Assessing prediction error of genetic variants in Cox regression models

Schwerpunkt genetischer Studien ist die Erkenntnis von genetischen Varianten, die im Zusammenhang mit der Entwicklung von Krankheiten stehen. In letzter Zeit gab es besonderes Interesse an Vorhersagen basierend auf genetischen Risiko-Scores und zur Klassifizierung von Patienten in verschiedene Risikostufen der Krankheitswahrscheinlichkeit. Zur Bewertung der Modellgüte für die Vorhersage wird ein zusätzlicher unabhängiger Datensatz als Testdatensatz benötigt, der nicht immer zur Verfügung steht. Der 0,632 Schätzer ist eine gute Alternative, um dieses Problem zu überwinden. Wir kombinierten den 0,632-Schätzer mit Schoenfeld-Residuen als Kriterium zur Vorhersage von Fehlern in einem Cox-Regressionsmodell von Überlebenszeitdaten. Basierend auf diesem Schätzer, formulierten wir ein R-Quadrat Maß für die Vorhersage (R2-pred), welches schätzt, wie stark sich die Vorhersagegüte durch die Prädiktoren im Modell verbessert. Wir untersuchten die Leistung unseres Ansatzes durch Simulationsstudien mit genetischen Varianten als Prädiktoren für das Überleben. Wir verglichen unseren R2-pred Schätzer mit der entsprechenden Schätzung auf unabhängigen Validierungsdaten. Darüber hinaus wiederholten wir unseren Ansatz unter Verwendung des Brier-Scores anstelle der Schoenfeld-Residuen als Fehlermaß. Wir fanden, dass 0,632 Schätzungen von R2-pred, die auf Schoenfeld-Residuen basieren, am besten waren: Der 0,632 Schätzer approximiert am besten die erwarteten R2-pred Werte eines Cox-Modells, Schoenfeld-Residuen ermöglichten die beste Differenzierung der Verbesserung der Vorhersagegüte (im Vergleich zum Brier-Score). Wir präsentieren eine Anwendung auf eine klinisch-genetische Studie zur Stammzell-Transplantation, mit Fokus auf der Evaluierung der Prognose-Fähigkeit der Risiko-Scores für den Tod nach Transplantation

Tests for candidate-gene interaction for longitudinal quantitative traits measured in a large cohort

For the Framingham Heart Study (FHS) and simulated FHS (FHSsim) data, we tested for gene-gene interaction in quantitative traits employing a longitudinal nonparametric association test (LNPT) and, for comparison, a survival analysis. We report results for the Offspring Cohort by LNPT analysis and on all longitudinal cohorts by survival analysis with cohort effect adjustment. We verified that type I errors were not inflated. We compared the power of both methods to detect in FHSsim data two sets of gene pairs that interact for the trait coronary artery calcification. In FHS, we tested eight gene pairs from a list of candidate genes for interaction effects on body mass index. Both methods found evidence for pairwise non-additive effects of mutations in the genes FTO, PON1, and PFKP on body mass index

Stratified survival of resected and overall pancreatic cancer patients in Europe and the USA in the early twenty-first century: a large, international population-based study

Abstract: Background The prognosis of pancreatic cancer (PaC) strongly varies across different stages and age groups, which has unfortunately not been well recorded in the literature. This international population-based study aimed to provide tumor-node-metastasis (TNM) stage- and age-specific survival estimates and trends in resected and overall (resected and unresected) PaC in the early twenty-first century. Methods: Using data from the US Surveillance, Epidemiology, and End Results-18 Program and the national cancer registries of the Netherlands, Belgium, Norway, and Slovenia, short-term and long-term overall survival results stratified by TNM stage and age in resected and overall primary PaC, irrespective of being microscopically confirmed or not, in 2003–2014 were computed using the Kaplan-Meier method. The temporal survival trends over three predefined periods (2003–2005, 2006–2008, and 2009–2011) were further examined using the log-rank test. Results: In total, data for 125,183 patients were analyzed. Overall, age-stratified 3-year survival was 20–34% (< 60 years), 14–25% (60–69 years), and 9–13% (≥ 70 years) in stages I–II PaC; and 2–5% (< 60 years), 1–2% (60–69 years), and < 1–1% (≥ 70 years) in stages III–IV cancer. Patients who underwent operation had higher 3-year survival in each stage and age group (stages I–II: 23–39% (< 60 years), 16–31% (60–69 years), and 17–30% (≥ 70 years); stages III–IV: 5–19% (< 70 years) and 2–14% (≥ 70 years)). Perioperative survival also decreased with advancing stage and older age (stages I–II: 98–100% (< 60 years), 97–99% (60–69 years), and 94–99% (≥ 70 years); stages III–IV: 94–99% (< 70 years) and 81–96% (≥ 70 years)). Between 2003 and 2005 and 2009–2011, for overall PaC, both short-term and long-term survival improvements were observed in all countries except Belgium; for resected disease, short-term improvements were present only in the USA and Slovenia, but long-term improvements were observed in all countries except Slovenia, with stage-specific variations. Conclusions: Our large international study provides TNM stage- and age-specific population-based survival in overall and resected PaC that will facilitate clinical counseling. While the survival expectations for patients with resected PaC are substantially higher than the widely available and known dismal survival predictions for overall patients, conclusions on the benefits of resection cannot be made from this observational study. Patients with advanced-stage disease and/or older age should undergo careful risk assessment before treatment. Limited but inspiring improvement in survival is observed

Development and validation of a prognostic model to predict the prognosis of patients who underwent chemotherapy and resection of pancreatic adenocarcinoma: a large international population-based cohort study

Background: Pancreatic cancer (PaC) remains extremely lethal worldwide even after resection. PaC resection rates are low, making prognostic studies in resected PaC difficult. This large international population-based study aimed at exploring factors associated with survival in patients with resected TNM stage I–II PaC receiving chemotherapy and at developing and internationally validating a survival-predicting model. Methods: Data of stage I–II PaC patients resected and receiving chemotherapy in 2003–2014 were obtained from the national cancer registries of Belgium, the Netherlands, Slovenia, and Norway, and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program. Multivariable Cox proportional hazards models were constructed to investigate the associations of patient and tumor characteristics with overall survival, and analysis was performed in each country respectively without pooling. Prognostic factors remaining after backward selection in SEER-18 were used to build a nomogram, which was subjected to bootstrap internal validation and external validation using the European datasets. Results: A total of 11,837 resected PaC patients were analyzed, with median survival time of 18–23 months and 3-year survival rates of 21–31%. In the main analysis, patient age, tumor T stage, N stage, and differentiation were associated with survival across most countries, with country-specific association patterns and strengths. However, tumor location was mostly not significantly associated with survival. Resection margin, hospital type, tumor size, positive and harvested lymph node number, lymph node ratio, and comorbidity number were associated with survival in certain countries where the information was available. A median survival time- and 1-, 2-, 3-, and 5-year survival probability-predictive nomogram incorporating the backward-selected variables in the main analysis was established. It fits each European national cohort similarly well. Calibration curves showed very good agreement between nomogram-prediction and actual observation. The concordance index of the nomogram (0.60) was significantly higher than that of the T and N stage-based model (0.56) for predicting survival. Conclusions: In these large international population-based cohorts, patients with resected PaC receiving chemotherapy have distinct characteristics independently associated with survival, with country-specific patterns and strengths. A robust benchmark population-based survival-predicting model is established and internationally validated. Like previous models predicting survival in resected PaC, our nomogram performs modestly

Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: Colon cancer family registry: Genetic Variants inUgtandCyp2c9, Nsaid Use and Colorectal Cancer Risk

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of colorectal neoplasia. Previous studies have reported that polymorphisms in NSAID-metabolizing enzymes central to NSAID metabolism including UDP-glucuronosyltransferases (UGT) and cytochrome P450 (CYP) 2C9 may modify this protective effect. We investigated whether 35 functionally relevant polymorphisms within CYP2C9 and UGT genes were associated with colorectal cancer risk or modified the protective effect of NSAIDs on colorectal cancer susceptibility, using 1,584 colorectal cancer cases and 2,516 unaffected sibling controls from the Colon Cancer Family Registry. A three-SNP genotype in UGT1A6 (G-A-A; Ala7-Thr181-Arg184) and the Asp85 variant in UGT2B15 increased the risk of colorectal cancer (OR 3.87; 95% CI 1.04-14.45 and OR 1.34; 95% CI 1.10-1.63, respectively). We observed interactions between UGT1A3 Thr78Thr (A>G) and NSAID use (p-interaction=0.02), a three-SNP genotype within UGT2B4 and ibuprofen use (p-interaction=0.0018), as well as UGT2B15 Tyr85Asp (T>G) and aspirin use (p-interaction=0.01). The interaction with the UGT2B4 and the UGT2B15 polymorphisms were noteworthy at the 25% FDR level. This study highlights the need for further pharmacogenetic studies to identify individuals who might benefit from NSAID use as part of developing effective strategies for prevention of colorectal neoplasia

Significance of Examined Lymph Node Number in Accurate Staging and Long-term Survival in Resected Stage I-II Pancreatic Cancer - More is Better?: A Large International Population-based Cohort Study

Objective:This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds.Summary Background Data:ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established.Methods:Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test.Results:Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from nodenegative to node-positive disease [ORSEER-18= 1.05, 95% confidence interval (CI) = 1.04-1.05; ORNCR= 1.10, 95% CI = 1.08-1.12] and serial improvements in survival (HRSEER-18= 0.98, 95% CI = 0.98-0.99; HRNCR= 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration.Conclusions:In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis

Significance of Examined Lymph Node Number in Accurate Staging and Long-term Survival in Resected Stage I-II Pancreatic Cancer - More is Better? A Large International Population-based Cohort Study

Objective: This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds. Summary Background Data: ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established. Methods: Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test. Results: Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from nodenegative to node-positive disease [ORSEER-18=1.05, 95% confidence interval (CI) = 1.04-1.05; ORNCR = 1.10, 95% CI = 1.08-1.12] and serial improvements in survival (HRSEER-18 = 0.98, 95% CI = 0.98-0.99; HRNCR = 0.98, 95% CI = 0.97-0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration. Conclusions: In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis