title: Predicting relapse in patients with medulloblastoma by integrating evidence from clinical and genomic features.
abstract: OBJECTIVE
  Despite significant progress in the molecular understanding of medulloblastoma, stratification of risk in patients remains a challenge. Focus has shifted from clinical parameters to molecular markers, such as expression of specific genes and selected genomic abnormalities, to improve accuracy of treatment outcome prediction. Here, we show how integration of high-level clinical and genomic features or risk factors, including disease subtype, can yield more comprehensive, accurate, and biologically interpretable prediction models for relapse versus no-relapse classification. We also introduce a novel Bayesian nomogram indicating the amount of evidence that each feature contributes on a patient-by-patient basis.
  
  
  METHODS
  A Bayesian cumulative log-odds model of outcome was developed from a training cohort of 96 children treated for medulloblastoma, starting with the evidence provided by clinical features of metastasis and histology (model A) and incrementally adding the evidence from gene-expression-derived features representing disease subtype-independent (model B) and disease subtype-dependent (model C) pathways, and finally high-level copy-number genomic abnormalities (model D). The models were validated on an independent test cohort (n = 78).
  
  
  RESULTS
  On an independent multi-institutional test data set, models A to D attain an area under receiver operating characteristic (au-ROC) curve of 0.73 (95% CI, 0.60 to 0.84), 0.75 (95% CI, 0.64 to 0.86), 0.80 (95% CI, 0.70 to 0.90), and 0.78 (95% CI, 0.68 to 0.88), respectively, for predicting relapse versus no relapse.
  
  
  CONCLUSIONS
  The proposed models C and D outperform the current clinical classification schema (au-ROC, 0.68), our previously published eight-gene outcome signature (au-ROC, 0.71), and several new schemas recently proposed in the literature for medulloblastoma risk stratification.
authors.affiliation: Eli and Edythe Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Aviad
authors.initials: A
authors.lastname: Tsherniak
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Lauren
authors.initials: L
authors.lastname: Ambrogio
authors.forename: Netteke
authors.initials: N
authors.lastname: Schouten-van Meeteren
authors.forename: Tianni
authors.initials: T
authors.lastname: Zhou
authors.forename: Allen
authors.initials: A
authors.lastname: Buxton
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
mesh_terms: D001499:Bayes Theorem; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology*; D002648:Child; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology*; D049451:Nomograms; D011237:Predictive Value of Tests; D011379:Prognosis; D012372:ROC Curve; D018570:Risk Assessment; D012307:Risk Factors