Gerard Foucher Critique Essay

** Translations of French texts quoted in this article are unofficial translations by the author.

1 If the author of this article is French, he has presently no position in France. Participant-observer indeed, he does not defend any ‘schools’ and does not belong to any networks.

2 Keep in mind that this article focuses on the state of IR in France and not in French-speaking countries. It might be confusing for non French-speakers to make the distinction to the extent that the language is the same. In Africa, in Canada, in Belgium, in Luxembourg and in Switzerland, the situation is absolutely incomparable to France. Additionally, some French academics have made a significant international breakthrough in IR abroad, chiefly in Québec or in Africa but do not qualify for inclusion in this article. On the other hand, some academics that do not have the French citizenship but have always been working in France will be included.

3Vennesson, P., ‘Les Relations Internationales dans la Science Politique aux États-Unis’, Politix, 11:1 (1998), pp. 181–2.

4 For instance, note the existence of the Association des internationalistes (Association of IR scholars) set up in 2010. It gathers most of French IR scholars notwithstanding their original disciplines (political science, geography, history, economics, and law).

5 In order to understand the peculiarities of French IR, it is necessary not to underestimate consequences of the numerous internal conflicts. According to Constantin: ‘The current situation results, first of all, in the history of a subject planned in certain curricula of universities; and like all subjects, international relations has been the object of covetousness, provoking its appropriation by fraternities or parishes who claim the monopoly of useful knowledge and attempt to neutralize, or even excommunicate, all applicants not acknowledged by the inner circle, according to power struggles between faculties, if not between colleagues.’ Constantin, F., ‘Les Relations Internationales dans le Champs Scientifique Français ou les Pesanteurs d'une Lourde Hérédité’, La Revue Internationale et Stratégique, 47:3 (2002), pp. 91–2. Let's mention also the Heisbourg Report (2000), titled officially Mission d'Analyse et de Proposition Relative à l'Enseignement et à la Recherche en ‘Relations Internationales’ et ‘Affaires Stratégiques et de Défense’, in which the word ‘barony’ is bluntly penned for describing the natural tendency of IR scholars to claim a monopoly of IR by the yardstick of their own discipline. Appointed in November 1998 and led by François Heisbourg, this commission had to make some propositions inter alia for reforming IR curricula in French universities. See François Heisbourg, Mission d'Analyse et de Proposition Relative à l'Enseignement et à la Recherche en ‘Relations Internationales’ et ‘Affaires Stratégiques et de Défense’ (2000), available at: {http://www.ladocumentationfrancaise.fr/var/storage/rapports-publics//004001058/0000.pdf} accessed 2 October 2013.

6 See the illuminating introduction of the book edited by Tickner, Arlene B. and Wæver, Ole on IR outside the US. ‘Introduction: Geocultural Epistemologies’, International Relations Scholarship Around the World (London and New York: Routledge, 2009), pp. 1–31. The authors have edited a brilliant book examining the ways in which IR has evolved and is practised based on 16 cases. Incidentally, notice that this piece of work belongs to the growing documentation on IR outside the Anglo-American mainstream. See also Tickner, Arlene and Blaney, David L. (eds), Thinking International Relations Differently (Routledge, 2012).

7 This is the observation made by Brown, Chris in his chapter ‘Fog in the Channel: Continental International Relations Theory Isolated’, in Crawford, Robert M. A. and Jarvis, Darryl S. L. (eds), International Relations – Still an American Science? Toward Diversity in International Thought (Albany: State University of New York Press, 2001), pp. 203–19.

8 In French, let us list Dario Battistella's analysis in the acute chapter, which ends the last edition of his manual. Battistella, Dario, ‘Les Relations Internationales en France’, in Battistella, Dario (ed.), Théories des Relations Internationales (4th edn, Paris: Les Presses de Sciences Po, 2012), pp. 689–721. The author, professor at Sciences po Bordeaux and well-known for being one of the few academics committed in favour of theories in IR, by analysing the evolution of IR (in political science) within the French academia, deals especially with the issue of theories; he argues that ‘theories … remains at the fringe compared to what is agreed to call the sociology of international relations’. There are also all the very interesting articles in the issue of the journal Revue Internationale et Stratégique dedicated on the state of IR in France. ‘Relations Internationales. La Tentation d'Exister’, La Revue Internationale et Stratégique, 47:3 (2002), pp. 77–167. N. Ragaru, ‘L'État des Relations Internationales en France’, pp. 77–81; M.-C. Smouts, ‘Entretien. Les Relations Internationales en France: Regard sur une Discipline’, pp. 83–9; F. Constantin, ‘Les Relations Internationales dans le Champ Scientifique Français ou les Pesanteurs d'une Lourde Hérédité’, pp. 90–9; J. J. Roche, ‘L'Enseignement des Relations Internationales en France: les Aléas d'une “Discipline-Carrefour”’, pp. 100–7; A.J.R. Groom, ‘Les Relations Internationales en France: un Regard d'Outre-Manche’, pp. 108–17; J. Laroche, ‘La Mondialisation: Lignes de Force et Objets de Recherche’, pp. 118–32; P. Ryfman, ‘Vers une “École Française” d'Analyse de l'Humanitaire?’, pp. 133–44; F. Petiteville, ‘L'Union Européenne, Acteur International “Global”? Un Agenda de Recherche’, pp. 145–57; G. Mink, ‘La Conversion de la “Soviétologie” Française après la Disparition de son Objet d'Étude’, pp. 158–67. Indeed, most of these authors are both judges and parties. In that sense, by analysing IR as an objet and as a subject, their axiological neutrality might be dubious. Yet, their analysis remains very relevant.

9 For instance, Henrik Ø. Breitenbauch carried out an intriguing doctoral dissertation at the University of Copenhagen under the supervision of Ole Wæver on the difficulties of the disciplinary field of IR in France go beyond a certain Cartesianism. By showing how French IR has evolved less comprehensively than transnational-American IR research practices toward an ideal-type form of the modern social science article, one of his main proposition is that compulsory standards of forms (chiefly the famous French school essay, la dissertation) have a central role in this area. Henrik Ø. Breitenbauch, Cartesian Limbo. A Formal Approach to the Study of Social Sciences: International Relations in France, PhD Thesis submitted to the Department of Political Science, University of Copenhagen 92008). His dissertation was recently published under the title International Relations in France: Writing between Discipline and State (London: Routledge, 2013). For his part, Chillaud published a policy-oriented paper in the journal European Political Science analysing the development of IR within French academe and reviewing the scholarly output of IR teaching. Chillaud, M., ‘International Relations in France: The “Usual Suspects” in a French Scientific Field of Study?’, European Political Science, 8 (2009), pp. 239–53. In a chapter in an edited volume, Giesen, by taking stock of the development of IR in France but also in other French-speaking countries, between 1945 and 1994, touches upon in a very fragmentary fashion our problematic issue. The author, who explores the Francophone particularities (not only in France), identifies the scholarly practice as one of the main reason of the peculiarities in France. Giesen, Klaus-Gerd, ‘France and other French-speaking Countries (1945–1994)’, in Jørgensen, Knud Erik, (ed.), International Relations in Europe: Traditions, Schools and Perspectives (London: Routlege, 2006), pp. 19–46. Last but not least, let's mention the chapter on IR in Western Europe written by Jörg Fridrichs and Ole Wæver in the intriguing book edited by Arlene B. Tickner and Ole Wæver. Friedrichs, Jörg and Wæver, Ole, ‘Western Europe. Structure and Strategy at the National and Regional Levels’, in Tickner, Arlene B. and Wæver, Ole (eds), International Relations Scholarship Around the World (London and New York: Routledge, 2009), pp. 261–86. There is also the chapter on France in the book penned by Jörg Fridrichs. In the two texts, the authors, by examining the development of IR studies in France, have a similar approach: they try to identify the reasons which contribute to the construction of the ‘French mansion’ as a part of many ones into a wider community. Friedrichs, Jörg, ‘International Relations Theory in France: three Generations of Parisian Intellectual Life’, in Friedrichs, Jörg (ed.), European Approaches to International Relations Theory. A House with Many Mansions (London and New York: Routledge, 2004), pp. 29–46.

10Bourdieu, P., ‘Le Champ Scientifique’, Actes de la Recherche en Sciences Sociales, 2:2–3 (1976), p. 89.

11Hoffmann, S., ‘An American Social Science: International Relations’, Daedalus, 106:3 (1977), pp. 41–60.

12 The very stimulating book International Relations – Still An American Social Science (2001) is telling. The very few references to French IR are made by the Francophone and Francophile British IR scholar A.J.R. Groom. See A.J.R Groom and Peter Mandaville, ‘Hegemony and Autonomy in International Relations: The Continental Experience’, in Crawford and Jarvis (eds), pp. 157–63.

13 Bourdieu, ‘Le Champs Scientifique’, p. 91.

14Duroselle, J.-B., ‘La Nature de la Politique Internationale’, Politique internationale, 4 (1979), p. 111.

15 Jörg Friedrichs and Ole Wæver, ‘Western Europe. Structure and Strategy at the National and Regional Levels’, in Tickner and Wæver (eds), p. 263.

16 M.-C. Smouts, ‘Les Relations Internationales en France. Regards sur une Discipline’, p. 84.

17 Jörg Friedrichs, ‘International Relations Theory in France: three Generations of Parisian Intellectual Life’, in Friedrichs (ed.), p. 29.

18 F. Constantin, ‘Les Relations Internationales dans le Champs Scientifique Français ou les Pesanteurs d'une Lourde Hérédité’, p. 90.

19 Friedrichs and Wæver, ‘Western Europe. Structure and Strategy at the National and Regional Levels’, p. 263.

20 Ole Wæver, ‘Aberystwyth, Paris: Copenhagen. The Europeanness of New “Schools” of Security Theory in an American Field’, in Tickner and Blaney (eds), pp. 48–71.

21 This could astonish foreigners who usually take for granted that the ‘Paris School’ is a major school of thought in France.

22 See, for example, the contributions in the forum dedicated to Foucault and IR in the journal International Political Sociology. IPS forum contribution, ‘Assessing the Impact of Foucault on International Relations’, International Political Sociology, 4:2 (2012), pp. 196–215. Broadly speaking, the philosophers who became so influential in Anglo-Saxon social sciences had little impact on IR scholarship in France itself.

23 A quick glance at the works of French IR scholars shows that – with the exception of Didier Bigo's – Foucault is very rarely quoted. Of course, this is absolutely not the case in philosophy and in sociology.

24Bigo, D., ‘Security’ in Adler-Nissen, Rebecca (ed.), Bourdieu in International Relations: Rethinking Key Concepts in IR (London and New York, Routledge, 2012), pp. 114–30.

25Battistella, D. and Cornut, J., ‘Des RI Françaises en Émergence. Les Internationalistes Français dans le Sondage TRIP 2011’, Revue Française de Science Politique, 63:2 (2013), p. 309.

26 Well shown by the chapter penned by Favre, Pierre and Dada, Nadine, ‘La Science Politique en France’, in Commission Européenne and IEP de Paris (eds), La Science Politique en Europe. Formation, Coopération, Perspectives, Conférence d'Évaluation (Paris: Fondation Nationale des Sciences Politiques, 1996), pp. 214–49.

27 Have in mind that political science – including IR – is taught in two kinds of institutions. The first, comprising the nine Instituts d'Études Politiques (IEPs), constitutes the most prestigious institutions of graduate education and research in French political science. IEPs that are considered to be Grandes écoles (literally ‘Great Schools’) are higher education establishments outside the mainstream system of public universities. Unlike French public universities, which have an obligation to accept all candidates in the same academic field, the selection criteria of Grandes écoles are competitive. The most prestigious IEP is the one in Paris (Sciences po Paris). Semi-autonomous public establishment, it arose from the old École libre des Sciences politiques in 1945. Afterwards, eight other IEPs were created. These institutions with selective recruitment are relatively independent in comparison with the universities to which they are administratively attached. The other type of institution where teaching takes place is the faculties of law, in which there are some law curricula but also often political science curricula (usually on the master level). This dates back to 1954, when a national regulation introduced political science as a compulsory discipline. Note that in law curricula, (which usually also include courses in other social sciences, such as sociology and political science), IR courses are usually run by lawyers, whereas in political science curricula they are run either by lawyers or political scientists. What is really odd in the French system is that political science is not exclusively taught in either IEPs or faculties of law.

28 It is usually taken for granted that IR emerged in 1919 and developed through the first great debate between realists and idealists. Yet, some scholars have contested this ‘myth’. This benchmark has been called into question, for instance, by Barry Buzan who has been carrying out an intriguing research programme on ‘the long 19th century’ as axial time of world politics. See Buzan, Barry and Lawson, George, ‘The Global Transformation: the Nineteenth Century and the Making of Modern International Relations’, International Studies Quarterly, 59:1 (2013), pp. 1–15. Nonetheless, without challenging the rise of IR before World War I, we prefer to stick to that date as a starting point to assess the trajectory of French IR in view of the fact that it has been since 1919 that IR has been considered as an academic field of research within universities.

29 We are extremely well informed about the various disciplines that dealt with international issues during the interwar period, thanks to the chapter by Pierre Renouvin in the fascinating book edited by UNESCO in 1950. Renouvin, Pierre, ‘La Contribution de la France à l'Étude des Relations Internationales’ in UNESCO (ed.), La Science Politique Contemporaine. Contribution à la Recherche, la Méthode et l'Enseignement (Paris: UNESCO, 1950), pp. 578–92. This book is a real mine of information on the institutionalisation of political science all over the world.

30 Friedrichs, ‘International Relations Theory in France: three Generations of Parisian Intellectual Life’, p. 30.

31 There were, however, some attempts to give IR its spurs. Aron, Raymond, a pioneer in that regard, published Paix et Guerre entre les Nations (Paris: Calmann-Lévy, 1962). In English, Aron, Raymond, Peace and War. A Theory of International Relations, trans. Howard, Richard and Backer, Annette (Garden City, New York: Double Day, 1966). Nevertheless, this was more of an essay than a manual. Marcel Merle (1923–2003) published La Vie Internationale in 1963, and afterwards Sociologie des Relations Internationales. Merle, Marcel, Sociologie des Relations Internationales (4th edn, Paris: Dalloz, 1988). Step-by-step manuals integrating debates on major IR theories were published. Some of these were written by academics coming from Sciences po and the CERI (Centre d'Études et de Recherche internationale). Originating from inside political science, this trend transposed its methods and approaches from the national to the international level. It is worth mentioning Badie, Bertrand and Smouts, Marie-Claude, Le Retournement du Monde. Sociologie de la Scène Internationale (Paris: Presses de Sciences Po, Dalloz, 1992) and Badie, B. and Smouts, M.-C., ‘The Turnaround of the World’, Geopolitics, 5:2 (2000), pp. 85–93. See also Smouts, Marie-Claude (ed.), Les Nouvelles Relations Internationales. Pratiques et Théories, (Paris: Presses de Sciences po, 1998) and Smouts, M.-C., ‘The Meanings of Violence and Its Role in Legitimation. Cultures et Conflits’, Mershon International Studies Review, 39:1 (1995), pp. 111–15, for the launching of the review Cultures et Conflits by Bigo. Other work was conducted in the framework of realism and strategic issues. The main advocate of this approach is Jean-Jacques Roche. Roche, Jean-Jacques, Théories des Relations Internationales (8th edn, Paris: Montchrestien, 2010 [orig. pub. 1994]) and Relations Internationales (Paris: L.G.D.J., 2001). Dario Battistella published a very stimulating manual, which comes from his teachings at Sciences po Bordeaux. Dario Battistella, Théories des Relations Internationales. Josepha Laroche, professor of political science at La Sorbonne, espouses a sociological approach to IR, chiefly from the perspective of international political economy. Laroche, Josepha, Politique Internationale (2nd edn, Paris: LGDJ, 2000 [orig. pub. 1998]). Pascal Vennesson took an interest in military sociology. Vennesson, Pascal, Les Chevaliers de l'Air. Aviation et Conflits au XXe siècle (Paris: Presses de Sciences po and Fondation pour les Études de Défense, 1997). See also Caplow, Theodore and Vennesson, Pascal, Sociologie militaire (Paris: Armand Colin, 2000). Frédéric Ramel, elected recently as professor of IR at Sciences po Paris, published an interesting book, with David Cumin, Philosophie des Relations internationales and a fascinating essay on the concepts of ‘polarisation’ and ‘seduction’ in IR. Ramel, Frédéric and Cumin, David, Philosophie des Relations Internationale (2nd edn, Paris: Presses de Sciences po, 2011 [orig. pub. 2002]); and Ramel, Frédéric, L'Attraction Mondiale (Paris: Presses de Sciences po, 2012). Thomas Lindemann is almost certainly the only scholar in France to work exclusively on constructivism, a research agenda neglected by most French researchers. Lindemann, Thomas, Penser la Guerre. L'Apport Constructiviste (Paris: L'Harmattan, 2008). Sabine Saurugger from Sciences po Grenoble wrote what is probably the first manual to make the link between theory and European Union studies. Saurruger, Sabine, Théories et Concepts de l'Intégration Européenne (Paris: Presses de Sciences Po, 2009). Franck Petiteville who teaches at the same place, got interested on the concept of mu ltilateralism in IR. Petiteville, Franck, Le Multilatéralisme (Paris: Montchrestien, 2009).

32 Roche, ‘L'Enseignement des Relations Internationales en France’, p. 101.

33 Ibid., p. 104.

34 There are three major French ‘think tanks’ (Institut français de Relations internationales/IFRI, Fondation pour la Recherche stratégique/FRS and Institut de Relations internationales et stratégiques/IRIS) to which one may add a research centre integrated into the military administration (Institut de Recherche stratégique de l'École militaire/IRSEM) and another one that depends on the Centre national de Recherche scientifique (CNRS), the Centre d'Étude de Recherches internationales (CERI). If the latter is certainly the most open to theories, this is probably because it belongs to the CNRS (a state organ) and as such it does not fear the paymasters' vagaries.

35 We might point out, nevertheless, that some significant French academic institutions were set up thanks to American foundations. For example, the prestigious La Maison des Sciences de l'Homme was mainly financed by the Ford Foundation. Let's also mention the Fondation nationale des Sciences politiques, which was financed inter alia by the Rockfeller Foundation.

36 J. Hubert-Rodier, ‘Enquête: le Pays Manque de Laboratoires d'Idées en Matière de Relations Internationales’, Les Echos (25 April 2007).

37 Even in the US, the problem is similar. In a Washington Post column, Joseph Nye has lamented the growing gap between theory and practice in the field of IR. ‘Scholars are paying less attention to questions about how their work relates to the policy world, and in many departments a focus on policy can hurt one's career. Advancement comes faster for those who develop mathematical models, new methodologies or theories expressed in jargon that is unintelligible to policymakers’. Joseph Nye, ‘Scholars on the Sidelines’, Washington Post (13 April 2009). One of the reasons is that there is a persistent chasm between what ‘suppliers’ of social research offer and what the prospective ‘users’ of this research seek.

38 See the intriguing rapport made by Marc Loriol , Françoise Piotet, and David Delfolie, Le Travail Diplomatique. Un Métier et un Art, Rapport de recherche pour le ministère des Affaires étrangères et européennes (MAEE), Laboratoire Georges Friedmann – UMR 8593 (December 2008), available at: {http://www.diplomatie.gouv.fr/fr/IMG/pdf/rapportfianl_sociologue.pdf} accessed 2 October 2013.

39 Friedrichs and Wæver, ‘Western Europe. Structure and Strategy at the National and Regional Levels’, p. 267. Jean-Michel Emery-Douzans, a prominent French scholar at Sciences Po Toulouse, has conducted extensive works on French elites and particularly on énarques (graduate of ENA). He addressed chiefly the issue of their atheoritical curriculum in his book, La Fabrique des Énarques (Paris: Économica, 2001).

40 Friedrichs and Wæver, ‘Western Europe. Structure and Strategy at the National and Regional Levels’, p. 263.

41Chillaud, M., ‘Strategic Studies in France. Plus Ça Change’, Res Militaris (), 3:1 (2012), pp. 6–7, available at: {http://resmilitaris.net}.

42 Bourdieu, ‘Le Champ Scientifique’, p. 91.

43 We might mention inter alia the Revue Française de Science Politique, Critique Internationale, Culture et Conflit, Revue d'Étude Comparative Est/Ouest, Politique Européenne. The journal Politique Étrangère has adopted a hybrid system. Some of the articles are selected through a process of peer review, others are not.

44Smith, A., ‘French Political Science and European Integration’, Journal of European Public Policy, 7:4 (2000), p. 663.

45 Even though it is really annoying that some expressions in English are lost in translation in French. The most illustrative example is the neologism securitisation translated absurdly in French by sécurisation, which means in English (as well as in French) the action to make safe.

46 There is an excellent synthesis on this issue by d'Aoust, A.-M., ‘Accounting for the Politics of Language in the Sociology of IR’, Journal of International Relations and Development, 15:1 (2012), pp. 120–31. It's worth noting that the author is French-Canadian and not French.

47 This aspect has been analysed by Bourdieu and Wacquant. See Wacquant, Loïc and Bourdieu, Pierre, ‘Sur les Ruses de la Raison Impérialiste’, Actes de la Recherche en Sciences Sociales, 121:121–2 (1998), pp. 109–18.

48 It is worth noting that a new journal, the European Review of International Studies, is to be launched in 2014. Published in English by the German publisher Barbara Budrich and sponsored inter alia by the Association of the Internationalistes and the Institut de Recherche Stratégique de l'Ecole Militaire, the editors are the Francophone British academic A.J.R. Groom and the director of CERI, the French Christian Lequesne. Indeed, this journal cannot be considered as being sensu stricto part of the IR French community. Nonetheless, the fact that it integrates international standards, chiefly the peer-review one, may bode a positive evolution.

49 It would be interesting to carry out a thorough study on the problematic issue of publication and advancement in academic careers. It seems it is thanks to their extremely protected status that French academics can possibly pursue a career without being obliged to publish. Jobard's study, which concerns only researchers from the Centre national de recherche scientifique, offers a few comments to add to the discussion. Jobard, Fabien, ‘Combien Publient les Politistes, la Productivité des Politistes du CNRS et leurs Supports de Publication’, Revue Française de Science Politique, 60:1 (2010), pp. 117–33.

50 Incidentally, the first to host papers in IR was precisely the Revue Française de Science Politique (founded in 1951). Battistella and Cornut notice that in the TRIP survey, 22 per cent of the respondents who are IR scholars say the Revue française de science politique is the journal where they would like to publish. That journal is the second one after International organization (41 per cent). Batisttela and Cornut, ‘Des RI Françaises en Émergence. Les Internationalistes Français dans le Sondage TRIP 2011’, p. 317.

51 CERI is a research centre in political science with strong links between IR and area studies, and between domestic political systems and the sociology of international ones. The meaning of its earlier acronym was Centre d'Études des Relations internationales. To stress the complementarity between IR and comparative political sociology, it was eventually decided, in 1976, to change the name to Centre d'Études de Recherches internationales, with an alteration of ‘Relations’ to ‘Recherches’ (research).

52 The CNU, which is made up of academics, is the state organ in charge of accreditation for PhD scholars who intend to continue in the academic world just after they defend their doctoral dissertation. Without the ‘passport’ granted by the CNU, it is not possible to apply for a position in a university or in an IEP. The CNU is divided into groups of sections. There are as many sections (77) as there are disciplines – but IR is not among them. It is worth noting that, from a strictly legal perspective, all theses – whatever their discipline – can be qualified by any kind of sections. In addition, a qualification granted for a section is worth legally for a qualification granted by all the sections. Nevertheless, this is evidently a legal fiction. Because of the scarcity of positions, the candidate will have no chance of being hired if his qualification does not match the discipline of the position. It is technically possible for a non-politist to be ‘accredited’ by the section in political science. The doctrine of section 04 accepts for qualification theses, which are not political science theses, if three conditions are met. Firstly, ‘beside the excellence of the dissertation’, it must deal with subjects of direct interest to the discipline of political science. Secondly, the PhD, through the doctoral dissertation and scientific articles, must show that s/he masters ‘tools and methods of research of the discipline. He must demonstrate his capacity to mobilize the scientific literature and theories used in political science.’ Thirdly, ‘the presence of a politist among the members of the jury’ is essential. Conseil national des universités, section 04, Rapport annuel d'activité. Qualification aux fonctions de maître de conférences et de professeur des universités (Session 2012), p. 17, available at: {http://www.afsp.info/omasp/cnu/rapports/rapportcnu2012.pdf} accessed 2 October 2013. The problem had been acute with lawyers who supervised doctoral dissertations labelled IR but in political science. If there is no legal hindrance for a professor of public law to supervise PhD candidates in political science, it is, according to Pierre Sadran the former president of the CNU with whom the author of these lines had an interview in January 2012 ‘on behalf of deontological grounds that the CNU demand that supervisors be politists’. Before the introduction of the agrégation of political science in 1973 which constituted de jure the autonomy of political science, academics wore two hats: public law and political science. They could supervise doctoral dissertations in either of the two disciplines.

53 Phone interview with Jacques de Maillard, member of the AERES Commission, 2 January 2012.

54 See Communiqué de presse en date du 14 octobre 2008 of the French association of political science in which it ‘questions the criteria initiated’ available at: {http://www.afsp.msh-paris.fr/activite/2008/afsp141008aeres.pdf.} accessed 2 October 2013.

55Liste des revues AERES pour le domaine SCIENCE POLITIQUE (Mise à jour le 29 January 2010) available at: {http://www.afsp.msh-paris.fr/activite/2008/afsp141008aeres.pdf.} accessed 14 June 2012.

56 For instance, in the public law list (Annuaire Français de Relations Internationales) or in the geography one (Hérodote).

57 Another aspect of the problem is that international rankings include rarely non English-speaking journals.

58Renouvin, Pierre and Duroselle, Jean-Baptiste, Introduction à l'Histoire des Relations Internationales (Paris: Armand Colin, 1964).

59Duroselle, J.-B., ‘L'Étude des Relations internationales: Objet, Méthode, Perspectives’, Revue Française de Science Politique, 2:4 (1952), pp. 676–701 and ‘Histoire des Relations Internationales’, Revue Française de Science Politique, 6:2 (1956), pp. 399–405.

60Duroselle, J.-B., ‘Pierre Renouvin et la Science Politique’, Revue Française de Science Politique, 25:3 (1975), pp. 561–74.

61Duroselle, Jean-Baptiste, Tout Empire Périra (Paris: Armand Colin, 1992), p. 17.

62 Quoted by Merle, M., ‘Sur la “Problématique” de l'Étude des Relations Internationales en France’, Revue Française de Science Politique, 33:3 (1983), p. 406.

63Laroche, Josepha, ‘Science Politique et Relations Internationales: Mettons les Pendules à l'Heure’, in Darras, Éric and Philippe, O. (eds), La Science Politique, Une et Multiple (Paris: L'Harmattan, 2004), pp. 210–1.

64Smouts, M.-C., ‘The Study of International Relations in France’, Millennium – Journal of International Studies, 16:2 (1987), p. 281. It is worth mentioning that Marie-Claude Smouts, like Marcel Merle, were initially both lawyers.

65Smith, A., ‘French Political Science and European Integration’, Journal of European Public Policy, 7:4 (2000), p. 666.

66 An intriguing work on the link between IR and international law is made in the book Droit international et relations internationales, published after a colloquium in 2008 dedicated to this issue. Société française de Droit international, Droit International et Relations Internationales. Divergences et Convergences (Paris: Pedone, 2010).

67 It is worth mentioning André Sigfried (1875–1959), who was among the founding fathers of political science in France and a disciple of the famous French geographer Paul Vidal de La Blache (1845–1918). His major book, Le tableau politique de la France de l'Ouest (1913) was a geographical and sociological explanation of electoral behaviour that set the foundation for political science.

68Gottmann, Jean, La Politique des États et leur Géographie (Paris: CTHS, 1951, ). See also his intriguing article, in English, ‘Geography and International Relations’, World Politics, 3:2 (1951), pp. 153–73.

69Lévy, Jacques, Géographies du Politique (Paris: Presses de Sciences po, 1991) and ‘Geopolitics after Geopolitics: A French Experience’, Geopolitics, 5:3 (2000), pp. 99–113.

70Foucher, Michel, Fronts et Frontières: Un Tour du Monde Géopolitique (Paris: Fayard, 1991), ‘La Fin de la Géopolitique? Réflexions Géographiques sur la Grammaire des Puissances’, Politique étrangère, 61:1 (1997), pp. 19–31 and ‘The Geopolitics of Front Lines and Borderlines’, Geopolitics, 5:2 (2000), pp. 159–70.

71Dussouy, Gérard, Quelle Géopolitique au XXIe siècle? (Paris: Les Éditions Complexe, 2001).

72Dussouy, Gérard, Traité de Relations Internationales: Tome 1, Les Théories Géopolitiques (Paris: L'Harmattan, 2006), Traité de Relations Internationales: Tome 2, Les Théories de l'Interétatique (Paris: L'Harmattan, 2007) and Traité de Relations Internationales: Tome 3, Les Théories de la Mondialité (Paris: L'Harmattan, 2009).

73 Yves Lacoste, La Géographie, çaSert, d'abord, à Faire la Guerre (Paris: Maspéro, 1976).

74 The anecdote is described by G. Minassian, ‘La Révolution Géopolitique Inachevée’, Le Monde (3 August 2010).

75Vernant, J., ‘Une Sociologie des Relations Internationales’, Politique Étrangère, 17:4 (1952), p. 229.

76 Aron, Paix et Guerre entre les Nations, p. 62.

77Aron, R., ‘Une Sociologie des Relations Internationales’, Revue française de Sociologie, 4:3 (1963), pp. 307–20.

78 Merle, Sociologie des Relations Internationales, p. 3.

79 Badie and Smouts, Le Retournement du Monde. Sociologie de la Scène Internationale, p. 19 and Badie and Smouts, ‘The Turnaround of the World’, p. 93.

80Charillon, Frédéric (ed.), Politique Étrangère. Nouveaux Regards (Paris: Presses de Sciences po., 2002).

81Devin, Guillaume, Sociologie des Relations Internationales (Paris: La Découverte, 2007), pp. 3–4.

82 Smouts, ‘The Study of International Relations in France’, p. 283.

83 Friedrichs, ‘International Relations Theory in France: three Generations of Parisian Intellectual Life’, p. 32. See also Duroselle, J.-B., ‘Les “Area Studies”. Problèmes de Méthodes’, Bulletin International des Sciences Sociales, 4:4 (1952), pp. 674–84. The article is a bit old but still very relevant in order to understand the consubstantiality between the French colonial legacy and the precocious study of area studies. Yet, it did not avoid a belated emergence of IR in French academia.

84 See, for instance, Feuer, Guy and Cassan, Hervé, Droit International du Développement (Paris: Dalloz, 1985).

85 Ryfman, ‘Vers une “École Française” d'Analyse de l'Humanitaire?’, pp. 133–44.

86Deriennic, Jean-Pierre and Moïsi, Dominique, ‘France’, in International Studies in Six European Countries, A Report to the Ford Foundation (Ford Foundation publisher, 1976), p. 44.

87Gonidec, Pierre-François, Relations Internationales (Paris: Montchrestien, 1977).

88 A small but very telling detail is that Edmond Jouve, supervised the doctoral thesis of the daughter of Gaddafi until recently.

89Jouve, Edmond, Relations Internationales (Paris: PUF, 1992).

90 Mink, ‘La Conversion de la “Soviétologie” Française après la Disparition de son Objet d'Étude’, pp. 158–67.

91Bouthoul, Gaston, Traité de Polémologie. Sociologie des Guerres (3rd edn, Paris: Payot, 1991).

92Coutau-Bégarie, Hervé, Traité de Stratégie (7th edn, Paris: Économica, Institut de Stratégie comparée, 2011 [orig. pub. 1999]).

93Sur, Serge, Relations Internationales (Paris: Montchrestien, 1995), p. 41.

94Roche, Jean-Jacques, Relations Internationales (Paris: L.G.D.J., 2001), p. 5.

95 Bourdieu, ‘Le Champ Scientifique’, p. 96.

96 The atheorism in IR is, in France, inversely proportional to the place of theories in other disciplinary fields of research such as philosophy. Even if this is not the place in that paper to pursue the debate, it would be, however, interesting to carry out research on the whys and the wherefores of this paradox.

97Wæver, O., ‘The Sociology of a Not So International Discipline: American and European Developments in International Relations’, International Organization, 52:4 (1998), p. 709.

98Roche, Jean-Jacques, ‘Relations Internationales (théorie des)’, in Mesure, S. and Savidan, P. (eds), Le Dictionnaire des Sciences Humaines (Paris: PUF, 2006), p. 990.

99 Ibid.

100Colas, Dominique, ‘La Recherche entre Sciences Juridiques et Sciences Politiques’, in Godelier, Maurice (ed.), Les Sciences de l'Homme et de la Société en France. Analyse et Propositions pour une Politique Nouvelle. Rapport Remis à Jean-Pierre Chevènement, Ministre d'État, Ministre de la Recherche et de l'Industrie, sur l'État des Sciences Sociales en France (Paris: Collection des rapports officiels. La Documentation Française, 1982), p. 365.

101 The most intriguing article on that issue is undoubtedly the one written by Guzzini, S., ‘The Significance and Roles of Teaching Theory in International Relations’, Journal of International Relations and Development, 4:2 (2001), pp. 98–117.

Abstract

Selected circulating microRNAs (miRNAs) have been suggested for non-invasive screening of non-small cell lung cancer (NSCLC), however the numerous proposed miRNA signatures are inconsistent.

Aiming to identify miRNAs suitable specifically for stage I-II NSCLC screening in serum/plasma samples, we searched the databases “Pubmed”, “Medline”, “Scopus”, “Embase” and “WOS” and systematically reviewed the publications reporting quantitative data on the efficacy [sensitivity, specificity and/or area under the curve (AUC)] of circulating miRNAs as biomarkers of NSCLC stage I and/or II. The 20 studies fulfilling the search criteria included 1110 NSCLC patients and 1009 controls, and were of medium quality according to Quality Assessment of Diagnostic Accuracy Studies checklist. In these studies, the patient cohorts as well as the control groups were heterogeneous for demographics and clinicopathological characteristics; moreover, numerous pre-analytical and analytical variables likely influenced miRNA determinations, and potential bias of hemolysis was often underestimated. We identified four circulating miRNAs scarcely influenced by hemolysis, each featuring high sensitivity (> 80%) and AUC (> 0.80) as biomarkers of stage I-II NSCLC: miR-223, miR-20a, miR-448 and miR-145; four other miRNAs showed high specificity (> 90%): miR-628-3p, miR-29c, miR-210 and miR-1244. In a model of two-step screening for stage I-II NSCLC using first the above panel of serum miRNAs with high sensitivity and high AUC, and subsequently the panel with high specificity, the estimated overall sensitivity is 91.6% and overall specificity is 93.4%. These and other circulating miRNAs suggested for stage I-II NSCLC screening require validation in multiple independent studies before they can be proposed for clinical application.

Keywords: microRNA, biomarkers, circulating, non-small cell lung cancer, stage I-II NSCLC

INTRODUCTION

Lung cancer is the most common cause of cancer death worldwide, globally accounting for an estimated 1.5 million deaths in 2012 [1, 2]. In Europe, every year lung cancer causes about 353000 deaths, which represent nearly 20% of total cancer deaths [3]. Approximately 15% of lung cancers are histologically classified as small cell lung cancer, a very aggressive and generally incurable tumor; the remaining 85% are cumulatively classified as Non-Small Cell Lung Cancer (NSCLC). The latter contains two main histological subtypes, adenocarcinoma (AC) and squamous cell carcinoma (SCC), and can often be cured if diagnosed at an early stage [4, 5].

The five-year survival rate of lung cancer is low worldwide (10–15%), mainly because the majority of cases are diagnosed with advanced stage, when treatment is rarely curative. In the NSCLC cases that are diagnosed at an early stage (stage I and II), the five-year survival rate dramatically improves, ranging from 70% to 85% for surgically resected stage I disease [6], lobectomy being the established and most effective therapeutic approach [7]. However, less than one third of NSCLC cases are diagnosed in early stage [8–10] and the methodologies currently available for early diagnosis present several limitations. Chest X-rays have low sensitivity for lung cancer detection, whereas low-dose chest computed tomography (CT) scan has high sensitivity but low specificity [11–14]. The latter is a relevant limitation of CT scan for screening, considering that among individuals at risk for lung cancer (heavy smokers and former smokers) 20–60% of chest CT exams show pulmonary nodules, the vast majority of which are eventually diagnosed as benign after completion of work up [15, 16]. Moreover, in many areas of the world chest CT is a rather expensive and not widely available screening tool [17].

Newer, minimally invasive and effective methods of screening for lung cancer are needed. MicroRNAs (miRNAs) are small non-protein-coding RNA molecules 18–25 nucleotide long that play an important role in eukaryotic gene expression regulation. They have been shown to be dysregulated in human diseases, including cancer [18, 19]. The aberrant expression of specific miRNAs in body fluids from individuals with cancer has suggested their possible application as cancer biomarkers [20–25]. The quantification of selected miRNAs in plasma or serum of high risk individuals has been proposed as a simple and potentially effective screening tool for early detection of NSCLC. Unfortunately, the miRNA signatures identified by numerous published studies of lung cancer patients are largely inconsistent, the reported miRNA profiles being incoherent [23, 26–33]. These studies have been the subject of several reviews and meta-analyses [34–40]. However, these reviews were not focused on circulating miRNAs in cancer stage I and II, potentially amenable to radical cure. Moreover, the accuracy of miRNA quantification in plasma/serum is known to be affected by several methodological variables, including modality of sample preparation, hemolysis, RNA isolation procedures, method of cDNA preparation and method used for miRNA measurement. These factors, that likely contribute to the puzzling inconsistency of the published miRNA profiles of NSCLC, were only partially addressed in the aforementioned reviews.

Here we aimed to review the literature in order to identify circulating miRNAs proven to be valuable and highly accurate for diagnosis of early NSCLC (stage I and II). Further, based on our analysis, we propose two panels of miRNAs for diagnosis of stage I-II NSCLC, with a two-tier screening method.

RESULTS

Included studies

Our literature search identified a total of 1712 articles, from which duplicates were removed, yielding 1239 papers. After reviewing titles, abstracts and full texts, 17 papers fulfilling our search criteria were finally included. Manual search of the bibliography of these papers led to include 3 additional records, yielding a total of 20 articles (Figure ​1). Among these, 8 papers studied single miRNAs only, 6 explored both single miRNAs and panels, and 6 focused on miRNA panels only. For the 20 studies included in the review, Supplementary Table 1A indicates the main characteristics of patients and controls, and the investigated individual miRNAs or panels; Supplementary Table 1B provides information on methods used for miRNA quantification.

Figure 1

PRISMA flow diagram illustrating the study selection process

The selected studies, all published in the years 2011–2017, included 2119 individuals in total (1110 NSCLC patients and 1009 controls). The sample size ranged between 11 and 126 for NSCLC cohorts and between 11 and 110 for controls. The median sample size was 56 patients (interquartile range 30–79) with 1.1 case/control ratio. In all selected papers the sample mean age ranged 60–65 years, except in the study by Shi and colleagues that was carried out in a younger patient group (patient mean age, 50) [41].

Of the 20 studies (10 from China, 4 from USA, 2 from Italy and 1 each from Poland, Norway, Russia and France), 8 were conducted on Caucasian patients (2 studies included African American subjects), 7 on Asian patients and 5 did not provide information on ethnicity (Supplementary Table 1A).

The NSCLC patient groups differed by clinicopathological status across the studies and some relevant data were missing. Regarding the patients’ smoking status and comorbidities, four studies did not report any data on smoking [41–44]; two studies included only smokers (with > 20 mean pack-years) [26, 30]; five studies included ≥ 85% of smokers among NSCLC patients [27, 29, 45–47]. Fourteen of the 20 studies provided no information on comorbidity of the patient cohort; the other 6 studies indicated that patients had no history of other cancers (Supplementary Table 1A) [26, 48–52]. A mix of the two main subtypes of NSCLC, AC and SCC, was present in all the selected papers, however only in 11 studies the accuracy of the miRNA profile of NSCLC was separately evaluated for AC and SCC [26, 29, 30, 41, 44, 46, 48–50, 53, 54]. The composition of control groups was also varied (Supplementary Table 1A). Four studies [30, 44, 53, 55] provided no medical information on the control group. In 4 studies, history of no tumor and negative chest imaging (X-rays or CT scan) were used to identify healthy controls [26, 46, 47, 51]. In the other 12 studies, individuals broadly defined “healthy subjects” or “non-neoplastic subjects” based on medical history, served as controls; 3 of these studies included patients with chronic obstructive pulmonary disease (COPD) [29, 45, 47] and 4 studies included controls with benign pulmonary nodules or non-cancerous lung disease [45, 48, 50, 52].

miRNA extraction

miRNAs were extracted from serum samples in 10 studies, from plasma samples in 9 studies, from whole blood in 1 study (Supplementary Table 1B). A training and a validation set were both described in 8 studies; of these, 4 reported two different procedures to quantify miRNAs in the training and validation sets. For miRNA extraction (Supplementary Table 1B), the mirVana PARIS RNA kit (Ambion, ThermoFisher) was used in 7 studies, the miRNeasy mini kit (Qiagen) in 3 studies, and in one study each the miRCURY RNA isolation kit (Exiqon), the RNA extraction kit (Applied Biosystems, AB), the NucleoSpin miRNA Plasma kit (Macherey-Nagel) were used. In the study by Yuxia et al. [42], RNA extraction was not performed, whereas 2 studies used phenol and guanidine isothiocyanate reagents only [27, 49]. Addition of spike-ins as a quality control step was reported in 5 papers (Supplementary Table 1B).

miRNA retrotranscription and quantification

In 13 studies “Taqman” stem&loop primers and kits (AB) were used for retrotranscription, combined with two quantification methods [Taqman Low Density Arrays microRNA signature panel (TLDA, AB)] or another array -6 papers- and/or probe based relative quantitative PCR (qPCR) -12 papers-, as detailed in Supplementary Table 1B. Absolute miRNA quantification by Droplet Digital PCR (ddPCR) was performed in only 1 study, after retrotranscription with stem&loop primers [28]. In 3 studies, qPCR based on intercalating dyes was used for miRNA quantification. In 3 studies insufficient details of the procedures were provided [29, 41, 48]; (Supplementary Table 1B).

Normalization

As shown in Supplementary Table 1B, in the 6 studies using TLDA for quantification, the data were normalized with a geometric mean of different miRNAs, or with global normalization, or with quantile normalization. In the 14 studies using qPCR quantification, a single endogenous reference molecule (miR-16 or U6) was used in 7 studies; 4 studies used means of at least two endogenous reference genes; 2 studies used a single exogenous spike-in; 1 study did not provide details about normalization [42] (Supplementary Table 1B).

Individual miRNAs

In the 20 selected studies, altogether 27 miRNAs were individually reported (Table ​1). Overall the studies were of medium quality as assessed by Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist, where “patient selection” and “index test” resulted the most critical domains. The diagnostic performance of individual miRNAs varied widely: sensitivity ranged between 30.4% and 96.1%, specificity between 38.2% and 100%; moreover, for some miRNAs (miR-223, miR-21, miR-145, miR-125b) the AUC differed substantially between independent studies (Table ​1), suggesting that variability of patients, controls or methods may affect miRNA levels.

Table 1

Sensitivity, specificity and AUC of the 27 individual miRNAs described in the selected studies

Identification of highly sensitive and highly specific miRNAs

Aiming to identify within Table ​1 the individual miRNAs suitable for possible clinical application as non-invasive screening tool, we needed first to eliminate miRNAs influenced by hemolysis, a major source of bias. Therefore, we decided to exclude those miRNAs described as influenced by hemolysis in 3 or more of the relevant independent studies reporting hemolysis-induced miRNA dysregulation [56–63]. Accordingly, five miRNAs listed in Table ​1 were excluded from possible clinical use: miR-486, miR-21, miR-21-5p, miR-126, miR-15b (see Supplementary Table 2). Among all miRNAs listed in Table ​1 and considered unaffected by hemolysis, only miR-223, miR-20a, miR-448 and miR-145 displayed AUC value > 0.80 and sensitivity > 80% as stage I-II NSCLC biomarkers in at least one study. Moreover, miR-628-3p, miR-29c, miR-210 and miR-1244, despite low sensitivity and modest AUC value, showed specificity > 90% in at least one study. For these two sets of miRNAs, highly sensitive and highly specific respectively, the diagnostic accuracy data are summarized in Table ​2. The seven studies analyzing these miRNAs [44, 46, 48, 50–53] are of medium overall quality according to the QUADAS-2 checklist; they included 649 NSCLC patients (median, 87 patients per study), predominantly smokers (62%) and represent 58% of the 1110 patients evaluated overall in the 20 selected studies. The miRNAs shown in Table ​2 have important biological functions related to tumorigenesis; although the analysis of these functions is beyond the purpose of this review, they are briefly described in Supplementary File 1.

Table 2

miRNAs with high sensitivity and high AUC (a), and miRNAs with high specificity (b).

miRNA panels

In the 20 selected studies, 12 miRNA panels featuring high sensitivity (> 80%) and/or high AUC (> 0.80) as stage I-II NSCLC biomarkers were reported (Table ​3). Five of these panels showed AUC> 0.90 and seven had AUC between 0.80 and 0.90; however some panels included miRNAs documented to be influenced by hemolysis (Table ​3).

Table 3

Sensitivity (Se), specificity (Sp) and AUC of miRNA panels described in the selected studies

Table ​4 illustrates miRNAs that were described (either individually or within miRNA panels) as biomarkers of stage I-II NSCLC in more than one of the selected studies.

Table 4

miRNAs indicated as stage I-II NSCLC biomarkers in more than one of the selected studies

miRNAs and NSCLC subtypes

None of the 20 studies included in this review separately evaluated miRNA signatures in SCC or AC. However, 11 of the 20 selected studies evaluated the performance of circulating miRNAs in distinguishing NSCLC subtypes, and the investigated individual miRNAs and miRNA panels completely differed across the studies. As summarized in Table ​5, the proposed miRNA signatures revealed: greater accuracy in identifying SCC than AC in 7 studies [26, 29, 41, 46, 48, 49, 53]; similar accuracy in 2 studies [44, 54]; higher sensitivity for diagnosing AC in one study [30]. Wang et al. [50] reported that circulating levels of miR-425-3p and miR-628-3p were significantly higher in AC than SCC, while miR-532 was significantly lower in AC than SCC (Table ​5). The AUCs for the miRNAs proposed as subtype-specific biomarkers were reported only in 4 studies [26, 48, 53, 54]. Altogether these findings show no consistent alterations of circulating miRNAs that may more accurately identify AC or SCC.

Table 5

Characteristics of the 11 included studies evaluating the performance of circulating miRNAs in distinguishing NSCLC subtypes

Proposal of a two-step screening with miRNAs

Based on the critique of the reviewed studies, we propose a model for screening of stage I-II NSCLC, using the two above indicated sets of individual miRNAs with the highest sensitivity/specificity (Table ​2), that were selected as detailed in the Methods section. Panels of miRNAs were arbitrarily excluded from this model as the AUC or specificity data were based on the panels, and to simplify its possible clinical application. Accordingly, screening with miRNAs should be carried out in two steps. The four miRNAs with high sensitivity (miR-223, miR-20a, miR-448 and miR-145) should be used for the first screening step (Test 1), and the four miRNAs with high specificity (miR-628-3p, miR-29c, miR-210 and miR-1224) for the second step (Test 2). In this model the two panels of miRNAs are combined in series, and Test 2 is run only if Test 1 is positive, as described in Supplementary File 2.

The final estimated performance of these miRNAs for the two-step screening of serum samples is overall sensitivity of 91.6% and overall specificity of 93.4%. The selected two sets of miRNAs with highest sensitivity/specificity are intended for preliminary screening of the general population at high risk of lung cancer, dominated by smokers. Subjects positive to miRNA screening should be offered low-dose CT-screening, thus possibly reducing the logistic/economic burden and harms of upfront CT-screening [12,14].

DISCUSSION

Diagnosing lung cancer at an early stage is a major clinical concern that in recent years has stimulated extensive research on non-invasive screening methods, including miRNAs as lung cancer biomarkers in circulating body fluids. Dysregulated miRNA profiles in cell-free blood were shown to indicate the presence of lung cancer many months ahead of the occurrence of symptoms [64], and even before the disease was detected by CT screening [26, 65]. Therefore, miRNAs are potentially interesting biomarkers for screening of lung cancer [66]. According to “Medline Trend”, the number of publications on the topic “miRNA and NSCLC” has dramatically increased in the last 10 years, however the plethora of circulating miRNA profiles proposed as lung cancer signatures are inconsistent. Six systematic reviews [34–37, 39, 40] have summarized the main findings of these studies, but have failed to clearly identify circulating miRNAs possessing high proficiency specifically for the diagnosis of stage I-II NSCLCs, which are the cancers potentially amenable to radical cure. Considering that miRNA signatures of early and late lung cancer stages frequently differ [50, 64, 67–69], we exclusively reviewed papers reporting miRNAs biomarkers of stage I-II NSCLC. We focused on miRNA molecules of high diagnostic accuracy and whose measurement is scarcely influenced by hemolysis. Among the initially retrieved 1712 papers fulfilling the search criteria, we only found 20 studies clearly reporting quantitative data on miRNA diagnostic proficiency specifically for stage I-II NSCLC. Our review confirms the variability of miRNAs proposed by many authors as lung cancer signatures. Notably, there were only 18 miRNAs identified as biomarkers of stage I-II NSCLC in more than one published paper (Table ​4).

For the 20 selected studies we highlighted demographics, clinicopathological characteristics and smoking habit of patients and controls; moreover, we evaluated the main pre-analytical and analytical variables known to influence circulating miRNA levels. Notably, the training set in the selected studies consisted of a median of only 56 NSCLC patients, meaning that the training sample frequently was of smaller size than that suggested by guidelines for studies of biomarkers for early detection of cancer [70]. Moreover, in some of the selected studies the training sample appears definitely undersized if one considers the rather low precision of miRNA assays [63] and the expected diversity of miRNA signatures due to molecular heterogeneity of NSCLC subtypes [36, 71–74]. Population ethnicity has been suggested as a potential source of miRNA level variability and of inconsistent miRNA signatures of lung cancer [77]. However, Shen et al. found no association between changes in circulating miRNA levels and patient ethnic group (African-American or Caucasian) [43]. As regards gender and age, several papers have documented that these variables do not significantly impact on lung cancer miRNA signatures [30, 44, 50, 75, 76].

The proportion of smokers varied among the studies and sometimes markedly differed between cases and controls within the same study. In 5 of the 20 papers, cigarette smoking data were not reported, an important lack of information because some circulating miRNAs are significantly dysregulated by smoking [34, 77, 78].

Across the 20 studies, the control groups were also very different. The majority of studies defined the control group as “healthy subjects” not otherwise specified, or “non-neoplastic subjects” based on medical history. Notably, the composition of control groups is a critical issue, because diseases of liver, heart, prostate and various other comorbidities in the control group may influence the diagnostic sensitivity and specificity of miRNA candidate biomarkers [79–81]. Only 4 of 20 studies subdivided control patients by comorbidity: benign lung nodules, COPD, noncancerous disease, smoker [29, 48, 50, 52]. It is debated if “controls” for lung cancer patients should be age-matched “healthy subjects” or subjects with a history of smoking, and whether COPD patients should be included as controls. Because levels of miRNA relevant for lung cancer may be altered in smokers [34, 77] and in COPD patients [82–84], the control group composition in terms of smoking pack/years and COPD prevalence may bias the accuracy of miRNAs selected as lung cancer biomarkers. In order to avoid a COPD-based miRNA signature, in the studies by Sanfiorenzo et al. [29] and Halvorsen et al. [47], non-neoplastic COPD patients were used as controls.

Elegant experimental studies have shown that miRNAs derived from cancer tissue can enter the circulation [24]. Moreover, in lung cancer patients several overexpressed circulating miRNAs (miR-21, miR-24, miR-145, miR-20a, miR-223, miR-486, miR-574-5p, miR-1825, miR-205, miR-19a, miR-19-b, miR-30b) were generally reduced a few days after tumor resection, strongly suggesting that these molecules are of tumor origin or tumor-induced [43, 51, 75, 85, 86]. It is therefore reasonable to assume that at least some of the aberrantly expressed miRNAs in the blood of lung cancer patients are genuine biomarkers of the tumor. The measurement of circulating miRNAs faces numerous technical challenges and may be biased by multiple factors, partly explaining the inconsistency of published miRNA profiles of lung cancer [51]. Because several circulating miRNAs are blood-cell derived [56, 59–62, 87], spurious miRNA level dysregulations that may result from platelet contamination and red blood cell lysis in plasma/serum samples are a major concern. Our review suggests that potential bias of hemolysis on miRNA levels has often been underestimated, as only in 2 of the 20 reviewed studies was hemolysis of specimens ruled out [29, 54]. In order to avoid spurious effects of undetected hemolysis of samples, in agreement with Pritchard and collaborators [88], we suggest that miRNAs influenced by hemolysis should preferably not be used as NSCLC biomarkers.

For analysis of circulating miRNAs, both serum and plasma are acceptable sample types, and a good correlation between serum and plasma miRNA determinations has been documented [89]. However, serum and plasma determinations cannot be automatically interchanged, because differences in specimen preparation and/or measurement platform are known to influence the results. As an example, in normal subjects miR-15b and miR-16 showed higher concentrations in plasma relative to serum in one study [63], while the concentration of the same two miRNAs was higher in serum relative to plasma in another independent study using a different platform [90].

It is currently debated whether serum or plasma should be used for circulating miRNAs determination; mirroring this uncertainty, 10 of the 20 selected studies were performed with serum samples and 9 with plasma. Serum has not been generically recommended over plasma as a sample type [87]; however, serum has less platelet contamination than plasma, and this may decrease bias in miRNA determination [63]. Regarding the method for miRNA quantification, all the reviewed studies except that of Ma et al. [28] used qPCR platform and performed normalization of results predominantly with endogenous miR-16 and U6, or with spike-ins. The normalization step is likely to contribute to the scarce reproducibility of miRNA determinations, as reported by others [33]. Normalization with miR-16 can be criticized because this miRNA has been described as a lung cancer biomarker itself [91–93]. U6, a small nuclear RNA, was shown to fluctuate markedly across samples [94], and such variability may contribute to inconsistency of miRNA findings. For miRNA measurement Ma et al. [28] used ddPCR, a recently introduced technique reported to be advantageous over qPCR (greater precision; no need to normalize results; higher sensitivity to low-level miRNA expression) [28, 95]. Altogether, these considerations underscore the importance of knowing the miRNA quantification procedure details, to allow reproducibility of methods and external validation of studies.

Distinguishing between the AC and SCC lung cancer subtypes on the basis of specific circulating miRNAs’ aberrant expression may provide important information, relevant both for understanding the subtypes’ pathogenesis and for tailored selection of cytotoxic chemotherapy in NSCLC without a driver mutation [96]. Moreover, although histology and immunohistochemistry (IHC) currently are the gold standards for NSCLC diagnosis, the subtype classification of difficult cases (scarce biopsy sample; hazardous/difficult biopsy; uncertain IHC) could be facilitated if subtype-specific circulating miRNA signatures were available. Few studies have been conducted in stage I-II NSCLC patients to identify circulating miRNA profiles than may be more accurate for either AC or SCC. In our systematic review we only found 11 studies that separately analyzed AC and SCC cases [26, 29, 30, 41, 44, 46, 48–50, 53, 54], and none of these provided convincing evidence that a specific miRNA signature exists for each of the two subtypes. A notable methodological weakness in 9 of these 11 studies [26, 29, 30, 41, 44, 46, 48–50, 53, 54] is the inclusion of many lung cancers in advanced stage (stage > II) in the subtype analysis, likely to compensate for small sample size of the AC and SCC sub-cohorts. Of note, Bianchi et al. [26], Geng et al. [48], Powrozek et al. [46], Sanfiorenzo et al. [29], Shi et al. [41], Ulivi et al. [49] and Wang et al. [53] proposed very different miRNA signatures of early stage NSCLC, yet all these signatures better differentiated SCC than AC from controls. Altogether, the available data are insufficient to define serum/plasma miRNA profiles that may reliably discriminate between AC and SCC in stage I-II lung cancer.

Strengths and limitations

A strength of this review is the critique focused on circulating miRNA biomarkers of stage I-II NSCLC, the disease stages often amenable to radical cure and for which non-invasive screening by miRNAs may be proposed. Another strength is the assessment of factors potentially influencing miRNA levels and the evaluation of miRNAs’ accuracy as stage I-II NSCLC biomarkers by quantitative data (sensitivity, specificity, AUC).

This review has important limitations. First, miRNA signatures of NSCLC may be biased by pre-analytical and analytical factors, and by clinicopathological features of patients and controls. Second, in many of the selected papers the validation sample was relatively small (median, 56 patients), with limited power to correctly identify the miRNA signature of stage I-II NSCLC. Third, lack of methodological details in some studies prevented thorough evaluation of the quality of methodology used. Data on comorbidities, some of which may affect miRNA expression [79–81], were not provided in some papers. Accordingly, at QUADAS-2, “patient selection” and “index test” resulted the most critical domains, and overall the studies were only of medium quality. Another limitation is that the miRNA panels for our two-step model of screening were obtained from studies where only the majority of lung cancer patients (62%) were smokers, while screening for lung cancer is currently recommended exclusively in smokers (11). In this review, we aimed to identify circulating individual miRNAs with sensitivity > 80% and AUC > 0.80 as biomarkers of stage I-II NSCLC, for possible clinical application as non-invasive screening tool. Based on the reviewed studies, we found four individual miRNAs that fulfilled these criteria: miR-223, miR-20a, miR-448 and miR-145; four other miRNAs showed very high specificity (> 90%): miR-628-3p, miR-29c, miR-210 and miR-1244. Among factors potentially affecting circulating miRNAs, the only two that were considered for miRNAs selection were the stage of NSCLC (all studies were stages I-II) and the impact of hemolysis (miRNAs potentially affected by hemolysis were excluded). Other factors, such as smoking habits, age, ethnicity, methodological issues of RNA extraction, could not be controlled because they varied widely among the selected studies.

Screening for lung cancer with circulating miRNAs, preliminary to CT-screening, is a minimally invasive and safe blood test that may offer several advantages over upfront CT-screening: reduction of number of CT-screens (to be performed only in miRNA screening-positive individuals) and of radiation risk; decrease of false-positive CT-screening rate and consequent reduction of complications and costs from futile lung biopsies (12,14). We have proposed a two-step model of miRNA screening for stage I-II NSCLC, based on the measurement of the serum level of the above indicated selected miRNAs (Table ​2): the panel of four miRNAs with high sensitivity should be used for the first screening step, and the panel with high specificity for the second step. Based on our model, for the two miRNA panels combined in series for screening of serum samples the estimated performance is overall sensitivity of 91.6% and overall specificity of 93.4%. The estimated diagnostic accuracy of the proposed model is similar to that of the 12 miRNA panels found in the selected papers (Table ​3), most of which featured high sensitivity (> 80%) and/or high AUC (> 0.80) as stage I-II NSCLC biomarkers. However, several of these panels contain miRNAs that are not ideal biomarkers; as Table ​3 shows, 6 of the 12 panels included miRNAs influenced by hemolysis. Moreover, Nadal et al. and Wozniak et al. provided no sensitivity nor specificity data for their panels [45, 54] and the panels tested by Powrozek et al., Halvorsen et al., and Foss et al. showed modest specificity (76.3%, 74% and 71%, respectively) [27, 46, 47]. The panel proposed by Wang et al. featured high proficiency in diagnosing AC, without containing hemolysis-influenced miRNAs [50].

MATERIALS AND METHODS

Search strategy

A systematic review of the scientific literature was conducted using the following key words: [(NSCLC OR Non Small Cell Lung Cancer) AND (lung cancer) AND (miRNA OR MicroRNA) AND (diagnosis)]” on the search engines of the databases “Pubmed”, “Medline”, “Scopus”, “Embase” and “WOS”. The research was first performed on July 21st 2016 and results were regularly updated until April 12th 2017. Including criteria were: i) circulating miRNAs; ii) histologically/cytologically defined NSCLC stage I and/or II (studies of patients with NSCLC at any stage were included only if a sub-analysis for stage I-II was provided); iii) studies reporting quantitative data on the efficacy of specific miRNAs as tools for stage I-II NSCLC screening (sensitivity, specificity and/or AUC); iv) English language. Studies analyzing single miRNAs and/or panels of miRNAs were included. Duplicate publications were eliminated through the Mendeley software [97]. All articles of interest were then evaluated and screened for eligibility by two researchers, independently, and controversies were resolved by consensus. Bibliography of the selected papers was manually examined to retrieve further articles with eligibility criteria.

The protocol was registered at the international prospective register of systematic reviews (PROSPERO, ID: CRD42017056943). The PRISMA statement and the Cochrane Handbook for Diagnostic Test Accuracy Reviews were followed as reference protocol standards.

Data extraction

From the eligible studies the following information was collected: a) author name, year and country where the study was performed; b) sociodemographic and clinical information on population under study (ethnicity, sample size, age, smoking status, comorbidity, NSCLC stage); c) individual miRNAs and/or miRNA panels under study; d) methodological issues regarding miRNAs extraction [type of specimen (plasma/serum/whole blood), hemolysis assessment, RNA isolation and measurements procedures]; e) quantitative data of diagnostic accuracy (sensitivity, specificity, AUC) for stage I-II NSCLC.

The papers then underwent rigorous critical evaluation, taking into account: i) quality of the study, assessed by the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist [98]; ii) factors identified as potentially affecting miRNA quantification (Table ​6). Two investigators independently assessed the seven domains of the QUADAS-2. Any discrepancies were resolved through discussion.

Table 6

Factors potentially affecting circulating miRNA quantification in NSCLC patients

Selection of circulating miRNAs for a two-step screening preliminary to CT-screening

Within studies with overall satisfactory quality by QUADAS-2, we identified individual miRNAs showing at least in one study high diagnostic proficiency as stage I-II NSCLC biomarkers (arbitrarily stated as sensitivity > 80% and AUC > 0.80, or specificity > 90%) and scarcely influenced by hemolysis according to the pertinent literature [56–63]. Altogether eight individual miRNAs revealed the aforementioned high diagnostic proficiency as stage I-II NSCLC biomarkers (miR-223, miR-20a, miR-448, miR-145, miR-628-3p, miR-29c, miR-210 and miR-1244; Table ​2). These miRNAs with the highest sensitivity/specificity can be applied in a mathematical model, that we are here proposing, to estimate their overall sensitivity and specificity for stage I-II NSCLC screening. The model consists of a two-step screening test, first using the panel of selected circulating miRNAs with high sensitivity and high AUC, then the panel of selected miRNAs with high specificity, as illustrated in Supplementary File 2. We arbitrarily excluded miRNA panels from the model since the AUC or specificity data were based on the panels and not individual miRNAs, aiming to simplify possible clinical application of the test. However, for comparison of our model’s diagnostic accuracy, the other miRNA panels included in the review are discussed.

Statistical analysis

The proposed two-step model for estimating overall sensitivity and specificity of circulating miRNAs to be used for stage I-II NSCLC screening was developed using the formulas described in Supplementary File 2.

CONCLUSIONS

Several pre-analytical and analytical variables of circulating miRNA measurements, especially hemolysis of samples, may bias the accuracy of miRNAs as biomarkers of stage I-II NSCLC. Evidence-based data are insufficient to reach a robust conclusion as to which circulating miRNAs are the best biomarkers of early lung cancer, and also insufficient to define serum/plasma miRNA profiles that may reliably discriminate between AC and SCC.

Nevertheless, based on critical review of the literature, selected circulating miRNAs that are scarcely influenced by hemolysis could be tested for screening early lung cancer in smokers and former smokers. For our theoretical model of two-step screening for stage I-II NSCLC, first using a panel of miRNAs with high sensitivity and then a panel with high specificity, we estimated overall sensitivity of 91.6% and overall specificity of 93.4%. The circulating miRNAs we selected as potentially valuable biomarkers of early lung cancer based on this review, as well as those described by other authors, require validation in multiple independent studies before they can be proposed for clinical application.

Acknowledgments

PDA and MC are PhD students of the “Biotechnology, Biosciences and Surgical Technology” course at Università degli Studi dell’Insubria.

We are extremely grateful to Mr. Piero Francesco Macchi and Mrs. Carlotta Biasini for their generous donation to support this study.

Abbreviations

ABApplied Biosystems
ACadenocarcinoma
AUCarea under the curve
COPDchronic obstructive pulmonary disease
CTcomputed tomography
ddPCRdroplet digital PCR
IHCimmunohistochemistry
miRNAmicroRNA
NSCLCNon-small cell lung cancer
qPCRquantitative (realtime) PCR
QUADASQuality Assessment of Diagnostic Accuracy Studies
SCCsquamous cell carcinoma
TLDATaqman Low Density Arrays

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