Pitfalls in prediction modeling for normal tissue toxicity in radiation therapy: an illustration with the individual radiation sensitivity and mammary carcinoma risk factor investigation cohorts

Purpose To identify the main causes underlying the failure of prediction models for radiation therapy toxicity to replicate. Methods and Materials Data were used from two German cohorts, Individual Radiation Sensitivity (ISE) (n=418) and Mammary Carcinoma Risk Factor Investigation (MARIE) (n=409), of breast cancer patients with similar characteristics and radiation therapy treatments. The toxicity endpoint chosen was telangiectasia. The LASSO (least absolute shrinkage and selection operator) logistic regression method was used to build a predictive model for a dichotomized endpoint (Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer score 0, 1, or ¿2). Internal areas under the receiver operating characteristic curve (inAUCs) were calculated by a naïve approach whereby the training data (ISE) were also used for calculating the AUC. Cross-validation was also applied to calculate the AUC within the same cohort, a second type of inAUC. Internal AUCs from cross-validation were calculated within ISE and MARIE separately. Models trained on one dataset (ISE) were applied to a test dataset (MARIE) and AUCs calculated (exAUCs). Results Internal AUCs from the naïve approach were generally larger than inAUCs from cross-validation owing to overfitting the training data. Internal AUCs from cross-validation were also generally larger than the exAUCs, reflecting heterogeneity in the predictors between cohorts. The best models with largest inAUCs from cross-validation within both cohorts had a number of common predictors: hypertension, normalized total boost, and presence of estrogen receptors. Surprisingly, the effect (coefficient in the prediction model) of hypertension on telangiectasia incidence was positive in ISE and negative in MARIE. Other predictors were also not common between the 2 cohorts, illustrating that overcoming overfitting does not solve the problem of replication failure of prediction models completely. Conclusions Overfitting and cohort heterogeneity are the 2 main causes of replication failure of prediction models across cohorts. Cross-validation and similar techniques (eg, bootstrapping) cope with overfitting, but the development of validated predictive models for radiation therapy toxicity requires strategies that deal with cohort heterogeneity

Dietary B vitamin and methionine intake and MTHFR C677T genotype on risk of colorectal tumors in Lynch syndrome:the GEOLynch cohort study

Dietary intake of B vitamins and methionine, essential components of DNA synthesis and methylation pathways, may influence colorectal tumor (CRT) development. The impact of B vitamins on colorectal carcinogenesis in individuals with Lynch syndrome (LS) is unknown but is important given their high lifetime risk of developing neoplasms. The role of MTHFR C677T genotype in modifying these relationships in LS individuals is also unclear. We investigated associations between dietary intakes of folate, vitamins B2, B6, B12, and methionine and CRT development in a prospective cohort study of 470 mismatch repair gene mutation carriers. Dietary intakes were assessed by food frequency questionnaire. Cox regression models with robust sandwich covariance estimation, adjusted for age, sex, physical activity, number of colonoscopies during person-time, NSAID use, and mutual vitamins were used to calculate hazard ratios (HRs) and 95 % confidence intervals (95 % CIs). Analyses were also stratified by MTHFR C677T genotype. During a median person-time of 28.0 months, 131 persons developed a CRT. Fifty-one of these persons developed an incident colorectal adenoma, while there were four persons who developed an incident colorectal carcinoma. Compared to the lowest tertile of intake, adjusted HRs (95 % CIs) for CRT development in the highest tertile were 1.06 (0.59-1.91) for folate, 0.77 (0.39-1.51) for vitamin B2, 0.98 (0.59-1.62) for vitamin B6, 1.24 (0.77-2.00) for vitamin B12, and 1.36 (0.83-2.20) for methionine. Low vitamin B2 and low methionine intake were statistically significantly associated with an increased risk of CRT in MTHFR 677TT individuals compared to a combined reference of persons with low intake and CC genotype. There was no suggestion that intake of any dietary B vitamin or methionine was associated with CRT development among those with LS

Smoking increases the risk for colorectal adenomas in patients with Lynch syndrome.

Item does not contain fulltextBACKGROUND & AIMS: Individuals with Lynch syndrome have a high risk of developing colorectal carcinomas and adenomas at a young age, due to inherited mutations in mismatch repair genes. We investigated whether modifiable lifestyle factors, such as smoking and alcohol intake, increase this risk. METHODS: Using data from the GeoLynch cohort study, a prospective analysis of 386 subjects with Lynch syndrome, we calculated hazard ratios for the association between smoking and alcohol intake and development of colorectal adenoma. We used robust variance estimates in the calculation of 95% confidence intervals to account for dependency within families and adjusted for confounding by age, sex, smoking (in the analyses of alcohol intake), number of colonoscopies during the follow-up, colonic resection, and body mass index. RESULTS: During a median follow-up of 10 months, 58 subjects developed a histologically confirmed colorectal adenoma. The hazard ratio for current smokers was 6.13 (95% confidence interval, 2.84-13.22) and for former smokers was 3.03 (95% confidence interval, 1.49-6.16) compared with never smokers. Among ever smokers, a higher number of pack-years was associated with an increased risk for colorectal adenoma (P for trend = .03). There was a trend of alcohol intake increasing the risk of colorectal adenomas, although this was not statistically significant; the hazard ratio for the highest tertile of intake (median, 22 g/day) vs the lowest tertile (median, 0.4 g/day) was 1.56 (95% confidence interval, 0.71-3.43). CONCLUSIONS: Among people with Lynch syndrome, current smokers have an increased risk of colorectal adenomas. Former smokers have a lower risk than current smokers, but greater risk than never smokers. Individuals with Lynch syndrome should be encouraged to avoid smoking.1 februari 201

General characteristics of the mismatch repair gene mutation carriers in the GEOLynch prospective cohort study.

<p>a College or university degree</p><p>b Highest tertile of the physical activity score</p><p>c CRC =  colorectal cancer</p><p>d History of colorectal adenoma and/or carcinoma</p><p>e Use of any dietary supplement during the last month</p><p>f E.g. glucosamine/chondroitin supplements, and garlic pills</p

Polymorphisms in the Angiogenesis-Related Genes EFNB2, MMP2 and JAG1 Are Associated with Survival of Colorectal Cancer Patients

An individual&rsquo;s inherited genetic variation may contribute to the &lsquo;angiogenic switch&rsquo;, which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verh&uuml;tung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p &lt; 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome

Association of any dietary supplement use and colorectal adenoma risk stratified for smoking status and total fruit and vegetables intake in the GEOLynch prospective cohort study of MMR gene mutation carriers.

<p>a No use of dietary supplements during the last month</p><p>b Use of any dietary supplement during the last month</p

General characteristics of the mismatch repair gene mutation carriers stratified by dietary supplement use in the GEOLynch prospective cohort study.

<p>a Use of any dietary supplement during the last month</p><p>b No use of dietary supplement during the last month</p><p>c College or university degree</p><p>d Highest tertile of the physical activity score <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066819#pone.0066819-Pols1" target="_blank">[31]</a></p><p>e CRC =  colorectal cancer</p><p>f History of colorectal adenoma and/or carcinoma</p><p>g E.g. glucosamine/chondroitin supplements, and garlic pills</p><p>h Calculated using Mann-Whitney U test for continuous variables or the χ2 test for categorical variables</p