Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team. Criterion 1 -C1 : Scientific outputs and quality ; Criterion 2 -C2 : Academic reputation and appeal ; Criterion 3 -C3 : Interactions with the social, economic and cultural environment ; Criterion 4 -C4 : Organisation and life of the institution (or of the team) ; Criterion 5 -C5 : Involvement in training through research ; Criterion 6 -C6 : Strategy and five-year plan.

UMR 728 integrated specific research themes on GVH associated tumors and response of cancer to anti-angiogenic treatment. While in the early times the unit was dispersed in 3 locations in adjacent buildings, it has recently been regrouped in a single location within the renovated portion of the IUH. It is also mentioned in the report, with no further detail on the administrative status nor description of the facility and staff involved, that the team of Mr RAYMOND at the Hospital Beaujon in Clichy is associated with the Unit. Hence, UMR-S 728 associates several teams on separate locations over 5 kms apart.

Management team:

The unit is directed by Ms Anne JANIN. No detail given on the persons or group of persons assisting her in the management. No management structure (Codir, CoLab, SAB) is specified. At the scientific level:

AERES nomenclature:

-Most (more than half) of the publications in which the Unit has a lead role correspond to work on GvH by a scientist who has left the unit and it was understood that the GvH theme was going to an end in the unit. The programmed termination of this leading theme opens questions concerning future developments.

-The strategy concerning the improvement of anti-angiogenic treatments was not clearly defined and no associated resources justified.

-The nanoparticles project requires strong scientific support and long-term resources to achieve its goals at the clinical settings.

Recommendations:

-Need to build a management team which include PIs, -Need to define a strategy, identify priorities and reduce the number of themes for the coming 3 to 5 years and focus resources accordingly, -Formalize the position of and the projects developed by the scientists in the lab besides the team leader.

 Detailed assessments

Assessment of scientific quality and outputs:

Over the period 2007-2012 300 papers and review articles have been authored or co-authored by members of the unit, of which 120 published in journals with IF>5. However, 34/300 have members of the Lab as first or senior authors and were therefore actually produced by the unit 728. Most high impact publications (JCO or NEJM) have been published by one co-author among a relatively large list of clinically collaborating groups. Hence, the scientific output of the unit is judged as fair for a unit of that size.

Assessment of the unit's academic reputation and appeal:

Ms Anne JANIN is an energetic leader, whose action has led her to work with international working groups on biobanking. In addition she has set up an active and long standing cooperation with the University and Hospital of Shanghaï, Jiao Tong University. The strong links that have been established with Shanghai and have persisted since are a clear sign of appeal at the international level. The lab has trained a number of chinese PhD and MD students that have since obtained position and started a carrier in Shanghai.

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

The unit has been active on the valorisation side having filed several patents, some of them being licenced. CIFRE contracts and ongoing contracts with industrial partners. The development of virtual slides and micro-dissection programs and their dissemination is to be noted. Furthermore, several members of the unit, including the director, have participated to radioshows on science or medical matters.

Assessment of the unit's organisation and life:

The unit is presented as a single team/single theme (mono-équipe/mon-thématique) and it is an apparent will of the director to keep this organizational model for the next period. The report's structure does not make mention of specified themes nor of identified groups. However, it was apparent that several projects are developed in the unit, with no clear mention of the PI in charge and the human resources or budget allocated to it. Some points were clarified during the visit allowing to identify two broad research lines, (1) Cancer in transplanted patients, (2) Response to therapy. But globally the scientific management did not appear to follow predefined directions, and the unit's formal organisation should be clearly defined on the basis of the scientific projects.

A-Cancer in transplanted patients

This theme was central to the previous term and has made the reputation of the unit. Investigators contributed to the characterization of TH17 infiltrates in GvH target organs in humans. The team also contributed to the demonstration of the presence of cells of donor's origin in epithelial cancers occuring in recipients of allogenic hematopoietic cell transplantation. The unit has shown that tumors which occur secondary to tissue allograft comprised cells contributed by the graft resulting in chimeric tumors. This work was very largely contributed by a scientist who has left the unit in 2012, putting future developments on this line of research in question. It was not clear whether or not this line would be continued and who was in charge. A further point of concern was the overall lack of in vivo or in vitro models. Most results are description of phenotype or genotyping. If this line of research were to be continued it would be recommended to acquire expertise in the field of pathological assessment of immune cell infiltrates.

B-Response to therapy

This theme covers a rather diverse range of projects with different PIs in charge and different approaches.

1-Lymphoma.

The scientist in charge has an outstanding track record at both the clinical and research level (52 publications on lymphoma therapy topic since 2007, including high IF papers, NEJM, Lancet, JCO, Blood…). She investigates agressive B cell lymphomas with cerebral relapse and aims at improving the therapeutic response. This theme deals more specifically with MCL and Myc positive DLBCL and plans to perform combined transcriptome analysis and PET scan imaging. This project is said to involve both clinicians and researchers with no further detail on the personnel (technicians, docs or post docs) nor funds allocated to it. Links with the associate international laboratory of Shanghai Hematology Institute were mentioned with 4 shared PhD students (2 and 2) by both groups within 5 years. This collaboration produced 10 publications since 2007, none with the PI heading this program. Plans are to continue gene expression profilings with human samples and murine models, in search for genes associated with therapeutic response (such as PRDM1 & resp to anti CD20 (RTX) and to bortezomib). It was regretted that this high quality program has no identified staff, team and funding, at least from what the panel understood. Precise delineation of structures, roles, and means involved by the unit on the lymphoma research project should be considered in order to give this project the position it deserves according to its very good publication record.

2-Projects in the field of clinical oncology.

These projects are under the responsibility of a clinical oncologist acting at the Hospital Beaujon in Clichy. Original plans were that he would join Hosp St Louis as Chief of Medical Oncology, explaining why he joined the unit. Things went differently but links remained. This scientist has a good track record and has contributed to good papers (NEJM, Clin Cancer Res). His work has allowed to validate the administration of sunitinib (anti-angiogenic) and mTOR inhibitors in the treatment of chemoresistant renal and digestive track cancer. This clinical research activity is associated to biomarkers studies that are being developed within a laboratory (pharmacobiologie des anticancéreux, Hopital Beaujon). Aims of these studies are focused on EMT and its effector or inducing factors. Besides the preclinical assessment of new therapeutic compounds, no hypothesis or perspective were clearly defined in the written report or during the meeting. Of note, the scientist in charge has created a small company which valorizes some of these studies and subcontracts with pharmas. It was felt that care should be taken to draw the exact line of divide between the academic and commercial activities. Globally, the dynamism and the quality of the production of this scientist was positively acknowledged. It would certainly gain from a better definition of objectives and priorities, both at the level of the project per se and for what concerns its interrelations with the rest of the unit.

3-Protein-protein interactions linked to apoptosis.

These projects are under the responsibility of a scientist that has just joined the unit coming from the UMR 940 located at the IGM, rue Juliette Dodu, Paris. He originally joined the UMR940 as a Avenir young investigator and developed a project on protein-protein interactions linked to apoptosis. His objective is to identify small molecules that would disrupt these interactions. He has a good track record in his field. His project was presented on a poster (out of 15 of diverse impact), thus, the committee could not evaluate its potential in depth. It seems, however, that this full time researcher is entitled to develop a specific line of research and should be helped to do so.

4-Nano-particle as a tool in targeted therapy;

this project is developed in collaboration with a laboratory at the ESPCI (Ecole supérieure de physique chimie industrielle) which brings its expertise in the conception and assembly of the nanoparticles. INSERM U728 brings the tumour and the targeting models. The starting idea is to coat the particles with antibodies recognizing cancer stem cells and take advantage of the iron heart of the particles to concentrate them by means of a magnetic field at specific sites of the body where tumors or metastases reside. This project is at a rather early phase of its development and its high level of potential was underlined by the committee. The committee also recommended that great attention be put into the control of the Ig-coupling reactions and the choice of the antibodies used in the coating. This is given the fact that cancer stem cell markers are often a a matter of belief, which will not be enough to ensure efficiency in a therapeutic setting. It is also recommended that responsibilities in this project be clearly assigned to a senior researcher.

5-Xenograft as a model of dynamic tumour response;

the laboratory has set up a collection of tumour grafts established from fresh patient material. Preference was given to needle biopsies of metastases, which is a clear originality. They reported a good rate (no specific numbers, though) of take and rapid growth, despite the small amount of engrafted tumour. Plans are to use these grafts as a tool to assess response to therapy. One originality to this project is that they have implemented an approach allowing to monitor dynamically the response, by making sequential needle biopsies under ultrasound on the animal during treatment. This project is judged interesting and must be supported in the future. Recommendations are that specific staff should be identified in charge, with clealry defined resources against specific deliverables in defined tiome frames, with priorities.

C-Biobanking as a Scientific Resource;

The paraffin embedded tissue resource represents a large proportion of the diagnostic cases coming through the department. The frozen material is more limited, but is excellently archived and quality controlled. However, it was not clear how scientists and clinicians accessed these tissues and what the committee structure was that approved access. It is therefore recommended to follow international BioBanking Recommendations, which request that Biobanks are managed by mutidisciplinary research committees staffed with a majority of members independent of the BioBank Team. These recommendations were made to ensure that the resources are made available to the largest scientific community possible to ensure that donors wishes to get the best science from their gifts is ensured. It was not clear that such a structure was in place.

Little information was available on how the scientific life is organized within the unit except a weekly lab meeting for data presentation. In addition, the unit does not run any Lab committee (Conseil de Laboratoire). This aspect could be of particular importance given the existence of two labs located respectively at the Hospital Beaujon in Clichy and at the Hospital St Louis in Paris.

Assessment of the unit's involvement in training through research:

The unit has a clear and efficient involvement in training for which it must be congratulated. It is strongly committed in the B2T biology and biotechnology and Masters programs. In addition, the unit is member of a Doctoral School, with several MD and PhD students enrolled. Also, its strong input in biobankers training should be acknowledged.

Of note is the very interesting link and ongoing program with the international INSERM lab settled in Shanghai. This latter might eventually be assessed separately.

Assessment of the five-year plan and strategy:

The review panel noted that no clear scientific five-year plan nor strategy were defined in the written report and could not correct this impression during the visit. This did not come up during oral presentations and nor during private hearings with the director when asked about future plans for the unit.

Histogram

Response to the AERES evaluation report of U728, Director Anne Janin

The members of the research unit U728 thank the evaluation committee for the time and energy devoted to our unit evaluation, their constructive remarks and their assessment of the quality of publications, remarquable in put in setting up training program, good links in industry, clear sign of appeal at international level, four main topics required for research units, together with transdisciplinary project implementation and integration of clinical oncologists. We do agree that this project is at an early phase and needs long-term resources, and apart from the ANR international and ITMO cancer grants already acquired, A Janin as PI has applied for a senior ERC grant. In 2012, after selection in the first round, the project ranked 40th on 100 in the second round (only 30 projects were granted). A Janin was allowed to apply again in 2013 and the project has just been selected in April 2013 for the second round. The Inserm has applied as the host research institution for this ERC project. The Unit Council will assist the Director to coordinate and manage the research activities of the Unit. Each PI will be present or represented by a tenured scientist. The Council will meet each month to discuss scientific strategies, recruitment options, budget issues, equipment needs, problems and obligations inherent to hygiene and security, relationships with the Saint Louis campus. A written report of each Council meeting will be submitted to all members for approval at the next meeting. Budget allocation: No overhead charges are applied to externally-funded grants obtained by the PIs. The recurrent university budget (24 k€ available for the unit in 2012, reduced from 60k€ after institutional exceptional charges) is shared through all members and dedicated, after discussion with all PIs, to formation, missions and payments for students and trainees. The recurrent Inserm budget (90 k€ in 2012), the only one that can be used indifferently for consumables or for equipment, is used for the charges linked to the technology shared by all programs, particularly for the annual set up of microscopes, cryostats, microtome, laser microdissection, ultrasonography dedicated to small animal, immunohistochemistry device, and the whole budget of xenografts for the unit programs.Because of its critical importance on many in-house or collaborative projects, a particular attention is given to preservation of money till the end of the year for laser replacement for micro dissection.

Pr Anne Janin

  location of the unit : The INSERM unit 728 was created in 2005, in continuation of a university Paris 7 structure. The laboratory is part of the Institut Universitaire d'Hématologie (IUH, Université Paris 7) within the University Hospital St Louis in Paris, which has a long time history in haematological malignancies, both at the clinical and research level. Originally the creation of an INSERM team, initially devoted to technological developments in histopathology (ERM 0220) was an initiative of Ms Anne JANIN within the laboratory of Pathology at the Hospital St Louis. The creation of the unit extended and validated the long time effort of Ms Anne JANIN in setting up the central tumor bank at Hospital St Louis.

  Other permanent staff (without research duties) N4: Other professors (Emeritus Professor, on-contract Professor, etc.) spent at least 12 months in the unit* 4 Number of Research Supervisor Qualifications (HDR) taken 17 Qualified research supervisors (with an HDR) or similar positions 2  Assessment of the unit Strengths and opportunities: -Dedicated and energetic director with an internationally recognized expertise in pathology, -Central position in the provision of biological resources facilities at the Hospital St Louis, -Strong links with the clinical pathology and other clinical platforms (mainly imaging), -Location within a strong site and ties with the Institute of Haematology (IUH) with excellent clinicians and scientists, -Easily accessible high level core facilities at IUH, -Good links with the industry, -Strong ties with a cognate laboratory at the Shanghai University-Hospital, which it helped to establish, -Large staff resources, -A transdisciplinary approach of cancer covering biomarkers, drug targets, imaging and clinical response, -Strong history in pathology based technological developments, -Link with clinical oncologists, -Remarkable input in setting up training program, -An interesting preclinical program combining xenografts and serial fine needle aspirates to assess response to treatment, -Collaboration with chemists and physicists on nanoparticles, -Multidisciplinary environment of PhD/MD students and post-docs from diverse clinical and non-clinical disciplines. Weaknesses and threats: At the organizational level: -Neither a clearly defined strategy nor any identified priority for the coming 5 years, -No identified program/project with allocation of human resources and technological support, -No PI identified with responsibilities in the lab, -No budget allocation plans, -No emerging young investigator singled out, -Difficult to assess/ role and contribution of most of the University-Hospital staff.

4

  Conduct of the visit Specific premises visited: Institut Universitaire d'Hématologie, Hôpital St Louis, Paris. Locaux au premier étage occupé par l'unité. Locaux refaits à neuf, bien structuré et équipé. Délégué scientifique AERES : Mr Daniel OLIVE Comité Scientifique : Mr Charles THEILLET (Président) ; Experts Mr Jean Jacques FOURNIÉ (CSS8), Mr Barry GUSTERSON, Mr Bruno CLÉMENT, Ms Laurence LAMANT (CNU), Mr Christophe BORG. 8h30 -9h00 : Huis clos, présentation de l'AERES au comité par le Délégué 9h00 -9h15 : Devant l'unité, présentation du Comité de visite et présentation de l'AERES par le Délégué SESSION AUDITION 09h15 -10h00 : Ms Anne JANIN : Présentation de l'unité, réalisations et perspectives 10h05 -10h45 : Mr G. BOUSQUET, M. VARNA : Projet ERC 10h50 -11h20 : Mr WL ZHAO : Laboratoire International Associé Shanghai 11h25 -12h00 : Mr A. de GRAMONT : Innovation Research Cancer Network 12h00 -14h00 : Déjeuner de travail SESSION RENCONTRE AVEC LE PERSONNEL PERMANENT ET NON PERMANENT Le comité se répartit en trois sous-groupes 14h -14h45 : Rencontre avec les ITA titulaires, CDD Auditoire : membres du Comité, Délégué AERES, sans les Tutelles, ni la Direction Rencontre avec les doctorants et post-doctorants et/ou CDD « chercheurs » Auditoire : membres du Comité, Délégué AERES, sans les Tutelles, ni la Direction Rencontre avec les chercheurs et enseignants chercheurs titulaires Auditoire : membres du Comité, Délégué AERES, sans les Tutelles, ni la Direction, ni les responsables d'Equipes 14h45 -15h00 : Pause 15h00 -15h45 Rencontre avec les représentants de la Tutelle Auditoire : membres du Comité, Délégué AERES 15h45 -16h15 : Rencontre avec la direction de l'unité Auditoire : membres du Comité, Délégué AERES 16h30 -18h30 : Réunion du comité à huis clos Présence : Membres du Comité, délégué AERES 13 5  Statistics by field: SVE on 10/06/2013

  For the detailed assessment at the scientific level, 1. Cancer in transplanted patients: The studies in Biopsies of GVH patients were initiated by A Janin with E Gluckman since 1981. Before the arrival of G Socié, professor of clinical hematology, in 2002 in the unit, 22 publications were realized on GVH including Am J Pathol, Gastroenterol, Ann Int Med. One unique study was published with him in 2009 on cancer after bone marrow transplantation. Afterwards P Ratajczak post doc and now CR Inserm since 2011, has been PI in this program, with L Verneuil, post doc in the unit and now professor of dermatology, and J Verine PhD in the unit and now associate professor of pathology. The program has been extended to cancers in kidney transplant patients. The first studies are now at maturity and just published in 2012 (without G Socié), in J Invest Dermatol, and in Am J Transplant (ranked as first journals in dermatology and transplantation), and in revision in J Clin Invest (IF 14). For the recommandation to "acquire expertise in the field of pathological assessment of immune cells infiltrates", this expertise has been acquired by staff and pathologists of the unit for a long time, and acknowledged by the Inserm, since we participated in two Ateliers (129 in 2001 and 156 in 2004), and in the participants'training. This expertise of the unit is used for all our publications. 2. Lymphoma: the cooperation with Shanghai institute of hematology began in 2002, and has led to the creation of an Inserm international associated laboratory with W Zhao as PI. When in France, Chinese PhD in the unit train on animal model analyses and electron microscopy. C Thieblemont arrived at the end of 2008, with no previous history or experience of collaboration with China. One common paper with C Thieblemont was published in 2011, another in ongoing, from a cotutelle PhD. 3. Clinical oncology: the role and status of A de Gramont has been discussed and clarified in March 2013 with Jacques Grassi Head of the ITMO to which our unit is attached. A de Gramont is director of AAREC Filia Research for 65% of his time and paid for 20% of his time by the unit on a clinical research grant. E Raymond and colleagues are linked with the rest of the unit through their collaboration with Lu He, DR Inserm, the training of students, the use and development of xenograft models and novel predictive biomarkers as well as their interest for relevant expertise in pathology. 4. Protein-protein interaction linked to apoptosis: Our visibility convinced JL Poyet, DR Inserm, to join the unit because the development of his research project needs study of patient-derived cancer tissue xenografts, as models to qualify new anticancer drugs for study in human clinical trials. His position in the unit has been clarified as shown in the next page, as PI for the xenograft as model of dynamic tumor response. Xenograft models development, used by nearly all programs of the unit, is completely paid by the Inserm common budget of the unit. 5. Breast cancer stem cell and hybrid nanoparticles. This transdisciplinary project was designed by A Janin, G Bousquet oncologist, P Ratajczak CR1 Inserm, P Bertheau, M Varna post doc at the ESPCI, P Merlet nuclear medicine, G Lelong IMPMC Chemist.

6 .

 6 Biobanking as a scientific resource: as stated in the INCa annual report transmitted to the committee, around 30% of the 5000 new samples are used for research each year. These resources are made available through Material Transfert Agreement to scientific teams in France (U 727 Strasbourg, U 955 Institut Pasteur, CNRS 5238 Clcc Lyon, U954 Nancy, U1050 Collège de France in 2012) and abroad (Universities of Minnesota, Zurich, Genoa, and Regensburg, in 2012). 7. The publication report of our autoevaluation was established according to the Inserm recommendations: between 1/1/2007 and 17/1/2013, 315 publications, mean IF 7.15, total citations 5224, H-index of the unit: 35. The committee stated that "34/300 publications have members of the Lab as first or senior authors". The actual number is 104/300 and not 34/300. Pr Anne Janin In addition, Nicole Haeffner, in charge of the Inserm bibliometry unit, established for the ERC senior grant appliance the profile of A Janin, H-index 43, belongs to the top 1% scientists in clinical medicine, (ESI Thompson in February 2012 and again in October 2012). Position and projects developed by the scientists, five-year plan and strategy * PI, P Bertheau, Virtual slides, HU; C Miquel, , M Grossin, A de Roquancourt , post doc D Ameisen, F Bouhidel, staff : L Legres, IR 3-year plan: design and implementation of an automatic module for blur analysis, grant FlexMim, 5-year plan: ponderation of the blur in the anatomo clinic context, use of contextual graphs to modelize pathology practice. Collaboration with university informaticians. * PI C Thieblemont, Aggressive lymphoma, HU E de Kerviler, C de Bazelaire, J Frija, J Brière, P Brice, PhD M Romero, C Benet, staff D Geromin, IR 3-year plan:optimization of microbiopsy process for genomic analyses and xenograft model 5-year plan: development and implementation of a genomic tool dedicated to diagnosis and prognosis in aggressive Bcell lymphoma grants PHRC, INCa, FRM * PI P Ratajczak, CR1 and L Verneuil, Cancer in transplanted patients. HU J Verine, A Janin, P Mongiat Artus, V Meignin, M Battistella, staff: M ElBouchtaoui, Tech 3-year plan: chimerism and p53 mutations PHRC and ANR grant 5-year plan: Tumoral microenvironment angiogenesis and immune cells * PI E Raymond, Antiangiogenic therapeutic strategies. A de Gramont, Lu He, DR Inserm, post doc L Xerri, PhD S Albert, J Coelho, staff: H Ming 3-year plan: Characterization of vasculogenic mimicry and Epithelial Mesenchymal Transition in tumors treated by anti-angiogenic agents. 5-year plan: Development of new inhibitors targeting mesenchymal-like tumors cells. * PI JL Poyet, DR Inserm, Protein/protein interaction and xenograft as a model of dynamic tumor response HU M di Benedetto, H Bruzzoni, PhD D Rigue, Staff I Ferreira, IE, 3-year plan: Evaluation of the modulators of protein-protein interactions involved in the regulation of apoptosis we have developed (cell permeable peptides) in human cancer xenografts 5-year plan: Production, evaluation and optimization of small organic compounds derived from the above-mentioned peptides (lead compounds) for the development of novel pharmaceuticals. * PI W Zhao, lymphoma and response to chemotherapy. W Li, Y Fan, Z Wei, staff: Y Dong 3-year plan: autophagy in lymphoma cells and chemoresistance 5-year plan: miRNA oncologic clusters and lymphoma progression * PI A Janin Breast cancer stem cells and hybrid nanoparticles P Ratajczak, CR1 Inserm, G Bousquet, P Bertheau, P Merlet, post doc: M Varna, PhD L Vercellino, staff C Leboeuf IE, G Gapihan AI, 3-year plan: enginering, functional studies of hybrid nanoparticles, in vivo imaging approach 5-year plan: in vivo photothermal targeted therapy Management team: P Bertheau, C Thieblemont, P Ratajczak, JL Poyet, E Raymond, A Janin

Grades Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité C5 Implication dans la formation par la recherche C6 Stratégie et projet à cinq ans

	A+	67	62	52	73	65	60
	A	57	67	71	45	65	63
	B	12	7	4	7	6	14
	C	0	0	0	3	0	1
	Non Noté	3	3	12	11	3	1
	Percentages
	Critères	C1 Qualité scientifique et production	C2 Rayonnement et attractivité académiques	C3 Relations avec l'environnement social, économique et culturel	C4 Organisation et vie de l'entité	C5 Implication dans la formation par la recherche	C6 Stratégie et projet à cinq ans
	A+	48%	45%	37%	53%	47%	43%
	A	41%	48%	51%	32%	47%	45%
	B	9%	5%	3%	5%	4%	10%
	C	0%	0%	0%	2%	0%	1%
	Non Noté	2%	2%	9%	8%	2%	1%

 Supervising bodies' general comments


Clavel

Grading

Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team. Criterion 1 -C1 : Scientific outputs and quality ; Criterion 2 -C2 : Academic reputation and appeal ; Criterion 3 -C3 : Interactions with the social, economic and cultural environment ; Criterion 4 -C4 : Organisation and life of the institution (or of the team) ; Criterion 5 -C5 : Involvement in training through research ; Criterion 6 -C6 : Strategy and five-year plan.

With respect to this score, the research unit concerned by this report (and, when necessary, its in-house teams) received the following grades:

 Grading table of the unit: Genetic and Ecology of virus

Management team

A new organization is proposed with 2 teams instead of one: Team 1 "Evolution and viral pathogenesis" headed by Fabrizzio MAMMANO and Team 2 "Diversity and replication of virus", headed by François CLAVEL. 2  Assessment of the unit

AERES nomenclature

Strengths and opportunities

The unit in its new conformation has anticipated the relative loss of importance of drug resistance /fitness .

The integration of 2 clinical research teams of high quality and the arrival of two teams from Pasteur Institute represent a clear opportunity to develop new fields of research in particular on HIV reservoir.

The location in the IUH of St louis is also an opportunity to develop new collaborations and to benefit from high level research platforms.

Weaknesses and threats

Due to the challenges of the new location and of the integration of new teams, there is an heterogeneity in the numerous topics proposed, some of them having less interest in clinical or in basic research.

The present integration with clinical and microbiology laboratories is not fully profiled.

Funding for the mean/long term is not secured.

Recommendations

The unit should focus on the more relevant topics for the next 5 years and develop the opportunity of the integration of two clinical leading teams from St Louis Hospital.

 Detailed assessments

Assessment of scientific quality and outputs

The scientific output reflects the size of the group and the important recent transition. From 2007 to 2010, the unit has focused its research on HIV resistance to antiretroviral (ARV) drugs with an important contribution on the role of Gag mutations (PloS Pathogens). The group also studied the evolutionary pathways of integrase inhibitor resistance. With the arrival of the group from Pasteur in 2010, two important articles in J. Virol. were published on the mechanism of cell to cell transmission. Of public health importance, the cross neutralization between pandemic and seasonal A/H1N1 influenza viruses was described (PloS One). Additional findings are the description of novel aspects of the activity of human TRIM restriction factor that has been the subject of publications in J. Virol, Retrovirology and PloS One.

The clinical and microbiological teams have published a high number of articles in high profile journals (Lancet, Nature Med, CID, Lancet Infectious Disease).

Assessment of the unit's academic reputation and appeal

The previous work performed in the field of resistance is internationally recognised. The Atip /Avenir contract attributed to a young researcher who has recently joined the unit is promising. The head of the Unit is chair of scientific comittee 1 ANRS and member of the conseil d'administration of Paris 7 University.

One of the PIs is chair of AC5 ANRS (clinical trials) and frequently invited in international meetings, another one is chair from the comité scientifique Sidaction and member of different ANRS comittees.

Two members of the Unit are WHO experts.

8

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

The team received grants from ANRS, Sidaction and private companies. Two clinical researchers are involved in many experts groups. The Ipergay project which is leaded by a PI of the unit is in line with new societal questions in the field of HIV prevention.

Assessment of the unit's organisation and life

Until now, there was only one team in the unit with little hierarchical structure. The members of the unit were satisfied. With the arrival of two new teams and the integration of two clinical groups of St Louis, the unit will be reorganized in two teams. The new organization will have to facilitate the collaborations between the different groups

Assessment of the unit's involvement in training through research

The unit was largely involved in training PhD and M2 with all the necessary aspects (supervision, publications, presentations in english).

Assessment of the five-year plan and strategy

The unit is undergoing a number of transitions. Nine projects have been presented. Some of them seem to be more pertinent than others. For team 1, the perspective of collaboration with the clinical and microbiological groups is very promising (HIV evolution under selective pressure of IFN in HCV/HIV co-infected patients and HIV reservoirs in treated patients). For team 2, the ATIP/Avenir project and the studies on anti-integrase resistance and human restriction factors of HIV are the more pertinent. 9 4  Team-by-team analysis Overall, the team has published 41 articles, among which 27 with an author from the team in key position (either first or last author). The vast majority of the publications (about 30 of them) includes only authors from the clinical part of the team (coming from the Microbiology Laboratory or the Department of Infectious Diseases) among which articles with an author in key position in high profile journals: Lancet (2), Lancet Infectious diseases (1), CID (1).

Other articles were published in respected speciality journals (J Inf Dis (1), J Virol (2), AIDS (2)).

Assessment of the unit's academic reputation and appeal

The team has recently evolved with a better integration of researchers from the Laboratory of Microbiology and the Department of Infectious Diseases. The inclusion of these new leading investigators with important national and international involvements increases the reputation of the team and will promote many research projects. A Postdoctoral position granted by ANRS has been recruited.

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

The team received grants from ANRS and two contracts with private companies. Clinical researchers from the team are involved in many expert groups and well recognized at both national and international levels. The "Ipergay" project is in line with new societal questions in the HIV field.

Assessment of the unit's organisation and life

The structure of the team has recently evolved with closer integration and collaboration with the infectious disease clinical researchers, which is good. However, multiple research themes are proposed and it was not absolutely clear whether clinical and more fundamental researchers will really collaborate.

Assessment of the unit's involvement in training through research

The team was largely involved in training with 4 PhD and 2 M2 students. The scientific production of the PhD students is of quality and was published in journals with good impact factors. The current proposal includes 2 PhD students (IFN, super-infection) and 2 M2 students (reservoirs, CMV tropism).

Assessment of the five-year plan and strategy

The projects of the team 1 for the next 5 years will focus on five topics:

1.

HIV evolution under selective pressure of IFN in HCV-HIV co-infected patients. This ongoing project is of particular interest to understand the viral determinants targeted by IFN, and to functionally validate the association of viral determinants with changes in IFN susceptibility. The implication of known IFN-induced anti-HIV factors or new identified IFN stimulated genes will be studied. This project will benefit from the clinical group including HIV-HCV co-infected patients under IFN therapy, as well as methods to measure anti-HIV factors developed by different persons in the laboratory (link to team 2).

2.

Characterization of HIV superinfection resistance. The team would like to investigate the kinetics of susceptibility to HIV superinfection and determine the contribution of CD4-dependent and independent mechanisms of HIV interference. Expression of integrated genome in latently infected cells after HIV superinfection will be studied. Conceptually, this project appeared to be less competitive, compared to the other projects on HIV of the team.

3.

HIV resistance to integrase inhibitor, Raltegravir. The team will pursue their research on the evolutionary pathway of Raltegravir resistance according to genetic context (viral subtypes). In vitro resistance and replicative capacity will be studied for others rare resistance mutations and under the selective pressure of other integration inhibitors.

4.

HIV reservoirs in treated patients. The size of HIV reservoirs and the extent of replication will be evaluated in HIV infected patients who undergo chemotherapy and autologous stem cell transplantation because of lymphoma. This original research will allow a better understanding of HIV reservoirs, the main obstacle today to eradication. The development in the laboratory of novel approaches to measure of replication competent virus, and the inclusion of lymphoid tissues in their analyses are particularly interesting. This project is very pertinent and will take the advantages from a unique clinical situation, and will propably seals the collaboration between clinic and laboratory research.

5.

Impact of cell-to-cell transmission on CMV tropism. This project aims to characterize genotypically and functionally the tropism of primary CMV isolated from clinical samples and to explore the role of cell-to-cell transmission in the virus tropism. This study will benefit from methods developed by the laboratory and of access to CMV infected populations obtained in clinically relevant situations thanks to the National Reference Center for CMV. Nevertheless, this project appears to be more marginal.

Conclusion:

 Strengths and opportunities:

Both the better interactions with the clinicians and the Laboratory of Microbiology, and the new orientation of research themes in particular on HIV reservoir represent defined opportunities. They have correctly evaluated the relative loss of importance of the field of drug resistance/fitness, while maintaining some activity on the study of resistance to the last generation of integrase inhibitors.

 Weaknesses and threats:

The team projects include many topics, some of them have clearly less interest in clinical or in basic research. This could compromise the attractiveness of the unit, and success in fund raising. The size of the team and the numbers of ITA seem too low to allow state-of-the-art research in all the topics, and the project on reservoirs is not funded for the moment.

 Recommendations:

The team should focus on the more revelant topics for the next 5 years.

  Detailed assessments

Assessment of scientific quality and output

From 2007 to 2010, the team has focused its research on HIV resistance to antiretroviral (ARV) drugs (2 J Virol), with the detailed studies on the role of Gag and cleavage sites in protease inhibitors resistance (Plos Pathogens). The group also studied the evolutionary pathways of integrase inhibitor resistance (J Virol), using clinical samples from the Laboratory of Microbiology and samples from Thailand thanks to an international collaboration.

The scientific output reflects the size of the group and the important recent transitions (change of location and research themes, and recent arrival of a junior group). Thus, the most recent productivity is less favorable than in previous periods. They have correctly evaluated the relative loss of importance of the field of drug resistance/fitness, while maintaining some activity on the study of resistance to the last generation of integrase inhibitors. Importantly, the recruitment of a young researcher having an ATIP/Avenir grant brings complementary expertise and state of the art capacity for the study of cellular biology of HIV infection. This fits with the basic research agenda, and can also offer opportunities for competitive research in latency. The meticulous work of other researchers from the team adds contributions to the competitive field of restriction factors. They have provided novel insight on the interaction between innate and acquire immune recognition of the viral capsid (2 articles in J Virol). The new project on the expression of EBV glycoproteins by use of lentiviral vectors is too early to be assessed.

Assessment of the team academic reputation and appeal

The team is well known in the field because of previous work on resistance. The recruitment of an ATIP/Avenir young researcher is a welcome addition to renovate the presence of this group in the international forum.

Two Post-Doc positions (ANRS and Avenir) illustrate the attractivity of this team.

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

There are public (ANRS, Sidaction) and industrial contracts (Merck, ViiV Healthcare). Several PI are members of National science commissions (Sidaction, ANRS/CSS1 etc).

Assessment of the team organization and life

The team has until now worked as single unit, with little hierarchical structure and with shared resources. The various professional groups declare their satisfaction with the leadership and work environment.

Assessment of the team involvement in training through research

The training of PhD students includes all the necessary aspects for careers: close supervision, frequent interactions and opportunities to present, international exposure, use of scientific English and excellent support to find postdoctoral positions in competitive groups abroad.

Assessment of the five-year plan and strategy

This team is undergoing a number of transitions, from the field of resistance to that of pathogenesis, from the setting in Bichat to the new environment at St Louis. In addition, the recruitment of the ATIP/Avenir young researcher is very recent (6 months). It is in this unstable period that an emphasis on development and strategy would have been particularly valuable. It is through discussion with the PIs that a number of opportunities become clearer: the emphasis on the steps of uncoating emerges based on (not yet done) request of funding from the European community in collaboration with a German group leader in the field and the development of a HIV-2 project (restriction factors). The latter would be an opportunity in the field given its interest as a distinct model of pathogenesis -unfortunately, a first request for funding has not been successful. A second issue that relates to long term strategy is the limited securing of funds for some of the most attractive and competitive projects.

Conclusion

The team includes four separate main topics. The topics by themselves are not necessarily interacting, although the excellent general knowledge on basic lentiviral biology is a common point.

 Strengths and opportunities:

The first project "transport" applies state-of-the-art expertise and technology and has in the recent past resulted in numerous top level publications. The second project on the Capsid-TRIM5a-HLA interaction is of interest for progress in the field and has resulted in various publications in J Virol. It can set the basis for a new expanded project on uncoating. A component of the project relates to HIV-2, a virus that could provide valuable information on HIV-1 pathogenesis, but that has not been fully exploited in research. The analysis of restriction factors against HIV-2 could be of particular interest and the groups has novel data on this topic. Novel environment and relationship with clinical services and the basic research environment of IUH could be fruitful if adequately exploited.

 Weaknesses and threats: Some of the themes are losing interest in the clinical or basic research. This could compromise the attractiveness of the unit, or fund raising. The actual integration with Infectious diseases and Microbiology departments is not fully profiled. The association and collaboration with other groups at IUH is not clearly developed. The risks are the loss of notoriety of this team over the next period in detriment of the new groups.

The technical and administrative support is limited. Some of the novel equipment for new projects may not be available at the campus.

 Recommendations:

The new field of interest proposed, in particular the projects of the ATIP/Avenir team, the plans to converge around the topic of uncoating, and the efforts in HIV-2 virology are excellent choices to proceed -and they should be favored over other lesser projects. The future is unclear about i/the value of the EBV project that represents a strong local request, ii/ the availability of lentiviral technology, but that could prove to be non-competitive in the established field of herpes viruses.

  location of the unit Initially located in the campus of Bichat-Claude Bernard Hospital, U 941 moved to the Institut Universitaire d'Hématologie (IUH), hospital Saint-Louis. Two important research groups were integrated: the Department of Infectious Diseases (Pr JM MOLINA) and the Laboratory of Microbiology (Pr Fr SIMON) and two basic research groups joined U941: the team of Fabrizio MAMMANO (DR INSERM) moved from Pasteur in 2010 and the team of Nathalie ARHEL (CR CNRS) in 2012 (contrat ATIP/Avenir).

  spent at least 12 months in the unit 1 Number of Research Supervisor Qualifications (HDR) taken 1 Qualified research supervisors (with an HDR) or similar positions 10  Detailed assessments Assessment of scientific quality and outputs From 2007 to 2010, the unit has focused its research on HIV resistance to antiretroviral (ARV) drugs. With the arrival of the Pasteur group in September 2010, the themes of the research team evolved. The study of the mechanisms of HIV cell to cell transmission, started at the Pasteur Institute, was pursued. They have shown that cell to cell transmission required the production of infectious particles (J. Virol. 2009), and more recently that IFN was less efficient for preventing cell to cell transmission as compared to cell free virions (J. Virol 2012). The PI was awarded an ANRS contract on this subject.

Unit workforce Number as at 30/06/2012 Number as at 01/01/2014

	Doctoral students
	Theses defended
	Postdoctoral students having spent at least 12 months in the unit*
	Number of Research Supervisor Qualifications (HDR) taken
	Qualified research supervisors (with an HDR) or similar positions	10	10
	SVE1_LS1, LS2, LS6,LS7
	Unit workforce
	Unit workforce	Number as at 30/06/2012	Number as at 01/01/2014	2014-2018 Number of project producers
	N1: Permanent professors and similar positions	7	7	7
	N2: Permanent researchers from Institutions and similar positions	5	5	5
	N3: Other permanent staff (without research duties)	1	1
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)	1	1	1
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	4	4	4
	N6: Other contractual staff (without research duties)
	TOTAL N1 to N6	18	18	17
	Percentage of producers		100%

6 

 6 Statistics by field: SVE on 10/06/2013

	Grades

Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité C5 Implication dans la formation par la recherche C6 Stratégie et projet à cinq ans

	A+	67	62	52	73	65	60
	A	57	67	71	45	65	63
	B	12	7	4	7	6	14
	C	0	0	0	3	0	1
	Non Noté	3	3	12	11	3	1
	Percentages
	Critères	C1 Qualité scientifique et production	C2 Rayonnement et attractivité académiques	C3 Relations avec l'environnement social, économique et culturel	C4 Organisation et vie de l'entité	C5 Implication dans la formation par la recherche	C6 Stratégie et projet à cinq ans
	A+	48%	45%	37%	53%	47%	43%
	A	41%	48%	51%	32%	47%	45%
	B	9%	5%	3%	5%	4%	10%
	C	0%	0%	0%	2%	0%	1%
	Non Noté	2%	2%	9%	8%	2%	1%
	Histogram

Wenesday, 23, january, 9:00

End:

Wenesday, 23, january, 18:00

Visit site:

Hôpital Saint-Louis,

Institution:

IUH, Paris 7 University

Address:

Rue Claude Vellefaux, Paris

Conduct or programme of visit:


Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams).

This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team.

Criterion 1 -C1 : Scientific outputs and quality ; Criterion 2 -C2 : Academic reputation and appeal ; Criterion 3 -C3 : Interactions with the social, economic and cultural environment ; Criterion 4 -C4 : Organisation and life of the institution (or of the team) ; Criterion 5 -C5 : Involvement in training through research ; Criterion 6 -C6 : Strategy and five-year plan.

 Introduction History and geographical location of the unit

This application is for the renewal of the Inserm and University Paris7 -Denis Diderot support and funding to unit 946 which was created in 2009. The unit occupies 476 m 2 in the Fondation Jean Dausset-CEPH building. The expertise field of this unit is statistical methodology in genetic epidemiology and large-scale studies focused on the genetic epidemiology of asthma and allergy as well as cancers.

Management team

The unit is managed, as recommended for Inserm units of this size (i.e. single-team laboratories), on a daily basis by the unit Director assisted by an administrative manager. Permanent staff contribute to the organization of information technology resources, health and safety, continuing education, web site maintenance, and scientific animation. A lab management committee, including all permanent staff, is meeting twice a year. From discussions of the visiting committee with the personnel, it appears that there is a general approval of the management of this unit. 2  Assessment of the unit

Unit workforce

Strengths and opportunities

The unit has a very strong expertise in genetic epidemiology (one of the top groups in their field worldwide).

The unit demonstrates the capacity to publish in excellent journals.

The unit participates in major national/international consortiums (leader role in many of these) for the diseases of interest.

It develops very good collaboration.

It demonstrates a remarkable success in raising funds, also internationally. students and post-doctoral fellows are very well supervised.

The unit gathers very knowledgeable engineers with long-term experience in the field.

Weaknesses and threats

The committee believes that too many projects are coordinated at the same time for the number of permanent researchers in the unit.

So far, there is no scientist with a strong expertise in systems biology in the group.

Identification of theme 1 (statistical methodology in genetic epidemiology) gets lost in theme 2 (genetic epidemiology of asthma and cancers) and very few papers are published in statistical methodology journals.

Recommendations

Better prioritize the projects to maintain the actual level of scientific production.

Better valorize the statistical developments (for instance by publishing in statistical journals).

Attract a biologist in the unit or increase collaborations with biologists to help developing methods based on biological pathways.

Encourage young researchers to get their HDR and take more responsibilities in order to ensure the long-term future of the unit. This is particularly important since the team will have to identify, within the next fixe years, a leader able to supervise such a high-profile unit.

 Detailed assessments

Assessment of scientific quality and outputs Scientific achievements are clearly outstanding, especially when considering the size of the unit. Among 175 publications in peer-reviewed journals, 35 are in journals of IF ≥ 10, including New England Journal of Medicine (3), Nature (2), Nature Genetics (8) and Science (1). Notably, the permanent researchers of the unit have leadership positions on these publications (first or last authors). They have played a major role in genome-wide associations studies (GWAS) of asthma and cancers that resulted in the identification of novel genes and generated new hypotheses regarding the underlying disease mechanisms. Through statistical methods addressing phenotypic heterogeneity and gene-environment interaction, they provided new clues on the effect of a locus identified by an asthma GWAS and its interaction with smoking exposure. They also used family-based strategies, taking into account complex mechanisms, to discover new genes. They developed methods taking into account consanguinity to facilitate gene discovery and uncover new molecular mechanisms, notably in the Taybi-Linder syndrome. Finally, by combining clinical and genetic studies, they characterized molecular mechanisms predisposing to melanoma and renal carcinoma.

Assessment of the unit's academic reputation and appeal

The unit is very successful in attracting funding. It is engaged in many collaborations, both national and international. It is partner in 15 national networks (coordinator in 11/15) and in 17 European or international consortiums (coordinator in 5/17 and prominent team leader in 3/15). It is also founding member and coordinator, respectively, of two French "investissement d'avenir" programmes which are highly competitive. Members of the unit have received several awards and contribute to different national and also international scientific councils, i.e. the International Agency for Research on Cancer, the Max Planck Institute of Psychiatry, or the Swiss Cancer League. The head of the unit was President of the International Genetic Epidemiology Society (IGES), the only society that specifically represents the discipline worldwide. Staff members have participated in the organisation of several international meetings and many of them have been invited to give presentations at international conferences.

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

The unit has contributed to scientific popularization on cancer and asthma through various media, and has edited recommendations for medical practice (i.e., genetic counseling for familial melanoma). Several scientists have developed freely accessible software applications in genetic epidemiology and population genetics. Participation in a patent application (for developing methods and kits for disease diagnosis following the discovery of the responsible gene) and partnership with a few SMEs were also noticed.

Assessment of the unit's organisation and life

The visiting committee appreciated the friendly atmosphere despite the work load, and no obvious internal conflict was detected. All resources are shared, including scripts with appropriate documentation. PhD students and post-doctoral fellows appear pleased with the policy regarding publications and presentations at meetings. There are frequent contacts between the students and their advisors. Career plans seem to be discussed with the supervisors on a regular basis and there are frequent exchanges with foreign sites.

Assessment of the unit's involvement in training through research

The scientists of this unit are significantly involved in the organisation of the "M2 Génomique et génétique statistique" at the Universities of Paris Sud and of Evry and play a major role in the teaching and training of master and doctoral students in statistical genetics and genetic epidemiology of human diseases. French and foreign postdoctoral fellows are hosted in the unit and very well supervised. Participation in the organization of a European course in Genetic Epidemiology and node leadership in a European training network for PhD students further attest the recognition of this unit at the international level.

Assessment of the five-year plan and strategy

The questions asked are ambitious and relevant to the fields of genetic epidemiology and statistical genetics. There are several key aims in the research project. The first deals with statistical methodology and aims at developing new methods to account for the complex etiology of multifactorial diseases. These include cutting-edge multi-marker analyses, analyses of gene/environment interactions at the genome-wide level, and metanalyses taking into account genetic heterogeneity. The more long-term goal is to account for these complex mechanisms and integrate different genome-wide data (genomics, transcriptomics and epigenomics) to identify new genetic determinants of asthma, melanoma and bladder cancer. Members of this unit have access to very large cohorts of patients. They are involved in many national and international consortiums and have secured sufficient funding to develop these reseach activities. The only concern is that the number of topics this group offers to cover is very high, especially when considering the complexity of the questions asked, the international competition in the field and the comparatively small number of scientists with permanent positions currently in the unit (2 DR, 3 CR, 1 IR, 2 IE). The projects should be better prioritized in order for this unit to maintain its impressive level of scientific production.

Conduct or programme of visit:

The visit took place on December 13 th , 2012 and started with a short meeting of the visiting committee with the AERES scientific advisor and a reminder of the roles and procedures of AERES. This was followed by a general presentation by the head of the unit on the history of UMR 946, its functional organization, the staff participating in the project and the general strategy in terms of solving research challenges, teaching, training and getting research funds. Presentations on the different themes, i.e. statistical methodology in genetic epidemiology, genetic epidemiology of asthma, and genetic epidemiology of cancer were given by permanent researchers working on these projects and opened to discussion with the members of the committee. The committee met with local and national representatives (University, CEPH, Inserm) and with research scientists, technicians/engineers and students/postdoctoral fellows. The visit ended with a private meeting of the visiting committee, in the presence of the AERES scientific advisor, to prepare the evaluation report.

The detailed agenda of the site visite was the following : We thank the AERES committee members for their report and their recommendations following the site visit of our unit, UMR-946 Université Paris 7 Denis Diderot-Inserm ("Genetic Variation and Human Diseases"), on 13th December 2012.

We strongly appreciate the positive comments regarding UMR-946 strong expertise in genetic epidemiology ("one of the top groups in their field worldwide") together with its capacity in publishing in high-impact factor journals, in having a leading role in national and international consortiums, in training students and post-doctoral fellows in a manner particularly appreciated by the committee, in having very knowledgeable engineers with a long-term experience in the field and in generating funding from various sources nationally and internationally.

We would like to comment the remarks of the committee by putting them into perspective within the global strategy of our unit.

Regarding the first comment mentioning that "too many projects are coordinated at the same time for the number of researchers in the unit", we would like to point out that these projects are conducted by UMR-946 scientists in close collaboration with several groups nationally and internationally both for the development of statistical methodology in genetic epidemiology and large-scale genetic epidemiology studies of asthma, allergic diseases and cancers. Most of these projects have already been undertaken and have received funding from various sources at the national and international levels. We also would like to stress that we are more and more fostering a multidisciplinary and a networking-based approach of our research activities with shared responsibilities with our colleagues, which can greatly facilitate rapid advances in our research programs and maintain our level of scientific production that was noted to be "impressive" by the AERES committee.

Regarding the second comment raised by the committee on "the absence of a scientist with a strong expertise in systems biology in the group", the systems biology approach in genetic epidemiology is, for us, a new concept that covers multi-dimensional approaches of disease and integration of "omics" data (genomics, transcriptomics, epigenomics…) to progress in the understanding of the complex mechanisms underlying multifactorial diseases, as outlined in our AERES application. We are starting now new programs in this emerging topic with new funding. We are involved in a FP7-Marie Curie program in Machine Learning for Personalized Medicine which allows us recruiting a doctoral student to develop data mining and machine learning methodologies in genetic epidemiology and expanding our links with academic groups and private companies involved in systems biology. On the other hand, we are undertaking a new research project, which integrates genomic data and text-mining approaches, in collaboration with the Data Mining team of the LIPADE laboratory (Paris Descartes University). This program, which has just received funding from the PRES Sorbonne Paris Cité, includes training of post-doctoral fellows and doctoral students.

The integrated approach to complex diseases includes biological components that are developed through tight links with biologists from the Pasteur Institute, the CNRS, French Cancer Institutes (Curie and Gustave Roussy Institutes) and North-American Universities. Functional studies conducted by these teams following gene discovery can accelerate research translation.

Regarding the third comment of the committee underlining that" identification of theme 1 (statistical methodology in genetic epidemiology) gets lost in theme 2 (genetic epidemiology of asthma and cancer), we would like to point out that our work in the past five years has mainly focused on targeted approaches in rare disorders and on large-scale genome-wide studies leading to identification of novel genes and gene-environment interactions in allergic diseases and cancers and has been published in high-impact factor journals. These studies have often included major methodological developments that were included in the disease-oriented publications. Our work has also included comparisons of statistical methods that were carried out on real data rather than on simulated data and we chose to publish in genetic or epidemiological journals to reach a broader readership than usually achieved by pure statistical journals. As mentioned before, the extension of our collaborations to groups involved in methodological developments nationally and internationally will favor expansion of this field with joint publications in statistical methodology journals as well as in general and specialized journals.

  Closed-door meeting of the Visiting Committee (in presence of AERES Scientific Advisor) 18:00 End of the visit ______________________________________________________________________________ ________________ Genetic Variation and Human Diseases, UMR 946, University Paris 7 -Denis Diderot /INSERM, Ms Florence DEMENAIS 5  Statistics by field: SVE on 10/06

  72 50 02 -Fax : +33 1 53 72 50 49 -e-mail : florence.demenais@inserm;fr Response of UMR-946, Université Paris 7 Denis Diderot-Inserm, to AERES Evaluation Report

  Although the youngest researchers do not have yet their HDR ("Habilitation à Diriger des Recherches"), they have been involved in the training of students and are currently co-supervising doctoral students. They are encouraged to get their HDR soon in order to ensure the long-term future of our unit.Paris, 4th April 2013Florence Demenais Director of UMR-946

Unit workforce Number as at 30/06/2012 Number as at 01/01/2014

	Unit
				2014-2018
				Number of
				project
				producers
	N1: Permanent professors and similar positions	1
	N2: Permanent researchers from Institutions and similar positions	6	5	5
	N3: Other permanent staff (without research duties)	4	4	3
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)		1	1
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	3	4	4
	N6: Other contractual staff (without research duties)	3	2
	TOTAL N1 to N6	17	16	13

workforce Number as at 30/06/2012 Number as at 01/01/2014

	Doctoral students	11
	Theses defended	6
	Postdoctoral students having spent at least 12 months in the unit*	3
	Number of Research Supervisor Qualifications (HDR) taken
	Qualified research supervisors (with an HDR) or similar positions	3	2 + 2 (soon HDR candidates)

 Conduct of the visit Visit date: December 13, 2012 Start: December 13, 2012, 8:15 End: December 13, 2012, 18:00

 Supervising bodies' general comments