title: Contrasting analytical and data-driven frameworks for radiogenomic modeling of normal tissue toxicities in prostate cancer.
abstract: OBJECTIVE
  We explore analytical and data-driven approaches to investigate the integration of genetic variations (single nucleotide polymorphisms [SNPs] and copy number variations [CNVs]) with dosimetric and clinical variables in modeling radiation-induced rectal bleeding (RB) and erectile dysfunction (ED) in prostate cancer patients.
  
  
  METHODS
  Sixty-two patients who underwent curative hypofractionated radiotherapy (66 Gy in 22 fractions) between 2002 and 2010 were retrospectively genotyped for CNV and SNP rs5489 in the xrcc1 DNA repair gene. Fifty-four patients had full dosimetric profiles. Two parallel modeling approaches were compared to assess the risk of severe RB (Grade⩾3) and ED (Grade⩾1); Maximum likelihood estimated generalized Lyman-Kutcher-Burman (LKB) and logistic regression. Statistical resampling based on cross-validation was used to evaluate model predictive power and generalizability to unseen data.
  
  
  RESULTS
  Integration of biological variables xrcc1 CNV and SNP improved the fit of the RB and ED analytical and data-driven models. Cross-validation of the generalized LKB models yielded increases in classification performance of 27.4% for RB and 14.6% for ED when xrcc1 CNV and SNP were included, respectively. Biological variables added to logistic regression modeling improved classification performance over standard dosimetric models by 33.5% for RB and 21.2% for ED models.
  
  
  CONCLUSIONS
  As a proof-of-concept, we demonstrated that the combination of genetic and dosimetric variables can provide significant improvement in NTCP prediction using analytical and data-driven approaches. The improvement in prediction performance was more pronounced in the data driven approaches. Moreover, we have shown that CNVs, in addition to SNPs, may be useful structural genetic variants in predicting radiation toxicities.
authors.affiliation: Medical Physics Unit, Department of Oncology, McGill University Health Center, Montreal, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Coates
authors.affiliation: Medical Physics Unit, Department of Oncology, McGill University Health Center, Montreal, Canada.
authors.forename: Asha K
authors.initials: AK
authors.lastname: Jeyaseelan
authors.affiliation: Medical Physics Unit, Department of Oncology, McGill University Health Center, Montreal, Canada.
authors.forename: Norma
authors.initials: N
authors.lastname: Ybarra
authors.affiliation: Radiation Oncology Division, Department of Oncology, McGill University Health Centre, Montreal, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: David
authors.affiliation: Radiation Oncology Division, Department of Oncology, McGill University Health Centre, Montreal, Canada.
authors.forename: Sergio
authors.initials: S
authors.lastname: Faria
authors.affiliation: Radiation Oncology Division, Department of Oncology, McGill University Health Centre, Montreal, Canada.
authors.forename: Luis
authors.initials: L
authors.lastname: Souhami
authors.affiliation: Radiation Oncology Division, Department of Oncology, McGill University Health Centre, Montreal, Canada.
authors.forename: Fabio
authors.initials: F
authors.lastname: Cury
authors.affiliation: Radiation Oncology Division, Department of Oncology, McGill University Health Centre, Montreal, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Duclos
authors.affiliation: Medical Physics Unit, Department of Oncology, McGill University Health Center, Montreal, Canada. Electronic address: issam.elnaqa@mcgill.ca.
authors.forename: Issam
authors.initials: I
authors.lastname: El Naqa
mesh_terms: D000368:Aged; D056915:DNA Copy Number Variations; D007172:Erectile Dysfunction / Q000209:etiology; D006471:Gastrointestinal Hemorrhage; D023281:Genomics; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D011471:Prostatic Neoplasms / Q000532:radiotherapy*; D011832:Radiation Injuries / Q000532:radiotherapy; D011874:Radiometry; D012007:Rectum / Q000293:injuries; D012189:Retrospective Studies; D012306:Risk
keywords: Copy number variations; Normal tissue toxicity; Prostate cancer; Radiogenomic modeling; Radiotherapy