Journal of Molecular Neuroscience

, Volume 67, Issue 4, pp 550–558 | Cite as

Current and Potential Approaches for Defining Disease Signatures: a Systematic Review

  • Amos StemmerEmail author
  • Tal Galili
  • Tal Kozlovski
  • Yoav Zeevi
  • Mira Marcus-Kalish
  • Yoav Benjamini
  • Alexis Mitelpunkt


Identifying disease signatures in order to facilitate accurate diagnosis/treatment has been the focus of research efforts in the last decade. However, the term “disease signature” has not been properly defined, resulting in inconsistencies between studies, as well as limited ability to fully utilize the tools/information available in the evolving field of healthcare big data. Research was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines. The search (in PubMed, Cochrane, and Web of Science) was limited to English articles published up to 31/12/2016. The search string was “disease signature” OR “disease signatures” OR “disease fingerprint” OR “disease fingerprints” OR “subtype signature” OR “subtype signatures” OR “subgroup signature” OR “subgroup signatures.” The full text of the articles was reviewed to determine the meaning of the phrase “disease signature” as well as the context of its use. Of 285 articles identified in the search, 129 were included in the final analysis. The term disease signature was first found in an article from 2001. In the last 10 years, the use of the term increased by approximately ninefold, which is double the general increase in the number of published articles. Only one article attempted to define the term. The two major medical fields where the term was used were oncology (31%) and neurology (20%); 71% of the identified articles used a single biomarker to define the term, 13% of the articles used a pair of biomarkers, and 16% used signatures with multiple biomarker; in 42% of the identified articles, genomic biomarkers were used for the signature, in 17% measurements of biochemical compounds in body fluids, and in 10%, changes in imaging studies were used for the signature. Our findings identified a lack of consistency in defining the term disease signature. We suggest a novel hierarchical multidimensional concept for this term that would combine both current approaches for identifying diseases (one focusing on undesired effects of the disease and the other on its causes). This model can improve disease signature definition consistency which will enable to generalize and classify diseases, resulting in more precise treatments and better outcomes. Ultimately, this model could lead to developing a statistical confidence in a disease signature that would allow physicians/patients to estimate the precision of the diagnosis, which, in turn, may have important implications on patients’ prognosis and treatment.


Disease signature Systematic review Parkinson’s disease 



Preferred Reporting Items for Systematic Review and Meta-analyses



We thank Shiri Diskin, PhD, for her editorial assistance in manuscript preparation.

This work was performed in partial fulfillment of the M.D. thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University.

Funding Information

The research leading to these results has received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no. 604102 (Human Brain Project).


  1. American Psychiatric Association. (2013). Schizophrenia spectrum and other psychotic disorders. In: Diagnostic and statistical manual of mental disorders. Arlington, Va.
  2. (2017) First tissue-agnostic drug approval issued. Cancer Discov. 7:656.
  3. Ahmed N (2005) 23 years of the discovery of Helicobacter pylori: is the debate over? Ann Clin Microbiol Antimicrob 4(17):17. CrossRefGoogle Scholar
  4. Bevers TB, Ward JH, Arun BK, Colditz GA, Cowan KH, Daly MB, Garber JE, Gemignani ML, Gradishar WJ, Jordan JA, Korde LA, Kounalakis N, Krontiras H, Kumar S, Kurian A, Laronga C, Layman RM, Loftus LS, Mahoney MC, Merajver SD, Meszoely IM, Mortimer J, Newman L, Pritchard E, Pruthi S, Seewaldt V, Specht MC, Visvanathan K, Wallace A, Bergman MA, Kumar R (2015) Breast cancer risk reduction, version 2.2015. J Natl Compr Cancer Netw 13:880–915. CrossRefGoogle Scholar
  5. Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95. CrossRefGoogle Scholar
  6. Corti O, Lesage S, Brice A (2011) What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev 91:1161–1218CrossRefGoogle Scholar
  7. Cunningham D, Atkin W, Lenz H-J, Lynch HT, Minsky B, Nordlinger B, Starling N (2010) Colorectal cancer. Lancet 375:1030–1047. CrossRefGoogle Scholar
  8. da Veiga CRP, da Veiga CP, Drummond-Lage AP (2018) Concern over cost of and access to cancer treatments: a meta-narrative review of nivolumab and pembrolizumab studies. Crit Rev Oncol Hematol 129:133–145. CrossRefGoogle Scholar
  9. Dächsel JC, Farrer MJ (2010) LRRK2 and Parkinson disease. Arch Neurol 67:542–547. CrossRefGoogle Scholar
  10. Dickerson BC, Bakkour A, Salat DH, Feczko E, Pacheco J, Greve DN, Grodstein F, Wright CI, Blacker D, Rosas HD, Sperling RA, Atri A, Growdon JH, Hyman BT, Morris JC, Fischl B, Buckner RL (2009) The cortical signature of Alzheimer’s disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cereb Cortex 19:497–510. CrossRefGoogle Scholar
  11. Espay AJ, Schwarzschild MA, Tanner CM, Fernandez HH, Simon DK, Leverenz JB, Merola A, Chen-Plotkin A, Brundin P, Kauffman MA, Erro R, Kieburtz K, Woo D, Macklin EA, Standaert DG, Lang AE (2017) Biomarker-driven phenotyping in Parkinson’s disease: a translational missing link in disease-modifying clinical trials. Mov Disord 32:319–324. CrossRefGoogle Scholar
  12. Garbuzova-Davis S, Hernandez-Ontiveros DG, Rodrigues MCO, Haller E, Frisina-Deyo A, Mirtyl S, Sallot S, Saporta S, Borlongan CV, Sanberg PR (2012) Impaired blood–brain/spinal cord barrier in ALS patients. Brain Res 1469:114–128. CrossRefGoogle Scholar
  13. Katsnelson A (2013) Momentum grows to make “personalized” medicine more “precise”. Nat Med 19:249–249. CrossRefGoogle Scholar
  14. Li J-Q, Tan L, Yu J-T (2014) The role of the LRRK2 gene in parkinsonism. Mol Neurodegener 9:47. CrossRefGoogle Scholar
  15. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–e34. CrossRefGoogle Scholar
  16. Medicine U.S. National Library of 2014 (2014) Statistical reports on MEDLINE®/PubMed® baseline data. Accessed 9 Dec 2018
  17. Mekahli D, Liutkus A, Ranchin B, Yu A, Bessenay L, Girardin E, van Damme-Lombaerts R, Palcoux JB, Cachat F, Lavocat MP, Bourdat-Michel G, Nobili F, Cochat P (2009) Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study. Pediatr Nephrol 24:1525–1532. CrossRefGoogle Scholar
  18. Metaxas O, Dimitropoulos H, Ioannidis Y, Paedigree M (2014) AITION: a scalable KDD platform for big data healthcare. In: IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI). IEEE, 345 E 47TH ST, NEW YORK, NY 10017 USA, pp 601–604Google Scholar
  19. Mirelman A, Bernad-Elazari H, Thaler A, Giladi-Yacobi E, Gurevich T, Gana-Weisz M, Saunders-Pullman R, Raymond D, Doan N, Bressman SB, Marder KS, Alcalay RN, Rao AK, Berg D, Brockmann K, Aasly J, Waro BJ, Tolosa E, Vilas D, Pont-Sunyer C, Orr-Urtreger A, Hausdorff JM, Giladi N (2016) Arm swing as a potential new prodromal marker of Parkinson’s disease. Mov Disord 31:1527–1534. CrossRefGoogle Scholar
  20. Pearce JMS (2011) Disease, diagnosis or syndrome? Pract Neurol 11:91–97. CrossRefGoogle Scholar
  21. Scully JL (2004) What is a disease? EMBO Rep 5:650–653. CrossRefGoogle Scholar
  22. Somme JH, Molano Salazar A, Gonzalez A, Tijero B, Berganzo K, Lezcano E, Fernandez Martinez M, Zarranz JJ, Gómez-Esteban JC (2015) Cognitive and behavioral symptoms in Parkinson’s disease patients with the G2019S and R1441G mutations of the LRRK2 gene. Parkinsonism Relat Disord 21:494–499. CrossRefGoogle Scholar
  23. Steinlein OK (2008) Genetics and epilepsy. Dialogues Clin Neurosci 10:29–38Google Scholar
  24. Strimbu K, Tavel JA (2010) What are biomarkers? Curr Opin HIV AIDS 5:463–466. CrossRefGoogle Scholar
  25. Thenganatt MA, Jankovic J (2014) Parkinson disease subtypes. JAMA Neurol 71:499–504. CrossRefGoogle Scholar
  26. Tikkinen KAO, Leinonen JS, Guyatt GH, Ebrahim S, Järvinen TLN (2012) What is a disease? Perspectives of the public, health professionals and legislators. BMJ Open 2:e001632. CrossRefGoogle Scholar
  27. Tombak M (n.d.) Disease - what is it. [online] Available at: Accessed 4 Jul 2016
  28. Valle L (2017) Recent discoveries in the genetics of familial colorectal cancer and polyposis. Clin Gastroenterol Hepatol 15:809–819. CrossRefGoogle Scholar
  29. Weed LL (1968) Medical records that guide and teach. N Engl J Med 278:593–600. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  2. 2.Department of Statistics and Operations ResearchTel Aviv UniversityTel AvivIsrael
  3. 3.The Sagol School for NeurosciencesTel Aviv UniversityTel AvivIsrael
  4. 4.Pediatric NeurologyDana-Dwek Children’s Hospital, Tel Aviv Medical CenterTel AvivIsrael

Personalised recommendations