CFAS - Advisory Committee

The MRC Cognitive Function and Ageing Study (MRC CFAS) was set up in 1991 ago to address areas of concern on ageing to society. It is multidisciplinary, working with populations of 65 years and over. Its aim is to throw light on areas of key significance for ageing societies: health and frailty, including their prediction and natural history in old age, their relationship to quality of life and maintenance of independence.

CFAS is a longitudinal, multi-centre (Cambridge, Gwynedd, Liverpool, Newcastle, Nottingham and Oxford), observational, population based study with original aims of examining descriptive epidemiology of dementia across sites within England and Wales, along with cognitive decline, consequent disability and resource implications. A neuropathological component to the study was added and the scope of the study has become broader since its inception. CFAS has been collecting brain, blood and salivas from the population sample since early in the study. This resource has been used already for scientific analyses, including DNA analysis. More detail on the aims and different aspects of the study is available on the website, together with the bibliography (web site address: www-cfas.medschl.cam.ac.uk ) The management structure of the study, current and historical is described in Appendix 1. Current CFAS management of the biological resources is given in Appendix 2.

1.2 CFAS Advisory Committee

The collection of brains, bloods and salivas from the study should be open to scrutiny. It is an unique collection. The best possible use of the resources must be encouraged and supported, whilst ensuring fair access to existing collaborators and new collaborations. In 1997 the Neurosciences Board and later the CFAS Steering Committee (SC) recommended that CFAS set in place a separate committee with external representation to advise on the use of the tissue and blood resources of the study. A document laying out the possible committee was approved by Study Management Group (SMG) in February 1998 with the modification that it deals with issues related to DNA in the first instance: this revised document was discussed with the Chair of the SC in March 1998. It was agreed that, pending general and high level discussions surrounding the issues of stewardship of research resources, CFAS set up an Advisory Committee. A first brief of this committee was developed and considered at the first meeting of the Advisory Committee. When CFAS became a Cooperative the remit of the group was widened to that of a Biological Resource Advisory Committee. The Committee has become an integral part of the study irrespective of the CFAS financing arrangements.

RETURN TO TOP

2 Committee Tasks

2.1 Purpose

The overarching purpose of the Committee is to:

advise on the scientific prioritisation of the stored biological resource of the study, and
ensure accountability for best use of these materials

2.2 Phase I (up to 2004)

It will screen proposals from within and outside the study for new scientific work which requested access to the brain and/or blood resource. It will advise on fair access to the materials. Pilot work can be approved without reference to external peer review. Substantive pieces of work will be assessed according to the terms of reference but will also be expected to have been peer reviewed. CFAS will seek external peer review if the proposed collaboration does not need to seek external funding (as part of a peer reviewed competition).

2.3 Phase II (from 2004)

Its tasks are to oversee the management (including the advisability of any duplication of research), maintenance, quality control, security, ethical issues and confidentiality of the resources with regard to ongoing and future research, ensuring proper implementation of procedures are in place and reporting back to the Cooperative Management Committee (see Appendix 2 for current management of biological resources). It will advise on the timeliness and appropriateness of proposed work. The Committee will report to the MRC Cross Board Group or the Neurosciences Board as appropriate. It will monitor progress of ongoing collaborations, and check on the timely return of genotypic data to the main database. It will advise on data release and linking of biological data to clinical data. It will receive reports on outputs and their impact.

2.4 Relation to Multicentre Research Ethics Committee

Current MREC approval for the CFAS study (MREC Reference: 99/5/22) requires that the Advisory Committee and CFAS Cooperative Management Committee have seen and approved use of study based tissues and that LREC or equivalent approval is in place in each locality that tissues might be used. This is taken to mean studies on which MRC have funded the infrastructure which enable collections.

2.5 Relationship to Research Governance

The Biological Resource Advisory Committee of the CFA Study is covered by the University of Cambridge’s policies on good research governance. It reports to the General Board’s Research Policy Committee, Chaired by the Vice-Chancellor Professor Alison Richard, Secretary Dr David Secher. All users will be expected to comply in all sites with DOH and University research governance frameworks, or equivalent, where outside the UK.

RETURN TO TOP

3 Membership and method of working

3.1 Committee Membership

The Committee has been set up under a Chairperson (Professor Allen), who is independent of CFAS, and with no vested interest in the ongoing studies. It comprises:

Chair:	Professor Ingrid Allen (independent neuropathologist and previously chair of the CFAS Steering Committee)
Neurosciences Board Representative
Independent Member (Neurobiologist)	Professor Roy Weller

CFAS membership:
Chair of CFAS Cooperative	Professor Carol Brayne
Lead neuropathologist	Professor Paul Ince
Centre representative	Dr C McCracken
Lay member	Simon Harrison, Frank Weiss
MRC representative	Jo Latimer
Genetic representative

The meeting is minuted by a member of the CFAS core team. The Department of Health declined to nominate a representative, but requested to be kept informed.

A third honest broker represented genetics on the Committee but this function is now fulfilled by specific request for assessment where our own honest brokers feel the request is outside their area of knowledge

3.2 Term of Office

Four years for independent scientists. CFAS members, as appropriate to representation.

3.3 Declaration of Interests for Members

Each member will declare his/her interests (Appendix 3).

RETURN TO TOP

4 Accountability, for what and to whom

The Committee is accountable for advising on stewardship of biological materials in CFAS on which it has been informed. In the first instance the Committee oversaw the proper and appropriate scrutiny of proposals and access to tissues. The audit of materials was conducted from 2004-2005 and is now in place. The Committee is accountable for its advice regarding the wider remit outlined above. It is accountable to the Cross Board Group/Neurosciences Board to whom it will report as appropriate. CMC will report on fieldwork and research governance arrangements. The Committee's Terms of Reference and membership have been approved by the MRC's Management Group and will be within the University of Cambridge’s Research Governance structure.

RETURN TO TOP

5 Method of working

5.1 Meetings

Meetings will be held to ensure Terms of Reference remain appropriate and to review progress, approximately once a year. Ad hoc meetings can be called if appropriate on the request of the Chair.

5.2 E-mail

Proposals will be circulated to appropriate members of the Committee by e-mail.

Appendix 1

MRC CFAS STRUCTURE

See Word version for diagram.

A. The members of the CFAS Cooperative

The collaborative group consists of investigators from the six sites of MRC CFAS, members of the MRC Biostatistics Unit (BSU) and investigators from the component projects using the CFAS data, blood or brain resource. Initially there were separate epidemiological collaborations and neuropathological collaborations, but since 1996 these have merged. CFAS became a Cooperative in February 2001. It received continued MRC funding in 2005.

B. Historical development of CFAS structures – to December 2000

a. Steering Committee (SC)

The overall direction of the main study and approval of bolt-on studies was approved by the SC, formed at the onset by the MRC. This committee met at regular intervals to monitor and approve the progress of the study, and draw attention to areas of concern (Chair, Professor Allen 1990-1999)

b. Study Management Group (SMG)

This consisted of all investigators, members of the MRC BSU, the study manager and the study administrator. The detailed implementation of the proposal and study contact was the responsibility of the SMG which met from the beginning of the study at regular intervals, from two to four times a year to the start of the cooperative. It oversaw detailed progress of each centre, approved decisions about study matters, agreed collaborations, and prioritised areas for analysis and publication. An authorship agreement was developed. The procedure to agree to bolt-on studies from within and outside the collaborative group was structured with many such requests have been discussed and considered, with varied outcomes. It was expected that, as the study progressed and the Advisory Committee was convened, requests for access would increase (Chair, Professor Day 1990-1999, Professor Brayne 1999-present).

c. Analysis Group up to mid-1998

This consisted of all investigators and those involved in data management, analysis and writing up. It met every six weeks either in Cambridge or London. Agenda items included details of data management, postcoding of textual data, systematic approaches to data versions and analysis and progress on analysis and paper writing. Due to limited funding, matters relating to this Group were discussed at SMG meetings from October 1998.

d. IPH CFAS Analysis Group (ICAG)

This consisted of all researchers and data management staff who are based in the Institute of Public Health at Cambridge. It met approximately every three weeks and dealt with issues related to data handling, cleaning, versioning and analysis, identifying logjams and defining priorities. This group continued into the Cooperative structure, until 2002 (Chair, Dr A Johnson 1992-2002, Dr F Matthews 2002).

e. Neuropathology Analysis Group

This consists of all neuropathologists and core members of CFAS. It is held about once a year and discusses local tissue issues and the research programme (Chair Professor Esiri 1993-1998, Professor Ince 1998-present).

C. Current structure of the MRC CFAS Co-operative Group (from 1/2/2001)

a. Cooperative Management Committee

The MRC Cooperative has a Management Committee with representation from centres which have ongoing fieldwork and current grants. It oversees activity, approves and encourages new collaboration. See figure 1 for diagram of management structure (Chair, Professor Brayne).

b. Advisory Committee

It was agreed by SMG in February 1998 that the Advisory Committee would provide advice to it, in the first instance on work related to the DNA resource broadening to include the full biological resource. The Committee would have the responsibility of advising SMG in ensuring appropriate storage of tissue, documentation, and scrutiny of proposed collaborative projects. This is in two stages. In the first instance to scrutinise and advise on proposed projects which involve use of biological material collected in the study. It was recommended that this Committee include, as independent advisors, one or more external experts, with no direct or potential involvement in the study (see minutes of first meeting of Advisory Committee). It was recognised that such an additional committee is appropriate to facilitate the optimal use of the scientific material. The opinion of an honest broker beyond the Committee with knowledge of CFAS will be sought when the committees indicate further expert scrutiny is necessary (e.g. molecular genetics). The current MREC approval for CFAS requires consideration and approval of the activities, ethics and use of all biological materials (for which MRC have funded infrastructure), by BRAC before submission can be made.

RETURN TO TOP

Appendix 2

A. Management of Biological Resource

a. Declarations of Intention to Donate Tissue (DOI)

Centres vary in their approach to DoI and retrieval of brains. Some centres rely entirely on pre-existing agreement of the respondents and their carers. Others also carry out opportunistic collection. All centres include the more intensively investigated CFAS respondents: some centres include also those who have been screened only. Documentation of centre procedures and samples is essential to appropriate choice of material later.

b. Brains

Death notification is routinely received from the Office of National Statistics, but this is inappropriate for the purposes of brain retrieval due to the time lag of notifications. An infrastructure is in place in each centre for the ongoing collection of brains, although only funded by MRC in Newcastle. There are procedures in place for brain retrieval in each centre. Minimal funding has been requested to allow retrieval at all centres to continue beyond August 1998. Each centre follows a standard protocol for extraction and handling of the tissue, and all centres fix at least one hemisphere. Those centres with appropriate facilities snap freeze material also. Storage is currently at each centre (Gwynedd brains are stored at Liverpool), with completion of the basic CERAD neuropathological forms by the local neuropathological CFAS investigator. These data are entered onto the CFAS database at the Biostatistics Unit. At present those wishing to collaborate with the group are recommended to view the CFAS website http://www-cfas.medschl.cam.ac.uk and are then directed to an appropriate CMC member, who then represents their proposal to the Group.

c. Documentation

Local documentation varies, with feedback to the central administration about successful collection only, rather than details of the exact location and nature of tissues available. This needs to be co-ordinated further with creation of a detailed database for monitoring exact uses. This is part of the general discussion about future work on the brain resource led by Professor Ince (originally at Newcastle, now Sheffield). Following discussion at previous Advisory Committee meetings Professor Ince successfully bid to MRC for an infrastructure post based at Sheffield dedicated to the brain resource.

d. Brains and Genetic Work

It was agreed by SMG in 1996 that brain tissue should be available for genetic collaboration. Measurement of ApoE was proposed under previous CFAS agreements but, as it has only been carried out on the blood and saliva to date, Professor Morris in Newcastle store this work which has been continued in collaboration with Professor Nicoll.

B. Current management of the resources – Saliva and Blood

a. Saliva

i. Saliva as part of the neurological examination bolt on studies

In Cambridge and Nottingham salivas were taken as part of the neurological examination bolt on studies. The Cambridge samples have been analysed as a pilot for the total study. The Nottingham samples were handled and stored separately. This resource was mostly exhausted in the original DNA work.

ii. Saliva as fall back during 1996-8 phase

In the 1996-8 fieldwork phase, in which all assessed individuals were contacted for approach, where it was not possible to take a blood sample from an individual, a saliva sample was obtained. This is stored with the blood DNA resource.

