoing problem in cancer prognostic studies using microarrays in order to use such genes to achieve more accurate prognoses. The least absolute shrinkage and selection operator (lasso) is often used for gene selection and parameter estimation in high-dimensional microarray data. The lasso shrinks some of the coefficients to zero, and the amount of shrinkage is determined by the tuning parameter, often determined by cross validation. The model determined by this cross validation contains many false positives whose coefficients are actually zero. We propose a method for estimating the false positive rate (FPR) for lasso estimates in a high-dimensional Cox model. We performed a simulation study to examine the precision of the FPR estimate by the proposed method. We applied the proposed method to real data and illustrated the identification of false positive genes

A New Test Statistic Based on Shrunken Sample Variance for Identifying Differentially Expressed Genes in Small Microarray Experiments

Choosing an appropriate statistic and precisely evaluating the false discovery rate (FDR) are both essential for devising an effective method for identifying differentially expressed genes in microarray data. The t-type score proposed by Pan et al. (2003) succeeded in suppressing false positives by controlling the underestimation of variance but left the overestimation uncontrolled. For controlling the overestimation, we devised a new test statistic (variance stabilized t-type score) by placing shrunken sample variances of the James-Stein type in the denominator of the t-type score. Since the relative superiority of the mean and median FDRs was unclear in the widely adopted Significance Analysis of Microarrays (SAM), we conducted simulation studies to examine the performance of the variance stabilized t-type score and the characteristics of the two FDRs. The variance stabilized t-type score was generally better than or at least as good as the t-type score, irrespective of the sample size and proportion of differentially expressed genes. In terms of accuracy, the median FDR was superior to the mean FDR when the proportion of differentially expressed genes was large. The variance stabilized t-type score with the median FDR was applied to actual colorectal cancer data and yielded a reasonable result

Estimating the False Discovery Rate Using Mixed Normal Distribution for Identifying Differentially Expressed Genes in Microarray Data Analysis

The recent development of DNA microarray technology allows us to measure simultaneously the expression levels of thousands of genes and to identify truly correlated genes with anticancer drug response (differentially expressed genes) from many candidate genes. Significance Analysis of Microarray (SAM) is often used to estimate the false discovery rate (FDR), which is an index for optimizing the identifiability of differentially expressed genes, while the accuracy of the estimated FDR by SAM is not necessarily confirmed. We propose a new method for estimating the FDR assuming a mixed normal distribution on the test statistic and examine the performance of the proposed method and SAM using simulated data. The simulation results indicate that the accuracy of the estimated FDR by the proposed method and SAM, varied depending on the experimental conditions. We applied both methods to actual data comprised of expression levels of 12,625 genes of 10 responders and 14 non-responders to docetaxel for breast cancer. The proposed method identified 280 differentially expressed genes correlated with docetaxel response using a cut-off value for achieving FDR <0.01 to prevent false-positive genes, although 92 genes were previously thought to be correlated with docetaxel response ones

Autosynchronized systolic unloading during left ventricular assist with a centrifugal pump

AbstractObjectives: The purpose of this study was to investigate how the inflow cannulation site of the left ventricular assist system with a centrifugal pump would influence cardiac function on failing heart models. Methods: In 10 sheep, a left ventricular assist system was instituted by an outflow cannula in the descending aorta, two inflow cannulas in the left atrium and the left ventricle, and connecting those cannulas to a magnetically suspended centrifugal pump. A conductance catheter and a tipped micromanometer for monitoring the pressure-volume loop were also inserted into the left ventricle. Myocardial oxygen consumption was directly measured. Heart failure was induced by injection of microspheres into the left main coronary artery. The assist rate was varied from 0% to 100% at each inflow cannulation site. Results: The pump flow with left ventricular cannulation increased during the systolic phase and decreased during the diastolic phase, whereas it was constant with left atrial cannulation. Ejection fraction with left atrial cannulation decreased as the assist rate increased, whereas that with left ventricular cannulation was maintained up to 75% assist. The external work with left atrial cannulation decreased gradually as the assist rate increased, whereas the external work with left ventricular cannulation did not decrease until the assist rate reached 75%. The myocardial oxygen consumption in both cannulations decreased proportionally as the assist rate increased; they were significantly less with left ventricular cannulation at the 100% assist rate than with left atrial cannulation. Conclusion: Left ventricular cannulation during left ventricular assistance maintains ejection fraction and effectively reduces oxygen consumption.J Thorac Cardiovasc Surg 2003;125:353-6

Safety analysis of two different regimens of uracil–tegafur plus leucovorin as adjuvant chemotherapy for high-risk stage II and III colon cancer in a phase III trial comparing 6 with 18 months of treatment: JFMC33-0502 trial

PURPOSE: The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil–tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses. METHODS: Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m(2)) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated. RESULTS: A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group. CONCLUSIONS: Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-014-2461-5) contains supplementary material, which is available to authorized users