A pseudo-R2 measure for selecting genomic markers with crossing hazards functions

<p>Abstract</p> <p>Background</p> <p>In genomic medical studies, one of the major objectives is to identify genomic factors with a prognostic impact on time-to-event outcomes so as to provide new insights into the disease process. Selection usually relies on statistical univariate indices based on the Cox model. Such model assumes proportional hazards (PH) which is unlikely to hold for each genomic marker.</p> <p>Methods</p> <p>In this paper, we introduce a novel pseudo-R²measure derived from a crossing hazards model and designed for the selection of markers with crossing effects. The proposed index is related to the score statistic and quantifies the extent of a genomic factor to separate patients according to their survival times and marker measurements. We also show the importance of considering genomic markers with crossing effects as they potentially reflect the complex interplay between markers belonging to the same pathway.</p> <p>Results</p> <p>Simulations show that our index is not affected by the censoring and the sample size of the study. It also performs better than classical indices under the crossing hazards assumption. The practical use of our index is illustrated in a lung cancer study. The use of the proposed pseudo-R²allows the identification of cell-cycle dependent genes not identified when relying on the PH assumption.</p> <p>Conclusions</p> <p>The proposed index is a novel and promising tool for selecting markers with crossing hazards effects.</p

Strongly self-interacting vector dark matter via freeze-in

We study a vector dark matter (VDM) model in which the dark sector couples to the Standard Model sector via a Higgs portal. If the portal coupling is small enough the VDM can be produced via the freeze-in mechanism. It turns out that the electroweak phase transition have a substantial impact on the prediction of the VDM relic density. We further assume that the dark Higgs boson which gives the VDM mass is so light that it can induce strong VDM self-interactions and solve the small-scale structure problems of the Universe. As illustrated by the latest LUX data, the extreme smallness of the Higgs portal coupling required by the freeze-in mechanism implies that the dark matter direct detection bounds are easily satisfied. However, the model is well constrained by the indirect detections of VDM from BBN, CMB, AMS-02, and diffuse $\gamma$/X-rays. Consequently, only when the dark Higgs boson mass is at most of ${\cal O}({\rm keV})$ does there exist a parameter region which leads to a right amount of VDM relic abundance and an appropriate VDM self-scattering while satisfying all other constraints simultaneously.Comment: 29 pages, 8 figure

Patterns of chromosomal copy-number alterations in intrahepatic cholangiocarcinoma

International audienceBackground: Intrahepatic cholangiocarcinomas (ICC) are relatively rare malignant tumors associated with a poor prognosis. Recent studies using genome-wide sequencing technologies have mainly focused on identifying new driver mutations. There is nevertheless a need to investigate the spectrum of copy number aberrations in order to identify potential target genes in the altered chromosomal regions. The aim of this study was to characterize the patterns of chromosomal copy-number alterations (CNAs) in ICC. Methods: 53 patients having ICC with frozen material were selected. In 47 cases, DNA hybridization has been performed on a genomewide SNP array. A procedure with a segmentation step and a calling step classified genomic regions into copy-number aberration states. We identified the exclusively amplified and deleted recurrent genomic areas. These areas are those showing the highest estimated propensity level for copy loss (resp. copy gain) together with the lowest level for copy gain (resp. copy loss). We investigated ICC clustering. We analyzed the relationships between CNAs and clinico-pathological characteristics. Results: The overall genomic profile of ICC showed many alterations with higher rates for the deletions. Exclusively deleted genomic areas were 1p, 3p and 14q. The main exclusively amplified genomic areas were 1q, 7p, 7q and 8q. Based on the exclusively deleted/amplified genomic areas, a clustering analysis identified three tumors groups: the first group characterized by copy loss of 1p and copy gain of 7p, the second group characterized by 1p and 3p copy losses without 7p copy gain, the last group characterized mainly by very few CNAs. From univariate analyses, the number of tumors, the size of the largest tumor and the stage were significantly associated with shorter time recurrence. We found no relationship between the number of altered cytobands or tumor groups and time to recurrence. Conclusion: This study describes the spectrum of chromosomal aberrations across the whole genome. Some of the recurrent exclusive CNAs harbor candidate target genes. Despite the absence of correlation between CNAs and clinico-pathological characteristics, the co-occurence of 7p gain and 1p loss in a subgroup of patients may suggest a differential activation of EGFR and its downstream pathways, which may have a potential effect on targeted therapies

Finding exclusively deleted or amplified genomic areas in lung adenocarcinomas using a novel chromosomal pattern analysis

<p>Abstract</p> <p>Background</p> <p>Genomic copy number alteration (CNA) that are recurrent across multiple samples often harbor critical genes that can drive either the initiation or the progression of cancer disease. Up to now, most researchers investigating recurrent CNAs consider separately the marginal frequencies for copy gain or loss and select the areas of interest based on arbitrary cut-off thresholds of these frequencies. In practice, these analyses ignore the interdependencies between the propensity of being deleted or amplified for a clone. In this context, a joint analysis of the copy number changes across tumor samples may bring new insights about patterns of recurrent CNAs.</p> <p>Methods</p> <p>We propose to identify patterns of recurrent CNAs across tumor samples from high-resolution comparative genomic hybridization microarrays. Clustering is achieved by modeling the copy number state (loss, no-change, gain) as a multinomial distribution with probabilities parameterized through a latent class model leading to nine patterns of recurrent CNAs. This model gives us a powerful tool to identify clones with contrasting propensity of being deleted or amplified across tumor samples. We applied this model to a homogeneous series of 65 lung adenocarcinomas.</p> <p>Results</p> <p>Our latent class model analysis identified interesting patterns of chromosomal aberrations. Our results showed that about thirty percent of the genomic clones were classified either as "exclusively" deleted or amplified recurrent CNAs and could be considered as non random chromosomal events. Most of the known oncogenes or tumor suppressor genes associated with lung adenocarcinoma were located within these areas. We also describe genomic areas of potential interest and show that an increase of the frequency of amplification in these particular areas is significantly associated with poorer survival.</p> <p>Conclusion</p> <p>Analyzing jointly deletions and amplifications through our latent class model analysis allows highlighting specific genomic areas with exclusively amplified or deleted recurrent CNAs which are good candidate for harboring oncogenes or tumor suppressor genes.</p

Integrating NGS-derived mutational profiling in the diagnosis of multiple lung adenocarcinomas

MICROABSTRACT: Integration of Next Generation Sequencing (NGS) information for use in distinguishing between Multiple Primary Lung Cancer and intrapulmonary metastasis was evaluated. We used a probabilistic model, comprehensive histologic assessment and NGS to classify patients. Integrating NGS data confirmed initial diagnosis (n = 41), revised the diagnosis (n = 12), while resulted in non-informative data (n = 8). Accuracy of diagnosis can be significantly improved with integration of NGS data. BACKGROUND: Distinguishing between multiple primary lung cancers (MPLC) and intrapulmonary metastases (IPM) is challenging. The goal of this study was to evaluate how Next Generation Sequencing (NGS) information may be integrated in the diagnostic strategy. PATIENTS AND METHODS: Patients with multiple lung adenocarcinomas were classified using both the comprehensive histologic assessment and NGS. We computed the joint probability of each pair having independent mutations by chance (thus being classified as MPLC). These probabilities were computed using the marginal mutation rates of each mutation, and the known negative dependencies between driver genes and different gene loci. With these NGS-driven data, cases were re-classified as MPLC or IPM. RESULTS: We analyzed 61 patients with a total of 131 tumors. The most frequent mutation was KRAS (57.3%) which occured at a rate higher than expected (p < 0.001) in lung cancer. No mutation was detected in 25/131 tumors (19.1%). Discordant molecular findings between tumor sites were found in 46 patients (75.4%); 11 patients (18.0%) had concordant molecular findings, and 4 patients (6.6%) had concordant molecular findings at 2 of the 3 sites. After integration of the NGS data, the initial diagnosis was confirmed for 41 patients (67.2%), the diagnosis was revised for 12 patients (19.7%) or was considered as non-informative for 8 patients (13.1%). CONCLUSION: Integrating the information of NGS data may significantly improve accuracy of diagnosis and staging

A constrained polynomial regression procedure for estimating the local False Discovery Rate

<p>Abstract</p> <p>Background</p> <p>In the context of genomic association studies, for which a large number of statistical tests are performed simultaneously, the local False Discovery Rate (<it>lFDR</it>), which quantifies the evidence of a specific gene association with a clinical or biological variable of interest, is a relevant criterion for taking into account the multiple testing problem. The <it>lFDR </it>not only allows an inference to be made for each gene through its specific value, but also an estimate of Benjamini-Hochberg's False Discovery Rate (<it>FDR</it>) for subsets of genes.</p> <p>Results</p> <p>In the framework of estimating procedures without any distributional assumption under the alternative hypothesis, a new and efficient procedure for estimating the <it>lFDR </it>is described. The results of a simulation study indicated good performances for the proposed estimator in comparison to four published ones. The five different procedures were applied to real datasets.</p> <p>Conclusion</p> <p>A novel and efficient procedure for estimating <it>lFDR </it>was developed and evaluated.</p

HER2 Status in Ovarian Carcinomas: A Multicenter GINECO Study of 320 Patients

BACKGROUND: Despite a typically good response to first-line combination chemotherapy, the prognosis for patients with advanced ovarian cancer remains poor because of acquired chemoresistance. The use of targeted therapies such as trastuzumab may potentially improve outcomes for patients with ovarian cancer. HER2 overexpression/amplification has been reported in ovarian cancer, but the exact percentage of HER2-positive tumors varies widely in the literature. In this study, HER2 gene status was evaluated in a large, multicentric series of 320 patients with advanced ovarian cancer, including 243 patients enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin-based chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: The HER2 status of primary tumors and metastases was evaluated by both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analysis of paraffin-embedded tissue on conventional slides. The prognostic impact of HER2 expression was analyzed. HER2 gene was overexpressed and amplified in 6.6% of analyzed tumors. Despite frequent intratumoral heterogeneity, no statistically significant difference was detected between primary tumors and corresponding metastases. CONCLUSIONS/SIGNIFICANCE: Our results show that the decision algorithm usually used in breast cancer (IHC as a screening test, with equivocal results confirmed by FISH) is appropriate in ovarian cancer. In contrast to previous series, HER2-positive status did not influence outcome in the present study, possibly due to the fact that patients in our study received paclitaxel/carboplatin-based chemotherapy. This raises the question of whether HER2 status and paclitaxel sensitively are linked

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe:A descriptive study of test results

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA

Pooled Analysis of Prognostic Impact of Urokinase-Type Plasminogen Activator and Its Inhibitor PAI-1 in 8377 Breast Cancer Patients

Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph node-negative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). Conclusions: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategie