The current location of BioEmergences is in the Gif-sur-Yvette campus were it occupies 250 m 2 principally in the INAF building (wet lab, offices, systems, storage, servers) and secondarily in the IMAGIF building (storage, servers, clusters, and office and lab dedicated to the PharmaTox project). The strong connection between BioEmergence and the institute for Complex Systems has led to the creation of a space of 80-100 m 2 dedicated to BioEmergences in this institute. A strong collaboration between BioEmergences and Banyuls biology station should drive to some technological transfer to this station and will be therefore associated to BioEmergence dedicated space on this site.

Management team

BioEmergences will gather a team and a platform. They will be supervised by a director assisted by three PIs. 2  Overall assessment of the unit

AERES nomenclature

The BioEmergences unit has been tremendously successful in visualizing, analysing and reconstructing the collective behaviour of individual cells in developing embryos, with the aim of getting more insight into the mechanisms of development. Focusing primarily on solving this biological question, the unit has brought together an thriving and enthusiastic, interdisciplinary team of biologists, physicists, computer scientists, mathematicians, and technicians. Over the years, the team has developed new imaging technology, new algorithms for identifying and tracking individual cells in large volumes of data, data presentation and visualization technology, data integration methodology and computational and mathematical modelling techniques. As a result, the work has led to a number of high-impact publications to present the technology (e.g. Science, 2010) and to contribute to solving biological questions (e.g. Development, 2013). The experts committee was particularly impressed by the width of technologies "spinning off" from one ambitious (yet feasible) goal of reconstructing embryonic development at cellular detail. Despite the much more modest size of the BioEmergences project, the structure is reminiscent of "big science" projects as e.g. in particle physics. The results and technologies have already positively impacted developmental biology, and will likely have a much wider impact on studies of multicellular systems involving large scale data analysis.

Strengths and opportunities related to the context -innovative technology;

-whole pipeline -not only image acquisition, also data analysis, data structuring, modelling and simulation; -strong biological collaborators with relevant questions-> impact on developmental biology; -looking for additional applications (e.g. toxicology); -many developmental biologists will be interested in collaborating with the team; -setting the "standard" for data formats, etc. in the field.

Weaknesses and threats related to the context -width of technologies may lead to lack of coherence, especially further from data; -continuity: know-how may get lost if students graduate, postdocs move on, etc.; -modelling and simulation, needed to interpret data ('reconstruction') move away from project; -scientific and technological credits not always given to bioemergences by collaborators, not all output is visible.

Recommendations

-develop generic technologies, starting from specific, real-world questions -helps investigators further from data focus their efforts. specific technology can then be generalized; -spread know-how over multiple persons in the team, create overlapping terms of positions such that one postdoc can train the next; -reinvest in modelling & simulation efforts; -in collaborative projects, to ensure that proper scientific and technological credits are given to the bioemergences project, state the expectations (re: co-authorships, author positions, etc.) to collaborators formally and in advance. More prominent authorships (e.g., shared senior author) may be appropriate in cases where new scientific results are due to a large extent to results from the BioEmergences project.

 Detailed assessments Assessment of scientific quality and outputs

The BioEmergences project analyses embryogenesis at single cell level using advanced microscopy, and uses this data to reconstruct it using computational modelling. The team's philosophy is that to build accurate explanatory models of biological development, we cannot rely on hypothetical models that will be overturned by data later on. It is much better to collect accurate data right from the start. The team applies a strict multiscale and cell-based philosophy: biological development is the result of cross-scale interactions, including the molecular, cellular, tissue levels, in which the cellular level is the central scale. To this end, the team has developed a series of imaging pipelines in which cell behaviour can be followed at individual cells and often subcellular resolution, generating datasets that contain the trajectories of cells over time, and more recently the cell membranes, cell shapes, and additional attributes of the cells. In this way the fate of cell clones can be followed in unprecedented detail, generating datasets that would hitherto require tagging of individual cells or cell clones in many individual embryos.

The fact that such datasets can now be collected in individual embryos has the added advantage that now variations between individual specimens can be assessed.

The project has the potential of bringing the "data deluge" of biology to a next scale, that of individual cells and tissues, in interaction with gene expression. This is a key step with that may change the main approaches in biology and bioinformatics, which is still overly focused on the molecular scale because of the easy availability of molecular data. The methods that are further developed and applied to generate and analyse this data, breach a wide range of scientific fields in biophysics, informatics, and the mathematical sciences. They range from optics and bio-sensor development, to image analysis and machine learning, to topology, stochastics, and cell-based modelling methodology.

The team has already contributed to new insights into a range of biological questions, both as proof of concept of the prototypes, and in their role as service provider. For example, the cell lineage reconstruction software Mov-IT was applied to the reconstruction the first 10 cell divisions (producing 2^10=1024 cells) of the early zebrafish embryo. These results showed a progressive loss of synchrony of the cell division cycles and a number of apparent division waves. Follow-up work is precisely characterizing the cell behaviour during gastrulation and has yielded a dynamic atlas of gene expression during zebrafish development (submitted). The framework has also played a key role in identifying a unique, specialized vertebrate progenitor population in the zebrafish peripheral midbrain. The output has been impressive so far: by contributing detailed lineage traces this work is yielding surprising new insights and unveiling causalities into basic questions of developmental questions.

This work has resulted in five publications in high-impact factor biological journals, including Nature, Science, and Development, and in eight publications in high-ranking computational and methodological journals, including Bioinformatics and IEEE Transactions in Image Processing. In addition the work has resulted in five papers in the top conference EMBC (Annual International Conference of the IEEE Engineering in Medicine and Biology Society), which is listed among the top conferences by Microsoft Academic Search (note that in computer science top conferences have status comparable to the top biological journals). Also the team has written six reviews and book chapters. In at least two of those contributions (including the one in Science) the team and PI were the leading authors. Despite these top contributions, the experts committee understands that a challenge for the team is to not be perceived as a "mere technological contributor", but indeed as a key contributor to scientific results in which the BioEmergences members have played a driving, or even the main role. For example, middle co-authorships for mere "running" of datasets, whereas more prominent authorships would be appropriate if the data analysis plays a more steering, intellectual role in collaborative projects. Achieving this would defitely help the team to stabilize their scientific success and allows securing funding strongly needed to allows set-up maintenance, renew and recruitment.

Assessment of the unit's interaction with the social, economic and cultural environment

The work of the team is resulting in interesting social, scientific and potential economic valorisation. Notable examples include:

-the use of serious gaming to correct and validate cell lineage trees, which is currently tested in an old people's home in Aveyron, France;

  location of the unit The BioEmergences USR originated from the European project of the same name co-coordinated by a mathematician, and a developmental biologist (future director of the platform) from 2006-2009. The mathematician was at the time director of the CREA (Research Center in Applied Epistemology, UMR 7656 CNRS École Polytechnique). The BioEmergence future director was leading the Genetic Networks and cell morphodynamics team at the DEPSN (Development and Evolution of the Nervous System, UPS CNRS). The platform was labelled by the GIS IBISA in 2009 and created UPS 3674 by the CNRS in January 2014.

TOTAL N1 to N6 17 13 Unit workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students		6
	Theses defended		1
	Postdoctoral students having spent at least 12 months in the unit*	3
	Number of Research Supervisor Qualifications (HDR) taken	1
	Qualified research supervisors (with an HDR) or similar positions	5	5
	Domaine principal:	SVE1_LS3 Biologie cellulaire, Biologie du développement animal
	Domaines secondaires: ST1 Mathématiques
		ST6 Sciences et technologies de l'information et de la communication
	Unit workforce
		Unit workforce	Number as at 30/06/2013	Number as at 01/01/2015
	N1: Permanent professors and similar positions	1	1
	N2: Permanent researchers from Institutions and similar positions	5	4
	N3: Other permanent staff (without research duties)	1	1
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)	2	2
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	8	5
	N6: Other contractual staff (without research duties)

 Supervising bodies general comments

Centre National de la Recherche Scientifique -CNRS April 2014 Department for the evaluation of research units On behalf of AERES, pursuant to the Decree of 3 november 2006 1 , -Mr. Didier HOUSSIN, president -Mr. Pierre GLAUDES, head of the evaluation of research units department On behalf of the expert committee, -Mr. Roeland MERKS, chair of the committee 1 The AERES President "signs [...], the evaluation reports, [...

-contributions to the construction and roll-out of the UNESCO UNITWIN Complex Systems Digital Campus; -dissemination and sharing of automated cell-lineage reconstruction pipelines as a service provider.

Assessment of the unit's organisation and life:

The experts committee appreciated the very positive comments and opinions of researchers, PhD students, postdoctoral fellows, engineers, collaborators from different laboratories on the site (and from collaborators coming from European countries who were present), about the governance and atmosphere at BioEmergences. A scientific life well organized with weekly seminars and specific discussions within working groups and strong interactions between the personnel keeps a spirit of BioEmergence membership.

The surface allocated to BioEmergences is at present a little constrained, but it is expected that the unit finds new premises on the Gif-sur-Yvette campus in the coming years.

Assessment of the unit's involvement in training through research

The team has trained 7 PhD students and many postdocs over the years, who have found excellent next positions, e.g., at Université de Versailles, and the Institut Curie.

Assessment of the strategy and the five-year plan

The BioEmergences project has gained significant momentum since its inception in 2006. It is currently gearing up for its consolidation into a service provider of established pipelines and a developer of new prototypes of microscopy pipelines, with many new opportunities. A range of collaborations have been set up, both nationally and internationally, and ranging from methodological collaborations (e.g. development of new cell tracking algorithms) to biological collaborations (application of the pipelines to biological problems, e.g. notochord formation). Also it is bringing the technology to additional institutes, e.g. the Laboratory Arago, Banyuls biology station. A number of new innovative microscopy technologies are being set up, e.g. multi-photon microscopy, single plane illumination microscopy, Digital Scanned Laser Light-sheet Microscopy, second harmonic generation microscopy, etc). Also, a large number of qualified scientific and technological personnel has been trained over the last years (see section personnel above).

In this light, in the opinion of the evaluators, a potential threat is that coherence and continuity of the project is lost during the coming years. Without long term job security and persistent assignment of personnel to the project, a major threat is that specialized know-how gets lost, for example where it concerns the persons in charge of image acquisition, new applications microscopy development and running microscopy pipelines. With respect to the cell-based modelling and simulation of collective cell behaviour, some personnel have recently moved on to new positions. As modelling and simulation technology are essential for 'closing the loop' from data collection to finding causative developmental mechanisms that are analysed in the project, it is recommended to either support new efforts on modelling and simulation, or refocus efforts on data collection and analysis.

In relation to this point, the experts committee notes the width of the five-year plan, from data collection and mathematical methods for image analysis and data integration, to building knowledge maps and topological inference schemes to analyse the data. Indeed it is important to develop of such tools and techniques in conjunction with the data collection, such that they the algorithms are well adapted to the collected data and vice versa. The evaluators encourage the team to ensure that these components of the project remain closely knit to the rest of the project.


president  Mr Didier Houssin

Pierre

 Introduction History and geographical location of the unit

The unit was submitted to an important restructuration: formerly named UPEC EA 4393 (Laboratory of Clinical Investigation) devoted to several specialities (gastroenterology, rheumatology, epidemiology…) and goals, the unit is now presented with renewed team's members and objectives. Only three members of the previous unit are part of the present EC2M3 project, which switches from the optimisation of colorectal cancer (CRC) screening to identification and validation of new colorectal cancer biomarkers covering all the fields of this disease: screening, diagnosis, prognosis and prediction of therapeutic response. The project is based on two major points: constitution of cohorts and bio banks at each step of the disease, and collaborations with units performing basic research, with particular emphasis on microbial -gene markers. The unit is localized on the site of Henri MONDOR hospital with three main locations: the University building (bench working), the Center for Clinical Investigation (Bio banking) and the Clinical Department of Gastroenterology (screening and follow up of patients, collection of clinical data).

Management team

The director of the unit is Pr Iradj SOBHANI. The formal organisation of the scientific project is based on four Work packages (WPs) as follows: 1-constitution of cohorts including colon cancer patients and control with normal colonoscopy individuals at various risk levels of colorectal cancer (CRC); 2-clinical trials in CRC patients; 3-bio banking collections and discovery of biomarkers; 4-validation of biomarkers. The head of each WP is in charge of evaluation of the projects per WP and makes reports for the directory management committee. The unit created a directory management committee that comprises the PI of each WP together with the director (IS), and which is in charge of strategic decisions (starting new projects, ending current projects, significant investments, organisation of financial distribution, communication). 2  Overall assessment of the unit This is a positive restructuration of the unit that aims at isolating and characterizing new molecular markers for the early diagnosis of CRC. The unit comprises MD/PhDs involved in different steps of the work-plan from patients to bench and hopefully from patients to patients with the discovery of novel biomarkers. The Public Hospitals of Paris and the University Paris 12 support the unit that is also integrated in one of the DHU of the site (Virus Immunity and Cancer) and participates to the formation of future teachers and scientific researchers. The strategy of the unit is based on established annotated collections (stool, serum, biopsies, tissues) from several important prospective cohorts of CRC patients at different stages of the natural history of the disease: screening in general population, screening in patients with positive blood stool test, patients with polyadenomas and with cancer or with advanced cancer. These collections and cohorts are intensively used for: 1) fruitful research on molecular, epigenetic and proteomic studies (published or submitted); 2) patents and licences on which a start-up has been created with integration of a researcher and a post doctoral fellow from the team; 3) important collaborations highly useful for the scientific part of the project (i.e. proteomics, microbiote); 4) numerous grants including several PHRC and prizes. The project plan to: 1) validate faecal markers (epigenetics markers) and serum markers (protein markers) discovered by the team on existing cohorts, still followed-up, and in biological fluids and tissues of CRC patients; 2) characterize a bacterial signature of CRC. The unit possesses background, biorepository, financial support and adequate scientific collaborations for handling successfully this project within the next five years.

AERES nomenclature : SVE1_LS7

Unit workforce

Unit workforce

Strengths and opportunities related to the context

Ability and amounts of funding; federation and management of the project; creation of a start-up and valorisation; clinical and scientific networking; the project on CRC biomarkers based on the quality of the clinical cohorts and the availability of certified annotated biobanks; original translational aspects on microbiote and CRC studies/projects.

The quality of the cohort opens windows for collaboration with industry (testing new markers and responses to treatments, especially biotherapy) and for clinical valorisation in the field of early diagnosis of CRC.

Weaknesses and threats related to the context

Lack of permanent personnel, especially technicians and full-time researchers.

Wide-ranging objectives in respect to the composition of the team in the competitive field of biomakers for CRC.

Low number of PhD students.

Recommendatinons

The strategy should be focused on markers for diagnosis, prognosis, or response to treatment, but not for screening. The microbiote project is an opportunity for the team, and scientific output linked to the biorepository backbone, the life of the unit should be organized and structured to accomodate the upcoming studies 1) "validation of biomarkers thanks to the biobanks and clinical data and follow up of patients" ; 2) "identification of new biomakers from the microbiote studies". The bioinformatic and statistical aspects should be reinforced. Among the clinicial projects, the radiobiology project should be given a low priority/ abandonned.

 Detailed assessments Assessment of scientific quality and outputs

The unit published 144 original clinical and scientific articles. Among them, 25 are directly related to the core translational research, part of which is published in good or very good journals such as: Cancer Res, Gut, J Biol Chem, Genome Res, J Clin Oncol, Gastroenterology, … Members of the team are co-inventor of 5 patents (3 international extensions, 1 in France and 2 in Europe). They gave 8 Invited lectures including 6 in International meetings. There is a fruitful continuum from clinical trial, clinical data collection, biobanking annotation towards scientific platform and bench. A clever and realistic strategy has been set up to pick up knowhow and help from outside through scientific collaborations and platforms.

Assessment of the unit's academic reputation and appeal

The unit has been able to develop National Networks on CRC screening and clinico-biological collections through several PHRCs, as well as International Networks including collaborations with recognized national and international organisms/centers (Pasteur institute, INRA, EMBL Heidelberg, Imperial College of London…) as well as with groups involved in clinical research on CRC (GERCOR…). Collaborations with INRA/Imperial College are running, and the unit is involved in an M2R with Pasteur Institute. The unit organized several meetings and received Prices and Awards: a study has been distinguished by the United European Gastrointestinal society during the UEGWeek, October 2011 in Stockholm.

Assessment of the unit's interaction with the social, economic and cultural environment

The unit has organized networks, collected materials and contributed to novel structures (particularly in the field of screening) for reducing delays from bed to bench. Researchers discovered in parallel new biomarkers for early diagnosis of CRC. They have obtained money from PHRC, but even more importantly from industry. Several cohorts have been established and corresponding biobanks certified; a formal International scientific convention has been signed between EMBL (Heidelberg Germany) and Public Hospitals of Paris, and projects for a new patent are in progress. The topic of research on biomarkers of CRC has been selected as a priority field by Medicen, and the group has been funded accordingly. The project Horizon 2020 from EEC is also supported by Public Hospitals of Paris for an upcoming submission of a large project. On the basis of the discovery of a new marker, a start-up has been created after being awarded fundings by national bio emergence competition (in 2009) and creation competition (in 2010). The start up (Profilome) has been funded for the promotion of faecal and blood tests. Researchers have also initiated collaborations important for the scientific issues of the team: INRA and Pasteur Institute for microbial studies, the proteomic platform of IPC in Marseille. Several interviews and public broadcast were given on molecular or microbial markers as well as on CRC screening.

Assessment of the unit's organisation and life

The managment of technicians basic researcher and clinicians is very good in implementing the unit strategy.

Assessment of the unit's involvement in training through research

Team members participate in (or are in charge of) numerous teaching activities: among the GERCOR group, teaching and coordination of Digestive Oncology Paris 05 University, DIU of GI cancerology, regional colon cancer screening training, European courses in clinical IBD and cancer, international bi annual courses in oncology. A thesis has been defended and another one will be defended within one or two years. The unit welcomes M1 and M2R students.

Assessment of the strategy and the five-year plan

The strengths of this project are based on building important clinical networks on CRC and constituting/managing several biobanks, with clinical and biological data originating from the unit's own projects or from clinical trials. The general aim is the identification of new biomarkers (for screening, diagnosis, prognosis, prediction of therapeutic response) using several approaches (proteomic, DNA analysis, methylation, microbial analyses ...). Although this topic is highly competitive, the strength and originality of the project are: 1) large annotated biobanks of CRC at different stages (screening, low and high risk, adenomas, carcinoma); 2) molecular markers already identified (FoxP3, IL17, Wif-1, ...) that can be validated on prospective cohorts still followed-up; 3) the microbial aspect of the research with pre-clinical and upcoming clinical studies on fecal microbiote with metagenomic and influence of chemotherapy; 4) the potential to valorize their results with industry and the associated start-up; 5) the ability to join and train young clinicians and future teachers of the medical school, which warrants a long lasting scientific strategy and leadership in this domain.

Conclusion

This unit shows the capacity to lead recognized and fruitful translational research projects in the field of CRC, to raise funds and to valorize its discoveries. The main issue is the identification of molecular markers for early diagnosis of CRC and among them, microbial markers. This latter part is original and should be supported. Knowledge, means and strategy of the unit warrant the success of the project.

Number as at 30/06/2013 Number as at 01/01/2015 N1: Permanent professors and similar

	positions	8	8
	N2: Permanent researchers from Institutions and similar positions
	N3: Other permanent staff (without research duties)		2
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)	3
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	1	3
	N6: Other contractual staff
	(without research duties)

TOTAL N1 to N6 12 13 Unit workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students	1	1
	Theses defended	1	1
	Postdoctoral students having spent at least 12 months in the unit*
	Number of Research Supervisor Qualifications (HDR) taken	1	2
	Qualified research supervisors (with an HDR) or similar positions	3	3

 Supervising bodies' general comments

1 ,  Mr.


president  Mr Didier Houssin

Pierre

 Introduction History and geographical location of the unit

The unit U669 was created in 2005 in the Maison de Solenn of the Cochin Hospital in order to study eating disorders in adolescents. In 2010, at the renewal of the funding for INSERM U669, its size had dramatically increased from 30 to 130 members by attracting clinical psychiatrists from South Paris hospitals and researchers of any orientation and its thematic scope had been widened to three main topics:

1) harmful or self-harming behaviors;

2) evaluation of therapies and practices;

3) development of new methods in psychiatric research.

In addition, the unit constituted an official collaboration with the GRIP in Montreal (Groupe de Recherche sur l'Inadaptation Psychosociale, Montréal, directed by Mr Richard TREMBLAY) and the leader of the genomics and genetic epidemiology group established a close collaboration with the University of Singapore.

In view of the renewal of the funding, the unit has received an excellent evaluation by an expert team of AERES in 2009. The evaluation highlighted the following strong points of the unit:

 The team had a spectacular rate of growth since its creation;

 The members of the lab highly appreciated the enthusiastic and participative management style of the head of the unit;

 The team has developed an interesting international collaboration with the GRIP;

 The team has been able to attract three very promising young researchers who work in different fields;

 The team has strong educational activity, both for students and the general public.

The experts also identified some limitations of the unit:

 The team includes many projects of a variable scientific quality;

 The team members have an unequal level of scientific publications;

 The collaboration across members of the lab is underdeveloped.

The recommendations of the expert teams were as follows:

 Need of reorganization of the unit around a few major high quality projects with well identified leaders;

 Collaboration across members of the lab should be encouraged;

 More structural frame must be provided to minor projects and clinical research in hospitals.

After this first evaluation the unit continued to grow to currently more than 180 researchers and the reputation of the unit was constantly growing. The members of the unit published nearly 500 articles and established additional international collaborations particularly in Europe. The already strong involvement in training was even extended and many team members were present in media or national or international committees.

The unit was structured into 13 non-formal teams of about 10 members each:

1/ General epidemiology in adolescent mental health (axis 1), Ms Marie CHOQUET, Mr Nearkasen CHAU 2/ Clinical and epidemiological research into addictive disorders (axes 1 and 2), Mr Michel REYNAUD 3/ Borderline personality disorder (axis 1), Mr Maurice CORCOS 4/ Clinical and epidemiological research into eating disorders (axes 1 and 2), Ms Nathalie GODART The cohesion of the unit was mainly assured by the very efficient methodological center of the unit that served all of these teams.

Management team

The central managerial and methodological team is relatively small and includes the head of the unit, two secretaries and two methodology engineers. A half-time secretary and a laboratory technician of the former unit of Prof. Alain GARDIER have recently joined the team.  The unit has a very pragmatic and efficient approach to bring a large number of clinicians together with a relatively small number of INSERM full-time researchers, who provide the clinicians with the necessary scientific support to conduct their own research projects. Hence, the creation of the unit bridges the frequent gap between science and clinics. The support by the methodological center of the unit enables many clinicians to complete scientific projects in multiple domains, which otherwise would have probably never been initiated, and assures the methodological standard of the projects;

AERES nomenclature

SVE1_LS4

Unit workforce

Unit workforce

 The growth of the team has continued since the last evaluation in 2009, although in a more moderate way than before, which underscores the ongoing dynamic of the unit;

 The unit has developed several outstanding projects in its core domains of psychiatric epidemiology (mainly drug addiction and eating disorders) and the development of methodology;

 The multidisciplinary research strategy of the unit and the methodological support provided to clinician researchers is highly appreciated by the University Paris Sud;

 The international collaboration with the GRIP (Groupe de Recherche sur l'Inadaptation Psychosociale, Montréal) has cumulated in several publications in the most prestigious psychiatric journals with first and last authorship of members of the unit and new collaborations have been established in several European projects in child and adolescent psychiatry;

 Despite a relatively small structural support (Université Paris-Sud: 63860 € and INSERM: 77000 € in 2013) the unit was able to obtain the remarkable sum of 1.9 M. € by external public grants between 2008 and 2013;

 There is a high degree of satisfaction among the clinicians and PhD students of the unit, who appreciated very much the support by the methodological center and the dynamic style of the head of the unit;

 The team has trained an impressive number of PhD students and post-docs in the last 4 years and the collaboration between the unit and the University Paris Sud is excellent;

 Unit has an excellent, coherent and original five-year plan, which takes advantage in an optimal way of the accumulated skills of the team.

Weaknesses and threats related to the context

One drawback of the large and heterogeneous team composed mostly of clinicians is the variable scientific quality of the projects reflected also by the large variance of the qualitative level of the journals in which the articles of the unit appeared since 2008.

Given the impressive expertise in methodology and psychiatric epidemiology of the unit it is regrettable that the team did not respond to the recent call to propose the constitution of a psychiatric cohort. As a central project of the unit such a cohort could have had a federating effect for the team.

Given the continuing growth of the unit and the proposed subdivision into several formal teams there is a risk that the methodological center, which is the real glue of the unit, will be overload and cannot assure the coherence of the unit any longer. Indeed, although a new research engineer could be recruited for the methodological center of the unit in 2012, the engineer team is already now overwhelmed with demands.

Recommendations

The general impression is that in the next years the unit should make more effort to increase the quality rather than the quantity of the scientific output and to increase the visibility of the unit outside of French speaking countries by:  concentrating the efforts of each team to a smaller number of projects with outstanding scientific quality;

 adopting a more focused publication strategy that give more emphasis to the writing of articles for top psychiatric journals;

 taking on of more leadership roles by leading researchers of the unit in international collaborations (beyond the French speaking countries); members of the unit should also be more present in international committees and editorial boards of international journals.

Regarding the 5-year plan, the scientific quality of the projects of Team 4 (Impact of psychotrauma in overseas territories) needs to be improved and the way how this new heterogeneous team should be integrated into the unit should be better specified. Moreover, the methodological and administrative staff needs to be strengthened in order maintaining the coherence and the functioning of the growing unit.

 Detailed assessments

Assessment of scientific quality and outputs

During the period 2008 to early 2013, an impressive number of 480 papers (80 % in English) were published in 246 journals indexed in Pubmed focusing mainly on eating disorders, addiction in clinical populations and in the community, evaluation of interventions in early childhood, depression and its pharmacological treatment as well as the development of scientific instruments and biostatistics. However, given the heterogeneity of the team it is not surprising that also the level of the journals in which the members of the unit published was very heterogeneous. A small number of articles with first or last authorships of members of the unit were published in top journals with impact factors of 10 an more (one in BMJ, two in Molecular Psychiatry and two in American Journal of Psychiatry), whereas the bulk of publications of the unit appeared in journal with much lower impact factors.

The unit has initiated several studies with outstanding features, such as a randomized controlled trial on the efficacy of family therapy for patients with anorexia nervosa, which required data collection over 15 years, and the constitution over 2 decades of a large clinical cohort of eating disorder patients. Given the relatively low prevalence of eating disorders the recruitment of such cohorts is very tedious and typically takes many years. Accordingly the scientific values of such cohorts are very high. The evaluation of psychoanalytic treatments in autism is another example for the originality of the research of the unit given that in this therapeutic field there are hardly data available based on sound methodology.

On the methodological level the attempt to overcome the traditional opposition between the qualitative and quantitative evaluation approach is of high practical and scientific interest.

Since 2008 the group has obtained 1.9 M. € of public grants and 260 k€ from private foundation or companies, which is a very remarkable performance. These external grants constitute the bulk of financial resources for the projects of the unit.

Assessment of the unit's academic reputation and appeal

The unit has gained increasing international reputation in the last years. Its members were principal organizers of 22 international and 13 national congresses and were invited to 131 invited communications outside France since 2008. Two members are chairing or have chaired an international society.

Following the recommendations of the last evaluation of the unit, the team has extended its involvement in international projects. Beside the longstanding collaboration with the GRIP in Montreal, the unit has joint several European projects in its core domain, child and adolescent psychiatry.

Moreover, four members of the unit won national prizes.

Assessment of the unit's interaction with the social, economic and cultural environment Given the high societal impact of mental health issues, the unit has dedicated a large part of time and activity to interactions with society through media or contacts with politicians or directly with citizens. The influence of the unit is high in France, where several members of the team are opinion leaders in child psychiatry, drug addiction and depression, which culminated in more than 60 appearances of members of the unit in media since 2008. Moreover, an online seminar on research in psychiatry was created. The national influence of the unit is also reflected by the participation of several members in national scientific committees or governmental mental health expert committees.

The competence of the unit is also recognized by pharmaceutical companies. Two of them are developing assessment instruments in collaboration with members of the unit. Similarly, 4 randomized controlled trials were coordinated by members of the unit.

Moreover, rating scales to determine depression in dolecence and canabis use developed by the unit are now used in clinical settings in France.

Assessment of the unit's organization and life

The particular features of the unit (i.e. most members have a large or even full-time clinical activity) requires a very pragmatic organization of the unit's life given that the members have only a very limited amount of time available for regular meetings. In this context, as suggested by the previous evaluation in 2009, organization of the unit around the methodological center is the most promising solution and has been successfully implemented.

Moreover, the particular focus on the follow-up of PhD and Master students appears appropriate.

For the other researchers there are several meetings such as the mandatory "conseils de laboratoire" and "assemblée générale", the "reunion des seniors", the monthly seminar and the annual seminar of the LIA (international unit) as well as a 3-day writing in September. However, as shown by the network analysis of coauthorships, the real glue of the unit in the day-to-day scientific life is provided by the head of the unit and his methodological center, which offers methodological, statistical, administrative and logistic support to all researchers in problems. Both the students and clinical researchers are very satisfied with this flexible and pragmatic organization of the unit.

In contrast, the members of the methodological center (including 2 secretaries and 2 methodology engineers of the unit completed by a half-time secretary and a laboratory technician of the former team of Prof. Gardier), who are crucial for the functioning and cohesion of the unit, are progressively overwhelmed with work given the growing number of collaborators and projects.

Assessment of the unit's involvement in training through research

The unit is affiliated mainly to two Ecoles Doctorales: ED420 (Public Health) and ED158 (Neurosciences) and has a very large educational activity. A total of 42 theses have been defended since 2008 by PhD students of the unit, which is currently supervising 37 new students. Moreover, the director of the unit is also the head of the whole Masters degree in Public Health of the Paris-Sud University and all senior researchers of the unit are involved in courses of the Master or PhD tracks.

Assessment of the strategy and the five-year plan

Although the former focus of the unit will be maintained (patient-focused research with an integrative approach, treatment evaluations, strong interaction with society regarding mental health questions and methodological developments), the five-year plan proposes two major steps:

1. The incorporation of the team EA3544 of Pr. Alain GARDIER (Faculty of Pharmacy, Chatenay-Malabry, University Paris-Sud), specialized in the experimental pharmacology of anxiety and depressive disorders, in order to gain more biological expertise within the public health team and to promote a translational scientific approach.

2. The constitution of 6 teams:

1. Epidemiology of drug use: social and gender inequalities (Mr Stéphane LEGLEYE).

Addiction science (Mr Henri-Jean AUBIN).

3. Depression, plasticity and resistance to antidepressants (Ms Emmanuelle CORRUBLE and Mr Alain GARDIER).

4. Impact of psychotrauma in overseas territories (Mr Louis JEHEL).

5. Adversity Affects and Acquisitions: developmental and interventional perspective (Ms Sylvie BERTHOZ, Ms Sylvana CÔTÉ).

6. Analysis of complex phenomena with qualitative and quantitative approaches: genomics, adolescence and cross-cultural psychopathology (Mr Bruno FALISSARD).

Addiction research, a main domain of expertise of the unit, will be pursued by Team 1 and 2 using both epidemiological and clinical approaches. Team 4 will continue the well-established research on childhood disorders and trajectories and Team 6 is the statistical and methodological core group of the unit. Given the successful evolution of the unit up to this day, maintaining a particular focus on those domains where most expertise was generated is certainly appropriate. The recently constituted Team 3 will bring a new emphasis on translational research into the field of psychotropic medication research, which is a very timely and promising approach, whereas the other new Team 4 is not only geographically less connected to the unit, its scope on psychotrauma in oversea departments also lies beyond the unit's traditional field of expertise.

Given the large size of the unit with the risk of losing coherence, the constitution of formal teams around specific topics is a suitable approach to reorganize the unit around high quality projects with well identified leaders as suggested by the evaluation team in 2009. All teams are headed by very competent leaders and will continue to be supported by the methodological center of the unit. Hence, the five-year plan involves a coherent strategy to further improve the scientific quality of the unit and should culminate in an increasing number of publications in top psychiatric journals. The research topics proposed by the different teams are interesting and sometimes novel. However, almost all teams present too long lists of projects without clear priorities and a clear assignment of team members to the different projects. The concentration of the teams on a limited number of outstanding projects is likely to be a more promising strategy than the dispersion of the work forces and the methodological resources on a too large number of projects of variable scientific value. The integration of the new Team 4, which is spread out over many places far away from continental France, represents a very big challenge. Moreover, the projects of this team are only loosely connected with the traditional major focus of the unit. A reduction of the research axes of Team 4 seems necessary in order to focus the available resources on a limited number of projects with an acceptable scientific quality.

The cohesion of the whole unit and the control of the scientific quality of the multiple projects of the teams should continue to be assured by the outstanding methodological center, which is now grouped into Team 6. However, the members of this team are currently already overloaded with methodological and statistical demands. Given the continuous growth of the unit and the amplification of the number of projects, it will be more and more difficult for the methodological team to exert its federating and supportive function for the whole unit, if this team does not receive additional human resources. The members of this team have published 51 papers since 2008. Some of them were published in specialized international journals such as BMC Psychiatry (IF 2.23), Journal of Affective Disorders (IF 3.8), Drug and Alcohol dependence (IF 3.1), Addiction (IF 4.7), Addictive Behaviors (IF 2), Journal of Addictive Diseases (IF 2). Three publications focused on the CAST instrument, two on the impact of substance use, ten on social risk factors for substance use or prevalence, seven on prevalence and patterns of substance use and three on the identification of substances. A total of 26 publications were unrelated to substance misuse (mainly infectious diseases, medication use, sociology).

Assessment of the unit's academic reputation and appeal

The members of the team have established many national (French regulation and monitoring authorities: INPES, OFDT, INED) and international (Portugal, Italy, Sweden, Germany, USA, Denmark, Norway, Finland) collaborations, which allow them to analyze data collected within large representative surveys. In addition, the head of the unit organized a national symposium in 2012.

Assessment of the unit's interaction with the social, economic and cultural environment

The members of the team have published manuscripts with non-academic associated researchers. Moreover, they have elaborated and validated the CAST, a well-accepted, widely and internationally used self-rating instrument designed for the screening of cannabis abuse.

Assessment of the unit's organization and life

As this team has not existed before, the unit's organization and life cannot be evaluated.

Assessment of the unit's involvement in training through research

Two doctoral students defended their theses in the previous years and the team currently includes 1 PhD student and 1 post-doctoral fellow. The team members also organize training for PhD students in the unit.

Assessment of the strategy and the five-year plan

The team proposes research projects in three main domains. The first domain, Diffusion of drug use, is particularly interesting and original. This research will be based on surveys and sophisticated multilevel statistical analyses. Many investigation proposals focus on new problems. The second domain, Associations of drug use with some major public health concerns, is more traditional, but numerous interesting questions are addressed. The last domain, Survey methodology and development of screening tools, is mainly focused on the validation of the CAST.

Although a large number of projects are proposed, the plan is original and consistent. The feasibility of the projects is good as many projects involve the use of already collected data and are based on the collaboration with non-academic partners from national agencies. Some studies have already started with European or US partners.

The second domain, Associations of drug use with some major public health concerns, may partially overlap with the domain "prevention" of the addition science team given that the two teams are working on assessment tools.

Conclusion  Strengths and opportunities:

The team is well balanced between experimented researchers who have the necessary expertise to successfully complete projects and young scientists. Several members are involved in monitoring for national agencies.

The team will be able to use already collected data where first analyses have already been completed.

Large sets of data derived from numerous national and international collaborations will be available and will allow the researchers to conduct comparisons across various countries.

 Weaknesses and threats:

Some projects are only loosely associated with the main objectives of the team.

 Recommendations:

The team should focus on well-structured projects based on already collected data or data derived from collaborations, such as national surveys.

Given the small size of the team and the partial overlap of projects with the addiction science team, a strong collaboration between the two teams is advocated. The team has published two dozens of reviews and letters, which mostly appeared in international peerreviewed journals, and more than 50 original publications which are clustered around specific topics. Several of the original publications appeared in international journals with high impact factors.

The reviews and educational papers published in international journals cover a large part of the addiction medicine field, most articles though being related to tobacco smoking (11 articles) and alcohol use disorder (5 articles). The remaining reviews were related to cocaine, opiates, general psychiatry, or to general addiction topics (8 articles). Also, the capacity of the team-members to publish letters in the medical journals with the highest impact factors and case reports (5 articles) may be seen as a particular capacity to react on the ongoing scientific developments in the domain.

The original publications can be classified into the following clusters:

(A) 21 smoking-related articles, including papers in international journals with high impact factors: Members of the teams have published as first or last authors papers on the pharmacotherapy of nicotine addiction (with one meta-analysis with a first authorship of the team leader published in BMJ, on neuroimaging studies as well as on epidemiology and psychometrics.. They have furthermore participated as co-authors in further publications on smoking;

(B) 13 publications related to alcohol use disorder: While the team has played a central role in larger pharmacotherapy trials (as indicated by first-authorships of 2 publications), it has also participated through co-authorships in studies on neuropsychology, pharmacotherapy, epidemiology, neuroimaging and psychometry;

(C) A wider range of 17 publications as authors or co-authors of other addiction topics: on cocaine, cannabis, general addiction science issues, general neuropsychiatry topics of general medicine and medical education and spirituality.

Summing up the original publications, studies on nicotine addiction (and particularly pharmacotherapy-trials and epidemiological analyses seem to be topic which has given the highest scientific visibility to the group during the last years. This has recently be completed by medium-to high-impact publications on alcohol addiction. Thus, the main research competence seems to be currently in the field of legal drugs.

Assessment of the unit's academic reputation and appeal

Leading members of the team had leading roles in the organization of international conferences on smoking (Society for research on Nicotine and Tobacco Europe), and alcohol use disorder (International Society of Biological Research on Alcoholism). They are regularly and increasingly invited for conferences in Europe and abroad.

The team leader received three prizes and Mr Michel REYNAUD one. More specifically, they received prizes from the Académie Nationale de Médecine for their work on alcoholism prevention in 2012 and 2006, respectively.

The team organizes a yearly international conference (Les journées Albatros) gathering leading speakers from Europe and North America.

Assessment of the unit's interaction with the social, economic and cultural environment Different members of the team are regularly invited by TV, radio and the written press and play a central expert role in France regarding all forms of addiction. Moreover, numerous publications in French journals indicate the capacity of the team to resume current knowledge in a widely intelligible way.

The team leader received public grant from ANR in 2012 and private grants for the development of a selfreport questionnaire for alcohol use disorder and 3 randomized controlled trials. One of the team members is coordinator for a randomized controlled trial.

The team leader is presently developing a scale to measure quality of life in alcohol abuse in collaboration with Lundbeck.

Assessment of the unit's organization and life

As this team has not existed before, the unit's organization and life cannot be evaluated.

Assessment of the unit's involvement in training through research

The team is actively involved in the training of PhD students (3 current PhD students) and two dissertations of PhD students of the team have recently been defended.

Assessment of the strategy and the five-year plan

The creation of the Addiction Science team aims to coordinate projects in the field and improve the scientific attractiveness. The separate constitution of separate teams for more clinical Addiction Science and the Epidemiology of Addiction can be justified by the current publication activities and the specific technical skills of the two groups, an intensive and somewhat formalized interaction of the two teams could be particularly fruitful, as the Addiction Science team has already shown to be able to perform and prominently publish epidemiological projects.

As the team leader indicated during his presentation, the team aims not only to strengthen its currently principal research activities (related to nicotine and alcohol addiction) but also intends to give junior researchers the opportunity to develop their own research domains. While this comprehensive approach may have the advantage to more easily attract clinicians to research, it may become too cumbersome if too many and potentially divergent new methods need to be developed.

Conclusion

 Strengths and opportunities:

The group comprises several high profile researchers who have shown their ability to persistently produce high impact publications. Furthermore the team can currently be considered as the reference in France for all clinical and social issues related to drug consumptions and addictions. The group has strong links to the clinical practice as all its members are also active clinicians.



Weaknesses and threats:

The team's very eclectic approach may become a frailty. The definition of a clearer strategy forming the backbone of its various activities could counterbalance an otherwise potentially tedious tendency to energy diffusion. Also, the slip of its members between clinical and research activity can represent a particular challenge.

The geographical remoteness with regard to most of the other teams of the unit may represent a further challenge regarding the coordination of the activities with partner teams.



Recommendations:

A more focused strategy could help to bundle the rich and diverse activities and plans of the team. The activities could cluster around a specific topic, such as a specific addictive product (e.g. nicotine, alcohol) or specific research areas (e.g. pharmacotherapy, psychometry). This strategy should preferably be brought in line with the general strategy of the unit. The scope of new projects -be they generated by the unit itself or proposed from outside-should firmly be verified regarding their coherence with the unit's strategy.

A strong involvement of the team leaders into the coordination of the whole unit is likely to boost their contribution to projects across teams, motivate the recruitment of new researchers, and help to further develop coherent and feasibly research axes. Both PIs performed high quality research in their respective fields, as demonstrated by their bibliography and academic performances. The bibliographic analysis shows that both teams already efficiently collaborated during the past years, as demonstrated by the recent article published in Front Pharmacol (2013) on beta-arrestin.

Ms Emmanuelle CORRUBLE was the head of a team focusing on three main subjects: 1. Clinical psychopharmacology of antidepressants (agomelatine, citalopram), hormonal consequences, pharmacogenetics; 2. Depression -organ transplantation and other somatic problems; 3. Bereavement and depression (partly in relationship with DSM V). This team produced almost 3 dozens of papers, and in particular about 20 original papers published in good or excellent journals in the field of clinical psychiatry/psychopharmacology/epidemiology. About a dozen are full papers, and half a dozen short reports/letters (1 page).

Mr Alain GARDIER's team produced 39 peer-review articles, 4 book chapters and one patent regarding the CORT model. Several of these articles were published in high-ranked journal (IF>10). Although most of these papers were made in collaboration with an outstanding American unit, the contribution of the Gardier team was highly significant. In these articles the CORT mouse model of depression and transgenic mice was used. In particular, the authors showed that chronic antidepressant treatment reverse the phenotype of depression in the CORT model. They also demonstrated that the efficacy of fluoxetine was prevented only in some but not all behavioral paradigms after abolition of hippocampal neurogenesis, indicating that part of the action of the antidepressants is not mediated by this way. Moreover, they identified potential targets for treatments linked with serotonin and/or BDNF like the Barrestins signaling pathway and huntingtin. Finally, they also characterized the effect of new antidepressants like agomelatine, vortioxetin and indatraline in mice models.

Assessment of the unit's academic reputation and appeal

Ms Emmanuelle CORRUBLE was invited to give oral talks on depression at 5 international meetings (Asia, USA, Finland and other European countries), whereas Mr Alain GARDIER or members of his teams were invited to give oral talks on depression at 4 international meetings (USA, Spain, Turkey, UK).

Assessment of the unit's interaction with the social, economic and cultural environment

Ms Emmanuelle CORRUBLE participated several times to public debates and interviews in France. She is also involved in the organisation of national psychiatric congresses, in France and at the European level (European Association of Psychiatry).

Mr Alain GARDIER's team has obtained 17 contracts with pharmaceutical companies to study the mechanisms underlying the physiopathology of anxiety and depressive states as well as the mechanism of action of new antidepressive and anxiolytic drugs.

Assessment of the unit's organization and life

The team did not exist in this form before and therefore this issue cannot be evaluated.

Assessment of the unit's involvement in training through research

Ms Emmanuelle CORRUBLE's team has one scientist who successfully defended her PhD in the field of pharmacogenetics. There is another PhD candidate and one post-doc. Mr Alain GARDIER's team has 8 scientists who successfully obtained their PhD, four PhD candidates and three post-docs.

Assessment of the strategy and the five-year plan

The creation of the new team is very promising, as it will strongly favour translational collaboration between highly competent clinical and basic scientists.

The proposed research topics involve neurobiology and treatment of depression, and essentially includes two major axes. The first axis which is mainly based on a bottom up approach (from animal to human research), aims at the identification of markers and predictors of the response and resistance to antidepressants in major depression.

The second axis 2, which is mainly based on a top down approach (from human research to animal models) focuses on innovative therapeutic strategies. Both older drugs (citalopram, fluoxetine) and new compounds will be studied (vortioxetine), which is a very useful approach as it will enable comparisons between drugs representing different generations of antidepressants.

Conclusion

The project of this new team is relatively homogenous, centered on mainly one mental disease (depression) and represents a promising translational strategy. Despite this represents the project of a new unit, some articles were already published in good journals as the result of a team work (Front Pharmacol Res 2013). This translational collaboration is already ongoing and should be encouraged.

 Strengths and opportunities:

The project of this new team is relatively homogenous, centered on mainly one mental disease (depression) and represents a promising translational strategy.

The two team leaders are renowned experts in their scientific domains and they have already started their translational collaboration, which led to common publications in good journals.

The study of the role of arrestins in depression is an understudied topic as only few teams focus on this topic outside of Israel.



Weaknesses and threats:

The clinical projects are very ambitious, and their completion requires important efforts. However, the feasibility of the projects is difficult to evaluate, as the used cohort and samples are not described in detail in the proposal (no description of available control groups, selection of the patients, definition of response, resistance, treatments and evaluation procedures).

The experts are not specialists in the field of arrestins.



Recommendations:

As these projects are already ambitious, there is the risk that too many subprojects are included. It may be useful to focus efforts on a restricted number of projects. Moreover, given the different localization of the clinical and the basic science researchers, particular efforts should be made to assure the coordination between the two subteams. The number of PhD students should be increased in Ms Emmanuelle CORRUBLE's team if possible. Given that this new team was not part of the former unit and no information regarding the scientific output of the members was available in the printed report, the scientific quality and outputs could not be evaluated.

Assessment of the unit's academic reputation and appeal

The team leader and one of his team members are well known in the area of psycho-trauma.

Assessment of the unit's interaction with the social, economic and cultural environment

As this team has not existed before, the unit's organization and life cannot be evaluated.

Assessment of the unit's organisation and life

As this team has not existed before, the unit's organization and life cannot be evaluated.

Assessment of the unit's involvement in training through research

As this team has not existed before, the unit's organization and life cannot be evaluated.

Assessment of the strategy and the five-year plan

The objective of this team, led by different professors or researchers at different locations, is to estimate the prevalence and the impact of psychotrauma in overseas territories. The strategy is constructed around four research themes: 1) individual traumatic life events (traffic accidents, assault, and stroke), 2) addictions (cocaine/crack), 3) suicide and 4) naturals disasters. Accordingly, the five-year plan covers a rather heterogeneous spectrum of PTSDrelated research topics. 1) Individual traumatic life events including stroke: According to the description of this subproject "multimodal sensor systems (that) will combine Body Sensor Networks (BSN) and Speech analysis (…) for movement and cognitive states (…) among 40 patients" (p. 34, 1 st para). However, the inclusion of stroke in this subproject is problematic given that stroke is not a typical event for studying the pathogenesis of PTSD or treatment processes. Indeed, it is still not established whether stroke can precipitate the full PTSD symptom pattern in the usual time frame of PTSD development and maintenance, because the spontaneous remission rate of such illness-related PTSD is usually higher than in more typical, violence-related PTSD. Moreover, this subproject is not accurately described and a specific research question is missing. Accordingly, the questionable scope combining stroke, PTSD and a multimodal sensor systems and the small a small sample size affect the quality of this subproject.

2) Cocaine/crack addiction: This sub-project focuses on trajectories of the development of disorder and comorbidity within the TV-CRACK study. Neurobiological (e.g., genetic) and neuropsychological processes underlying the association between crack dependence and PTSD will be studied, which seems quite far away from the main objective of this team. Given the relatively small sample size a state-of-the-art assessment of possible traumatic trajectories according to trauma characteristics (repeated vs. single trauma; childhood vs. adolescent vs. adult trauma; man-made or accidental trauma) is feasible. Hence, this sub-study may be premature.

3) Suicide prevention: The proposal mainly describes the elevated suicide/suicide attempt rates in French oversea departments, but does not provide a satisfactory justification for combining suicide and PTSD research. It is stated that 44 % of suicidal patients have a history of psychological trauma (p. 35, 6 th para). However, there is no information on the reliability or validity of these data. Accordingly, prior to the establishment of prevalence or course data the researchers should rather focus on the reliability or validity of the assessment of traumatic events including cross-cultural presentations of trauma reports or PTSD (see: Hinton, D. E., & Lewis-Fernandez, R. ( 2010). Idioms of distress among trauma survivors: Subtypes and clinical utility. Culture, medicine and psychiatry, 34(2), 209-218). A second sub-project assessing the efficiency of a psycho-educational program in mental disorder patients with suicidal behavior could contribute to the accumulation of increasing knowledge in this area. Similarly, a third sub-project focusing on health care cost estimations seems generally useful. 4) Natural disasters: This project tries to overcome limitations of previous epidemiological studies in this area. It uses proper epidemiological methods and follow-ups. Data collection is already completed and analyses are ongoing. However, data have been collected in the Haitian community of Miami-Dade county, which may limit the generalisability of the findings.

Conclusion

 Strengths and opportunities:

The proposed projects are interesting from the cross-cultural perspective as they address PTSD-related topics in an under-studied geographical area. The combination of mental health and health economic research is valuable approach.

 Weaknesses and threats:

The coherence of the projects is lacking and a 'flagship' project that may serve as a core study is missing. Moreover, cross-cultural aspects-as discussed and addressed by outstanding research groups in this area: e.g. at Harvard University-are not considered in this proposal.

There may be considerable variance across populations in the overseas territories.

Team members are based on many locations, which is likely to make collaborations and day-to-day team life difficult.

There is a lack of full time EPST or EPIC researchers and there is only one Research Associate from Bordeaux.

 Recommendations:

Research questions need to be more accurately defined.

Prioritizing of projects is needed. It seems reasonable to concentrate the efforts on one (PTSD prevalence and its predictors) or at maximum two main research questions (PTSD and suicidality).

Given the localization of the team members a particular effort is necessary to build and maintain coherence across the team as well as between the team and the methodological center of the unit.

Assessment of the unit's academic reputation and appeal

The academic reputation and appeal of this team is excellent as evidenced by 14 invitations to international congresses and the number of 7 post-doctoral researchers and 7 currently engaged PhD students.

Assessment of the unit's interaction with the social, economic and cultural environment Part of the activity of this team is deliberately oriented towards interventions and prevention programs. For this reason, there are many interactions with medico-social structures such as Mother and Child Protection Services (PMI), hospitals, etc. Moreover, one of the team leaders is member of several mental health expert groups in France.

Assessment of the unit's organization and life

As this team has not existed before, the unit's organization and life cannot be evaluated.

Assessment of the unit's involvement in training through research

The number of qualified research supervisors is impressive (n=9) and as a consequence there are many Phd students. This is strong feature of the team.

Assessment of the strategy and the five-year plan

The research program of the team "3A" aims at: 1) understanding the factors underlying health behaviors (psychoactive substance use and misuse, nutrition,..), mental health (depression and eating disorders), and psychological adjustment (school success, criminality); 2) testing the efficiency of tailored treatments.

Being aware of the complexity of the mechanisms underlying these outcomes and the challenges to develop treatments or prevention programs, the strategy of this team to embrace different theoretical and methodological expertise. Indeed the multidisciplinary team has expertise in developmental psychology, psychiatry and neurology, developmental epidemiology, clinical epidemiology, and cognitive-affective neuroscience. The five-year research plan is ambitious, well described and the team has the resources to carry out the proposed projects. The three main research axes are as follows:

Axis 1: developmental epidemiology: risk factors for mental health problems and preventions programs:

The first part focuses on the relative importance of different risk factors, their developmental sequence from conception to adulthood, and the neurobiological consequences of early adversity. Developmental trajectories will be studied using several large-scale longitudinal data sets from France, UK, Ireland, Canada and US. From a methodological point of view, the use of data sets from different countries is a suitable approach. However, it remains unclear whether it will be possible to examine the same research questions and with the same measures in all cohorts. Finally, it needs to be clarified how the relative importance of risk factors for mental health in different cohorts will be studied.

The scope of the second part this research axis will be the evaluation of preventions programs, and the identification of factors involved in resistance to change. The objectives are to examine the extent to which services dedicated to early childhood care can reduce the risk of health and educational problems in high-risk families. The magnitude of the impact of care as a function of the timing (prenatal vs. post-natal) will also be determined. The feasibility of the projects of this sub-axis is very high as they are based on existing and ongoing experimental prevention programs. The results of one the programs already have contributed to the modification of the Paris "Mother & Child Protection Services" (PMI) organization for 2014-2020 period.

Axis 2: typical and altered neurodevelopment

The first aim in this axis is to specify and understand the neuropsychological and behavioral profiles of acquisition and acquisition disorders (i.e. cognitive, motor human development and learning disorders) as a function of pathological and environmental factors in both general population and clinical samples. The use of both clinical and community data is highly interesting and has a potential to shed some light on the underlying mechanisms of these disorders. The perspective of using medico-administrative databases (SNIIRAM) to study mental retardation and chronic psychiatric diseases in childhood and adolescence is also promising.

The second aim of this axis concerns planned intervention programs focusing on time perception and knowledge, brain tumors and neuropsychological dysfunction. Functional neuroimaging and genetics will be part of this vaguely described sub-project.

Axis 3: Disordered eating behaviors: clinical and general epidemiology and interventions programs

The first aim of this axis is to study the etiology of eating disorders and to know whether different subtypes represent entities or stages of the disorder. Both cross-sectional and longitudinal studies will be conducted to investigate risk factors associated with the emergence and/or severity and/or maintenance of disturbed eating behaviors. However, the rational for using cross-sectional data to study the etiology of eating disorders is doubtful. The project also mentions that a new collaboration has been established with the objective to set up an ancillary study on the prevalence as well as the somatic and psychological impact of disturbed eating behaviors based on data of the prospective CONSTANCES study. However, there is no guarantee that eating disorders according to the DSM classification can be established in this study.

The second aim of the third axis will be translation of fundamental knowledge into treatment. To do so, randomized control trials will be conducted in addition to clinical real-work treatment evaluation. The feasibility of these projects is very high given that two trials have already been initiated.

Conclusion

The strategy and research plan of this team is appropriate and the chances of success are good.

 Strengths and opportunities:

Experienced full-time researchers alongside with professors of medicine and clinicians, which guaranties a well balanced team.

There are multiple participations in various national and international long-term longitudinal studies, which offer access to national, international databases.

The team has a high level of multidisciplinary team with a strong clinical and epidemiological approach.

Interventions programs constitute a unique and innovative feature of this team.

The team has chosen an interesting translational research perspective.

Access to and participation in many national, international databases.

 Weaknesses and threats:

Role of team members in the specific axes not clearly determined. For this reason their contributions are difficult to appreciate.

 Recommendations:

The identification of specific areas of leadership in international projects would strengthen the team.

Given the use of multiple databases across countries, a comparative approach in order to get insight into the generalizability of the findings is also recommended. The members of this team have had a impressive academic output with approximately 200 articles since 2008 mostly in peer-reviewed international journals of various medical domains including mental health and psychiatry, genetics, cancer research, pediatrics, dermatology, pharmacology, psychosomatics, internal medicine and rheumatology, which reflects the high recognition of the methodological expertise of the team beyond the domain of mental health. Some of the articles with methodological contributions of the team leaders appeared in the most prestigious medical journals including The Lancet as well as in psychiatric top journals. The articles either focused on methodological issues or profited from the methodological and statistical contributions of the team. The international reputation of the team is also evidenced by more than 60 invitations to national and international conferences since 2008.

Assessment of the unit's academic reputation and appeal

The scientific contributions of this team are highly recognized in the community of researchers in psychiatry, but also in psychology, and in the whole field of human behavioral research.

Members of the team are involved in several collaborative projects (QUALIGRAMH, research network for the evaluation of psychodynamic interventions; INCANT study), the organization of national and international meetings and congresses and Mr Bruno FALLISARD is chairing an international association (IACAPAP). Moreover, Ms Marie-Rose MORO is the scientific director of the transcultural journal : "L'autre, Cliniques, Culture et Sociétés".

The biostatistical models developed by the team have multiple applications, e.g. models established for genomic analysis are used in oncology genomic, but also in therapeutical trials.

Assessment of the unit's interaction with the social, economic and cultural environment Members of the team are present in national media and are involved in national and international campaigns for the prevention of psychological distress in children and adolescents (e.g. Médecins sans frontières).

Assessment of the unit's organization and life

The team represents the methodological center of the whole U669, which is best reflected by the central position of the head of the unit according to the network analysis of co-authorships. The axes of the methodology team are under the direction of the three senior members: Mr Philippe BROËT for biostatistical methods, Ms Marie-Rose MORO for cross-cultural psychiatry, Ms Anne REVAH LEVY for adolescents studies. The team offers methodological, statistical, and logistic support to the researchers of all the teams of the U699 mostly through direct contacts.

Assessment of the unit's involvement in training through research

The team is very strongly involved in training, organizes specific research seminaries and supervises masterlevel (biostatistics, genomics and genetics) and PhD students. During the last 5 years 20 theses supervised by members of this team have been defended in the past 5 years and currently 26 PhD students are working in the unit. Almost all senior members of the team are participating in training and teaching.

Assessment of the strategy and the five-year plan

The team proposes eight projects for the years 2015-2020: one in molecular biology, 2 that use text mining and content analysis, 2 are new measurement instruments (related to cross-cultural phenomena) and 2 are purely qualitative studies. Highly interesting and novel topics are the development of statistical tools to overcome the traditional opposition between the qualitative and quantitative evaluation approach and analysis models that are not based on the traditional p-value as well as multifocal hermeneutic and spin glass models. These methods are likely to be very useful for the analyses of complex data in multiple domains of social and medical science.

Conclusion  Strengths and opportunities:

The team has an excellent reputation in methodology and statistics in the field of psychiatry and human behavior science.

The team has created a strong methodological and statistical platform which is involved in analyses of a large array of scientific domains. Such a platform is quite unique in France.

The team has an original scientific approach in the development of new statistical analyses tools.

 Weaknesses and threats:

The team is heterogeneous. Although the roles of the three senior researchers are well defined, the contributions of the other members to the proposed projects is not clearly specified. Moreover, the level of publications varies considerably across team members.

There is a risk that the team will not be large enough to assure the methodological support for all the new teams within the still growing U699 in the next years.

 Recommendations:

This team deserves additional resources in order to be able to continue to provide the necessary methodological and statistical support to the increasing number of the projects of the unit. In order to face the challenge of increasing demands for methodological support the team should better define its priorities and the role and position of each team member.

  5/ Longitudinal interventional studies: eating disorders, attachment relationships, (axes 1 and 2) Ms Sylvana CÔTÉ 6/ Determination of emotional endo-phenotypes (axis 1), Ms Sylvie BERTHOZ 7/ Psychiatric epidemiology in adults (axis 2), Ms Isabelle GASQUET 8/ Psychotropic medication: clinical and epidemiological evaluation (axis 2), Ms Emmanuelle CORRUBLE 9/ Neurodevelopment and learning disorders (axis 2 and 3), Ms Laurence VAIVRE-DOURET 10/ Complex identity construction / Transcultural psychiatry (axes 2 and 3), Ms Marie-Rose MORO 11/ Research methodology in psychiatry (axis 3), Mr Bruno FALISSARD 12/ Qualitative methods (axis 3), Ms Catherine JOUSSE

N3:N4:

  Permanent researchers from Institutions and similar positions NA 6 Other permanent staff (without research duties) NA 9 Other professors (Emeritus Professor, on-contract Professor, etc.) NA N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.spent at least 12 months in the unit 11 Number of Research Supervisor Qualifications (HDR) taken 8 Qualified research supervisors (with an HDR) or similar positions 25 NA 2  Assessment of the interdisciplinary unit Strengths and opportunities related to the context

4N3:N4:

   Team-by-team analysis Team 1 : Epidemiology of drug use: social and gender inequalities Name of team leader: Mr Stéphane LEGLEYE Permanent professors and similar positions NA 1 N2: Permanent EPST or EPIC researchers and similar positions NA 1 Other permanent staff (without research duties) NA 4 Other professors (PREM, ECC, etc.) NA N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsspent at least 12 months in the unit NA Number of Research Supervisor Qualifications (HDR) taken NA Qualified research supervisors (with an HDR) or similar positions NA  Detailed assessments Assessment of scientific quality and outputs

  Permanent professors and similar positions NA 4 N2: Permanent EPST or EPIC researchers and similar positions NA N3: Other permanent staff (without research duties) NA 5 N4: Other professors (PREM, ECC, etc.) NA N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, spent at least 12 months in the unit NA Number of Research Supervisor Qualifications (HDR) taken NA Qualified research supervisors (with an HDR) or similar positions NA  Detailed assessments Assessment of scientific quality and outputs

N4:

  Permanent EPST or EPIC researchers and similar positions NA N3: Other permanent staff (without research duties) NA 9 Other professors (PREM, ECC, etc.) NA N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.spent at least 12 months in the unit NA Number of Research Supervisor Qualifications (HDR) taken NA Qualified research supervisors (with an HDR) or similar positions NA  Detailed assessments Assessment of scientific quality and outputs This is a new team within INSERM U669, co-headed by Ms Emmanuelle CORRUBLE and Mr Alain GARDIER, with the goal to create a strong translational team on depression linking studies in mice models with clinical trials. It will also bring animal research expertise to the INSERM U669. EC was a clinical researcher of INSERM U669 and Mr Alain GARDIER was heading a team (EA 3544) outside of the U669 in the Faculty of Pharmacy of University Paris Sud. For this reason, the evaluation of the new team is only partially feasible.

N3:N4:

  Permanent EPST or EPIC researchers and similar positions NA 1 Other permanent staff (without research duties) NA 9 Other professors (PREM, ECC, etc.) NA N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsspent at least 12 months in the unit NA Number of Research Supervisor Qualifications (HDR) taken NA Qualified research supervisors (with an HDR) or similar positions NA  Detailed assessments Assessment of scientific quality and outputs

N3:N4:

  and Acquisitions: developmental and interventional perspective Name of team leader: Ms Sylvie BERTHOZ and Ms Sylvana CÔTÉ Workforce Permanent EPST or EPIC researchers and similar positions NA 3 Other permanent staff (without research duties) NA 3 Other professors (PREM, ECC, etc.) NA N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsspent at least 12 months in the unit NA Number of Research Supervisor Qualifications (HDR) taken NA Qualified research supervisors (with an HDR) or similar positions NA  Detailed assessments Assessment of scientific quality and outputs With more than 170 publications since 2008 the scientific quality of this team in psychometric tools development, behavior problems in children, eating disorders is indisputably high. The scientific output and its quality are excellent as indicated by several publications in the most prestigious psychiatric journals including Molecular Psychiatry, Archives of General Psychiatry and American Journal of Psychiatry.

N3:N4:

  Analysis of complex phenomena with qualitative and quantitative approaches: genomics, adolescence and transcultural psychopathology Name of team leader: Mr Bruno FALISSARD Workforce Permanent EPST or EPIC researchers and similar positions NA 1 Other permanent staff (without research duties) NA 5 Other professors (PREM, ECC, etc.) NA N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitorsspent at least 12 months in the unit NA Number of Research Supervisor Qualifications (HDR) taken NA Qualified research supervisors (with an HDR) or similar positions NA 6  Detailed assessments Assessment of scientific quality and outputs

  members, AERES scientific delegate, representatives of Université Paris sud (Prof. Mr Etienne AUGÉ, vice-président, Prof. Mr Jacques YOUNG, faculté de médecine, Hôpital Bicetre), Université Paris-Décartes (Ms Catherine LABBÉ-JULLIÉ, assistante du vice president de la recherche) and of INSERM (Ms Christine GUILLARD), without the direction of the unit and without team leaders 4. Meeting with representatives of the doctoral schools 1:00 pm Discussion with committee members Attending: Committee members and doctoral schools representatives (Mr Jean BOUYER, directeur de recherche à l'INSERM, Prof. Catherine DUBERNET, directrice adjointe à l'École Doctorale Innovation Thérapeutique de l'Université Paris-Sud). members, AERES scientific delegate, without representative of institution, without the direction of the unit and without team leaders 6Besides those already mentioned, the committee also met other representatives of the insitutions Mr Jean BOUYER, directeur de l'école doctorale ED 420 Ms Catherine DUBERNET, directrice de l'école doctorale ED 425 Mr Jasques JOUNG, UFR médecine Paris-Sud Ms Catherine LABBE-JULLIE, Université Paris-Descartes

 Observations générales des tutelles

1 ,  Mr.