title: Fuzzy logic selection as a new reliable tool to identify molecular grade signatures in breast cancer--the INNODIAG study.
abstract: BACKGROUND
  Personalized medicine has become a priority in breast cancer patient management. In addition to the routinely used clinicopathological characteristics, clinicians will have to face an increasing amount of data derived from tumor molecular profiling. The aims of this study were to develop a new gene selection method based on a fuzzy logic selection and classification algorithm, and to validate the gene signatures obtained on breast cancer patient cohorts.
  
  
  METHODS
  We analyzed data from four published gene expression datasets for breast carcinomas. We identified the best discriminating genes by comparing molecular expression profiles between histologic grade 1 and 3 tumors for each of the training datasets. The most pertinent probes were selected and used to define fuzzy molecular grade 1-like (good prognosis) and fuzzy molecular grade 3-like (poor prognosis) profiles. To evaluate the prognostic performance of the fuzzy grade signatures in breast cancer tumors, a Kaplan-Meier analysis was conducted to compare the relapse-free survival deduced from histologic grade and fuzzy molecular grade classification.
  
  
  RESULTS
  We applied the fuzzy logic selection on breast cancer databases and obtained four new gene signatures. Analysis in the training public sets showed good performance of these gene signatures for grade (sensitivity from 90% to 95%, specificity 67% to 93%). To validate these gene signatures, we designed probes on custom microarrays and tested them on 150 invasive breast carcinomas. Good performance was obtained with an error rate of less than 10%. For one gene signature, among 74 histologic grade 3 and 18 grade 1 tumors, 88 cases (96%) were correctly assigned. Interestingly histologic grade 2 tumors (n = 58) were split in these two molecular grade categories.
  
  
  CONCLUSIONS
  We confirmed the use of fuzzy logic selection as a new tool to identify gene signatures with good reliability and increased classification power. This method based on artificial intelligence algorithms was successfully applied to breast cancers molecular grade classification allowing histologic grade 2 classification into grade 1 and grade 2 like to improve patients prognosis. It opens the way to further development for identification of new biomarker combinations in other applications such as prediction of treatment response.
authors.affiliation: CNRS, LAAS, F-31400, Toulouse, France. tatianak0417@gmail.com.|Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. tatianak0417@gmail.com.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kempowsky-Hamon
authors.affiliation: Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. vallecarine@hotmail.com.|INRA, UMR792, Ingénierie des Systèmes Biologiques et des Procédés, F-31400, Toulouse, France. vallecarine@hotmail.com.|CNRS, UMR5504, F-31400, Toulouse, France. vallecarine@hotmail.com.
authors.forename: Carine
authors.initials: C
authors.lastname: Valle
authors.affiliation: Institut Claudius Regaud, Biology and Pathology Department; INSERM UMR1037, Toulouse, France. Lacroix.Magali@claudiusregaud.fr.
authors.forename: Magali
authors.initials: M
authors.lastname: Lacroix-Triki
authors.affiliation: CNRS, LAAS, F-31400, Toulouse, France. hedjazil@hotmail.com.|Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. hedjazil@hotmail.com.
authors.forename: Lyamine
authors.initials: L
authors.lastname: Hedjazi
authors.affiliation: Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. lidwine.trouilh@insa-toulouse.fr.|INRA, UMR792, Ingénierie des Systèmes Biologiques et des Procédés, F-31400, Toulouse, France. lidwine.trouilh@insa-toulouse.fr.|CNRS, UMR5504, F-31400, Toulouse, France. lidwine.trouilh@insa-toulouse.fr.
authors.forename: Lidwine
authors.initials: L
authors.lastname: Trouilh
authors.affiliation: Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. sophie.lamarre@insa-toulouse.fr.|INRA, UMR792, Ingénierie des Systèmes Biologiques et des Procédés, F-31400, Toulouse, France. sophie.lamarre@insa-toulouse.fr.|CNRS, UMR5504, F-31400, Toulouse, France. sophie.lamarre@insa-toulouse.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lamarre
authors.affiliation: Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. delphine.labourdette@insa-toulouse.fr.|INRA, UMR792, Ingénierie des Systèmes Biologiques et des Procédés, F-31400, Toulouse, France. delphine.labourdette@insa-toulouse.fr.|CNRS, UMR5504, F-31400, Toulouse, France. delphine.labourdette@insa-toulouse.fr.
authors.forename: Delphine
authors.initials: D
authors.lastname: Labourdette
authors.affiliation: Institut Claudius Regaud, Biology and Pathology Department; INSERM UMR1037, Toulouse, France. Roger.Laurence@claudiusregaud.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Roger
authors.affiliation: Institut Claudius Regaud, Biology and Pathology Department; INSERM UMR1037, Toulouse, France. Mhamdi.Loubna@claudiusregaud.fr.
authors.forename: Loubna
authors.initials: L
authors.lastname: Mhamdi
authors.affiliation: Dendris SAS, 8 Rue de Cugnaux, 31300, Toulouse, France. Dalenc.Florence@claudiusregaud.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.affiliation: Institut Claudius Regaud, Oncology Department, Toulouse, France. Filleron.Thomas@claudiusregaud.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: Institut Claudius Regaud, Biology and Pathology Department; INSERM UMR1037, Toulouse, France. Favre.Gilles@claudiusregaud.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Favre
authors.affiliation: Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. fran_jm@insa-toulouse.fr.|INRA, UMR792, Ingénierie des Systèmes Biologiques et des Procédés, F-31400, Toulouse, France. fran_jm@insa-toulouse.fr.|CNRS, UMR5504, F-31400, Toulouse, France. fran_jm@insa-toulouse.fr.|Dendris SAS, 8 Rue de Cugnaux, 31300, Toulouse, France. fran_jm@insa-toulouse.fr.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: François
authors.affiliation: CNRS, LAAS, F-31400, Toulouse, France. mvlelann@laas.fr.|Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. mvlelann@laas.fr.
authors.forename: Marie-Véronique
authors.initials: MV
authors.lastname: Le Lann
authors.affiliation: Université de Toulouse; INSA, UPS, INP; LISBP, F-31077, Toulouse, France. leberre@insa-toulouse.fr.|INRA, UMR792, Ingénierie des Systèmes Biologiques et des Procédés, F-31400, Toulouse, France. leberre@insa-toulouse.fr.|CNRS, UMR5504, F-31400, Toulouse, France. leberre@insa-toulouse.fr.
authors.forename: Véronique
authors.initials: V
authors.lastname: Anton-Leberre
mesh_terms: D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D003657:Decision Making; D005260:Female; D017143:Fuzzy Logic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D057285:Precision Medicine / Q000379:methods; D011379:Prognosis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity