title: A Transcriptional Signature of Fatigue Derived from Patients with Primary Sjögren's Syndrome.
abstract: BACKGROUND
  Fatigue is a debilitating condition with a significant impact on patients' quality of life. Fatigue is frequently reported by patients suffering from primary Sjögren's Syndrome (pSS), a chronic autoimmune condition characterised by dryness of the eyes and the mouth. However, although fatigue is common in pSS, it does not manifest in all sufferers, providing an excellent model with which to explore the potential underpinning biological mechanisms.
  
  
  METHODS
  Whole blood samples from 133 fully-phenotyped pSS patients stratified for the presence of fatigue, collected by the UK primary Sjögren's Syndrome Registry, were used for whole genome microarray. The resulting data were analysed both on a gene by gene basis and using pre-defined groups of genes. Finally, gene set enrichment analysis (GSEA) was used as a feature selection technique for input into a support vector machine (SVM) classifier. Classification was assessed using area under curve (AUC) of receiver operator characteristic and standard error of Wilcoxon statistic, SE(W).
  
  
  RESULTS
  Although no genes were individually found to be associated with fatigue, 19 metabolic pathways were enriched in the high fatigue patient group using GSEA. Analysis revealed that these enrichments arose from the presence of a subset of 55 genes. A radial kernel SVM classifier with this subset of genes as input displayed significantly improved performance over classifiers using all pathway genes as input. The classifiers had AUCs of 0.866 (SE(W) 0.002) and 0.525 (SE(W) 0.006), respectively.
  
  
  CONCLUSIONS
  Systematic analysis of gene expression data from pSS patients discordant for fatigue identified 55 genes which are predictive of fatigue level using SVM classification. This list represents the first step in understanding the underlying pathophysiological mechanisms of fatigue in patients with pSS.
authors.affiliation: Interdisciplinary Computing and Complex BioSystems Research Group, Newcastle University, Newcastle upon Tyne, United Kingdom.|Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: James
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.|Department of Biology, College of Science, University of Basrah, Basrah, Iraq.
authors.forename: Shereen
authors.initials: S
authors.lastname: Al-Ali
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tarn
authors.affiliation: Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cockell
authors.affiliation: School of Mathematics & Statistics, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Colin S
authors.initials: CS
authors.lastname: Gillespie
authors.affiliation: Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Hindmarsh
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Locke
authors.affiliation: Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Mitchell
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lendrem
authors.affiliation: Rheumatology Department, University Hospital Birmingham, Birmingham, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Bowman
authors.affiliation: Great Western Hospitals NHS Foundation Trust, Swindon, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Price
authors.affiliation: Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds & NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, United Kingdom.
authors.forename: Colin T
authors.initials: CT
authors.lastname: Pease
authors.affiliation: Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds & NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals Trust, Leeds, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.affiliation: Nottingham University Hospital, Nottingham, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Lanyon
authors.affiliation: Gartnavel General Hospital, Glasgow, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Hunter
authors.affiliation: Gartnavel General Hospital, Glasgow, United Kingdom.
authors.forename: Monica
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Barts and the London NHS Trust & Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Bombardieri
authors.affiliation: Barts and the London NHS Trust & Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Nurhan
authors.initials: N
authors.lastname: Sutcliffe
authors.affiliation: Barts and the London NHS Trust & Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
authors.affiliation: NHS Fife, Whyteman's Brae Hospital, Kirkcaldy, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: McLaren
authors.affiliation: Royal Hampshire County Hospital, Winchester, United Kingdom.|Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom.
authors.forename: Annie
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Royal Derby Hospital, Derby, United Kingdom.
authors.forename: Marian
authors.initials: M
authors.lastname: Regan
authors.affiliation: University College London Hospitals NHS Foundation Trust, London, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Giles
authors.affiliation: University College London Hospitals NHS Foundation Trust, London, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Isenberg
authors.affiliation: Queen Elizabeth Hospital, Gateshead, United Kingdom.
authors.forename: Vadivelu
authors.initials: V
authors.lastname: Saravanan
authors.affiliation: Sunderland Royal Hospital, Sunderland, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Coady
authors.affiliation: Southend University Hospital, Southend, United Kingdom.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Dasgupta
authors.affiliation: Royal National Hospital for Rheumatic Diseases, Bath, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: McHugh
authors.affiliation: Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Young-Min
authors.affiliation: Aintree University Hospitals, Liverpool, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Moots
authors.affiliation: Basildon Hospital, Basildon, United Kingdom.
authors.forename: Nagui
authors.initials: N
authors.lastname: Gendi
authors.affiliation: Royal Hallamshire Hospital, Sheffield, United Kingdom.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Akil
authors.affiliation: Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
authors.forename: Bridget
authors.initials: B
authors.lastname: Griffiths
authors.affiliation: Interdisciplinary Computing and Complex BioSystems Research Group, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Anil
authors.initials: A
authors.lastname: Wipat
authors.affiliation: Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.|Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Newton
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Jones
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.|National Institute for Health Research, Newcastle Biomedical Research Centre, Newcastle upon Tyne, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Isaacs
authors.affiliation: Interdisciplinary Computing and Complex BioSystems Research Group, Newcastle University, Newcastle upon Tyne, United Kingdom.|BioThink Pty Ltd, Brisbane, Australia.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hallinan
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.|National Institute for Health Research, Newcastle Biomedical Research Centre, Newcastle upon Tyne, United Kingdom.
authors.forename: Wan-Fai
authors.initials: WF
authors.lastname: Ng
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D005221:Fatigue / Q000097:blood / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D012720:Severity of Illness Index; D012859:Sjogren's Syndrome / Q000097:blood / Q000150:complications*; D059467:Transcriptome