b. Bloods

i. Old Bloods

Bloods have been taken in the past in Cambridge and Nottingham (500 each), funded by a different grant stored in freezer facilities in the Department of Psychiatry, Cambridge. 10mls of whole blood, with serum from earlier endocrine analyses on 1000 bloods have been stored. These are up to ten years old and have been stored in –20 freezers. The Nottingham bloods have been retrieved but despite extensive searching the Cambridge bloods have not been found.

ii. DNA from 1996-8

Blood was taken in the third wave of the study on assessed individuals. EDTA tubes were sent directly to the Clinical Genetics laboratory at Cambridge where DNA was extracted and stored in the diagnostic laboratory. The samples arrived in the laboratory and were logged onto the database with unique identifier and DNA bank number, back-up hard copy of the sample details is made. The DNA bank number allows efficient retrieval from the –80 freezer. DNA is extracted from blood or saliva using standardised procedures. Quality control procedures were routine. The samples are stored under the usual rigorous confidential and secure manner integral to Clinical Genetics. These have been transferred to Sheffield and are at present in Exeter for collaboration with Professor Melzer (NIA grant)

iii. Serum from 1996-8

Blood samples collected at the third wave of interviews were sent to the EPIC laboratory where they were handled according to the EPIC protocol. Labelled straws were filled with specific samples and are stored in clearly marked containers in liquid nitrogen Dewars. These are stored in Cambridge within the MRC Genetic Cooperative.

iv. Oxford bloods

At Oxford independent funding was obtained to enable collection of blood samples at the second wave of interviews. These may be available for collaborative purposes on request to Oxford PIs, but are not available within the CFAS collaboration. The CFAS Study and BRAC have no role in the use of these bloods. The Oxford investigators use the phenotype data provided by the CFAS collaboration but operate under different REC understandings. MREC do, however, expect to be approached for approval of single centre work in CFAS which may require Advisory Committee approval. DNA was extracted on these samples by Dr Rubinsztein and is stored in Exeter at present. Part of the DNA has been taken to the US in an Oxford-specific genetic collaboration.

C. Current Management of the Resources – Linked Data

Data Release

The basic principle is that biological: clinical data are not released. Under specific conditions this may be negotiated but must be approved by BRAC.

a.Brain Information

Information linking data from the CERAD* forms is held in MRC Biostatistics Unit, Cambridge. All neuropathological data is stored separately to respondent and informant data.

b. Genetic Data

All information on the genotyping information is stored separately to the interview information at MRC Biostatistics Unit, Cambridge.

*Consortium to Establish a Register for Alzheimer’s Disease

RETURN TO TOP

Appendix 3

MEDICAL RESEARCH COUNCIL CFAS

BIOLOGICAL RESOURCE ADVISORY COMMITTEE

REGISTER OF PRIVATE, PROFESSIONAL, COMMERCIAL AND OTHER INTERESTS

Name: …………………………………………………………………………………………………………

Name of Department and University or other employing body

…………………………………………………………………………………………………………………

Please indicate (►) and give details of any potential conflicts of interest arising out of the following:

► Company Appointments ► Directorships ► Consultancies

► Honorary Appointments ► Shareholdings ► Political/Pressure

► Group Associations ► Major Academic Collaborations ► Other

PLEASE PRINT

…………………………………………………………………………………………………………………

Please give details of any potential conflicts of interest that may arise out of family involvement in any of the above

…………………………………………………………………………………………………………………

I have read the Code of Best Practice for MRC Council and Sub-committee members and agree to abide by the terms of the Code. I undertake to declare at meetings on MRC CFAS business any private, professional, political, commercial or other interests that might be perceived to conflict with MRC interests and which have not been listed above. I accordingly agree to update this written declaration as circumstances arise.

Signature: …………………………………………………………….. Date ………………………..………

RETURN TO TOP

Appendix 4

Overview of Tissue donation/banking and distribution in CFAS

Tissue donation and consent

CFAS relies explicitly on the recruitment and participation of respondents during life to its donation programme. In earlier stages of the study selected respondents representing the whole spectrum of cognition were asked to consider brain donation after their own death. Those individuals who agreed, after consultation with family and others as appropriate, completed a form with a declaration of intention (“DOI”) to donate tissue. After death, if still in agreement, the next of kin sign a conventional post mortem consent form. Copies of the DOI and Post Mortem consent are attached for each centre, including those which have been modified in line with recent recommendations. The new forms in use in Cambridge are attached electronically and do include the possibility of pharmaceutical collaboration and we are in discussion of this aspect with the other Centres.

If, despite a DOI being in place, the family is not happy for donation to proceed, the donation does not take place.

In Oxford, Nottingham and Newcastle, in addition to the above, mortuary admissions and post mortem lists have been regularly checked for deceased CFAS respondents for whom there has been no declaration of intention to donate tissue. The local post mortem liaison staff in these Centres have then contacted the next of kin after death to seek consent for brain donation using conventional Hospital Autopsy procedures. Such an approach is only made after checking detailed records of any previous contact with these families to ensure that they have not previously registered their objection to this programme. In only a relatively small number of cases brain has donation occurred from this mechanism.

Tissue storage/banking

Professor Paul Ince, at Sheffield University, is the lead neuropathologist within CFAS. Neuropathology is performed in each centre using a standardised data capture form (CERAD). At Cambridge, MRC-BSU collect information on the completed CERAD forms from each centre which is stored anonymously, with a linked identifier to the main CFAS data sets in the CFAS data archive. CERAD forms are linked to interviews for “final diagnosis” using dementia status by the lead neuropathologist on dedicated visits to MRC-BSU. Version 3 of the neuropath dataset contains CERAD information on n-455 brains on people who died before 1 July 2004, and has been released.

Local arrangements are listed in the table:

Bank Location	Local arrangement
Cambridge	Half brain snap frozen in coronal slices, remainder formalin fixed. The entire collection is kept in the Cambridge Brain Bank Laboratory as frozen and fixed blocks. The Bank comes under the Addenbrooke's Tissue Bank and is overseen by Professor Collins. The brains from Cambridge have been moved to Sheffield.
Gwynedd	Whole brain formalin fixed These brains are temporarily stored in the NHS Mortuary (Gwynedd Hospital) before transfer to Sheffield.
Liverpool	Whole brain formalin fixed The brains have been transferred to the Department of Pathology having originally been collected and stored by the Department of Anatomy. The resource has been moved to Sheffield.
Newcastle	Half brain snap frozen in coronal slices, remainder formalin fixed. The brains are housed in the Newcastle Brain Tissue Bank at the MRC building and custodianship is administered by the staff of that Bank. This is supported by MRC in terms of banking infrastructure.
Nottingham	Limited tissue from cerebral poles of one hemisphere snap frozen for DNA, remainder formalin fixed intact. The brains have been looked after in the Department of Pathology (Professor Jim Lowe). The paraffin blocks and fixed tissues on cases have been transferred to Sheffield.
Oxford	Half brain slow frozen intact, remainder formalin fixed. The fixed tissue is in the Department of Neuropathology and custodianship is administered by the Radcliffe Infirmary. The resource has been moved to Sheffield.
Sheffield	Brains are received and archived from other Centres as above and for specific studies. They are stored in the Department of Neuropathology, Royal Hallamshire Hospital. Custodianship is administered by the Sheffield Tissue Bank within the Division of Genomic Medicine, Sheffield University through CFAS.

The full inventory and audit of banked material has been facilitated by the appointment of the Gill Forster CFAS cooperative Tissue Co-ordinator, funded by MRC.

Neuropathologists
Cambridge	Dr J Xeureb
Newcastle	Dr T Polvikovski
Nottingham	Professor J Lowe
Oxford	Professor M Esiri
Sheffield	Professor P Ince Dr S Wharton

Ethical approval

The procedures in each centre were approved by LRECs in the fieldwork and early stages. At the formation of the Cooperative full MREC approval for banking has been given with LREC notification. All consent forms and local procedures were scrutinized by MREC at the time of the approval (Ref: 99/5/22). Each individual use of tissue and biological resource has to go before MREC. Each request must provide evidence that the CFAS Cooperative Management Committee and the Biological Resource Advisory Committee has seen and supported the proposal.

RETURN TO TOP

Research Information: Background; Brief Introduction; Research Themes; Bolt-on Studies; Glossary of Terms; CFAS I; Design and Interview; Study Protocol; Scientific Strategy; CFAS II; Study Protocol; CFAS Wales; Introduction; Documentation; Study Information; Consent Forms; Neuropathology Forms; Questionnaires; Data; Data & Analysis; Liverpool Data; Oversight; Advisory Committee; Biological Resources; Fundings; Ethics & Legal Aspects; Archive Documents; Management Structure