Schleidgen et al. BMC Health Services Research (2017) 17:761 DOI 10.1186/s12913-017-2688-z RESEARCH ARTICLE Open Access Applying systems biology to biomedical research and health care: a précising definition of systems medicine Sebastian Schleidgen1*† , Sandra Fernau2†, Henrike Fleischer3†, Christoph Schickhardt4†, Ann-Kristin Oßa4 and Eva C. Winkler4 Abstract Background: Systems medicine has become a key word in biomedical research. Although it is often referred to as P4-(predictive, preventive, personalized and participatory)-medicine, it still lacks a clear definition and is open to interpretation. This conceptual lack of clarity complicates the scientific and public discourse on chances, risks and limits of Systems Medicine and may lead to unfounded hopes. Against this background, our goal was to develop a sufficiently precise and widely acceptable definition of Systems Medicine. Methods: In a first step, PubMed was searched using the keyword “systems medicine”. A data extraction tabloid was developed putting forward a means/ends-division. Full-texts of articles containing Systems Medicine in title or abstract were screened for definitions. Definitions were extracted; their semantic elements were assigned as either means or ends. To reduce complexity of the resulting list, summary categories were developed inductively. In a second step, we applied six criteria for adequate definitions (necessity, non-circularity, non-redundancy, consistency, non-vagueness, and coherence) to these categories to derive a so-called précising definition of Systems Medicine. Results: We identified 185 articles containing the term Systems Medicine in title or abstract. 67 contained at least one definition of Systems Medicine. In 98 definitions, we found 114 means and 132 ends. From these we derived the précising definition: Systems Medicine is an approach seeking to improve medical research (i.e. the understanding of complex processes occurring in diseases, pathologies and health states as well as innovative approaches to drug discovery) and health care (i.e. prevention, prediction, diagnosis and treatment) through stratification by means of Systems Biology (i.e. data integration, modeling, experimentation and bioinformatics). Our study also revealed the visionary character of Systems Medicine. Conclusions: Our insights, on the one hand, allow for a realistic identification of actual ethical as well as legal issues arising in the context of Systems Medicine and, in consequence, for a realistic debate of questions concerning its matter and (future) handling. On the other hand, they help avoiding unfounded hopes and unrealistic expectations. This especially holds for goals like improving patient participation which are intensely debated in the context of Systems Medicine, however not implied in the concept. Keywords: Bioinformatics, Conceptual vagueness, Data integration, Modeling, Patient participation, Stratification * Correspondence: [email protected] Sebastian Schleidgen, Sandra Fernau, Henrike Fleischer and Christoph Schickhardt share first authorship †Equal contributors 1Faculty of Nursing Science, University of Philosophy and Theology Vallendar, Vallendar, Germany Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Schleidgen et al. BMC Health Services Research (2017) 17:761 Page 2 of 16 Background searched PubMed using the keyword “systems medi- Systems Medicine recently became a buzz word in cine”. We focused on PubMed as we were interested in debates on biomedical research and future health care definitions of Systems Medicine virulent in the scientific [1, 2]. However, there is no consensus on the term’s context. We did not include MeSH-terms in the search meaning. Currently, five main positions seem to do- strategy as the thesaurus of the US National Library of minate the discussion: (a) Systems Medicine is the Medicine relates “systems medicine” to the term “system successor of Personalized Medicine [3, 4]; (b) Systems analysis”, which is defined as “[t]he analysis of an acti- Medicine is a precursor of Personalized Medicine or vity, procedure, method, technique, or business to deter- P4-Medicine [3, 5]; (c) Systems Medicine is an mine what must be accomplished and how the necessary equivalent term for Precision Medicine [4]; (d) Sys- operations may best be accomplished”.2 Including tems Medicine means the translation of Systems Biol- MeSH-terms would therefore have pre-selected certain ogy into medical practice [3, 5–7]; and (e) Systems articles according to this understanding of systems ana- Medicine is an “assemblage of scientific strategies and lysis. Excluding MeSH-terms, on the contrary, allowed practices that include bioinformatics approaches to us to stay open to alternative understandings of Systems human biology […]; ‘big data’ statistical analysis; and Medicine. We only searched titles and abstracts to iden- medical informatics tools” [8]. tify those articles in which Systems Medicine is the main This divergence in understanding is, however, prob- focus. Moreover, we assumed that those articles were lematic as it complicates sound debates on chances, risks more likely to contain a definition. We did not restrict and limits of Systems Medicine. Moreover, it is difficult the date of publication; our last search was performed to identify and solve ethical as well as legal issues that on December 31, 2015. Furthermore, we included only could arise in the context of Systems Medicine. As a articles written in English as our goal was to capture the consequence, it is impossible to discuss questions of its international debate. Subsequently, we checked full-text matter and (future) handling. Finally, the term’s under- availability of the articles identified. Where full-texts specification may lead to unfounded hopes of patients, were not available, we contacted the respective authors. for instance, regarding the possibilities of Systems Medicine approaches [6, 9]. Against this background, it Step 1: Description of the areas of application of systems becomes clear why it is still seen as one of the key chal- medicine lenges to define Systems Medicine [6]. To describe the areas of application of Systems Medi- The goal of this paper is to develop a sufficiently pre- cine, in a first step, all papers fitting our search strategy cise, formally adequate definition of Systems Medicine. were assigned to deductively developed main categories Hurley [10] differentiates, among others, between stipu- based on general presuppositions regarding content lative, lexical and précising definitions. While a lexical alignment of the papers. These main categories are: 1) definition captures the way a word is commonly used, a with reference to disease and 2) without reference to dis- stipulative definition arbitrarily assigns a meaning to a ease. This distinction was made in order to evaluate the certain expression, whereas a précising definition tries to current state of clinical application of Systems Medicine. reduce the vagueness of a term used in practice [11]. Several subcategories of category 1) were developed in- Hence, a précising definition is geared to the everyday ductively based on specific findings from the papers to usage of a term while, at the same time, it aims at ensure representing the whole spectrum of diseases dealt standardizing, harmonizing and structuring the different with in the articles. Due to the inductive approach, the occurring meanings in everyday usage with regard to classification of the diseases was mainly based on terms formal criteria for adequate definitions. and references used in the articles and does not refer to As the term Systems Medicine is already established in a specific disease ontology. However, by categorizing the everyday usage, however divergently understood, in the specific diseases we generally distinguish between following we develop a précising definition. For this pur- chronic, non-cancer diseases and hematological and pose, first, the usage of Systems Medicine in the relevant solid cancers as well as various (unspecified) forms of scientific literature was analyzed and, second, harmo- disease in order to examine the areas of application of nized by appealing to formal criteria in order to develop Systems Medicine. In main category 2), those papers a formally adequate definition of Systems Medicine. were included which have no reference to any disease or context of disease. Methods1 The first categorization showed that papers with as In order to identify definitions in the relevant scientific well as without reference to disease can be further publications on Systems Medicine and provide an overall specified with regard to their content alignment: they picture of the research field, we followed the approach are either research-related or programmatic articles, i.e. of a systematic literature review [12, 13]. We therefore both types of papers only partially relate to a