Pioneering ethics in a longitudinal study

Front matter

KAREN BIRMINGHAM

PIONEERING ETHICS IN A LONGITUDINAL STUDY

The early development of the ALSPAC Ethics and Law Committee

Contents

List of figures and photographs v List of abbreviations vi Authors and contributors, with current positions ix Acknowledgements xii Foreword xiv Preface xvii Introduction 1 Part One: ALSPAC Ethics and Law Committee: a new concept 8 one Preliminaries and pioneers: framing the questions 9 two Informal or casual: an unusual style 21 three Advisory to independent: a missed opportunity 30 tour Bureaucratic battles: liaison with Local Research Ethics Committees 39 Part Two: Policy development: a case of case law 48 five Confidentiality and anonymity: a rod for their own backs 49 six Informed consent: too much information 56 seven Child protection: an observational study? 69 eight Disclosure of individual results: foreseen feedback and incidental findings 76 nine Disclosure of individual results: participants’ requests 88 ten Participants’ problems: people not policies 95 eleven External databases: anonymous linkage 105

Part Three: Beyond policy: a broad remit

twelve Retention of the Cohort: incentives or inducements

thirteen Commercial collaborations: selling our souls

fourteen Comprehensive oversight: undocumented and unacknowledged fifteen Influence beyond ALSPAC: extension of expertise

Postscript Notes References Appendix 1: ALSPAC Steering Committee: founding members Appendix 2: ALSPAC Ethics and Law Committee members: appointed 1990—2005 Appendix 3: Letter to participants: further information concerning confidentiality Appendix 4: Young Mothers paper by Elizabeth Mumford Appendix 5: The Children of the Nineties study (ALSPAC) and collaboration with pharmaceutical companies

116 117 126 137 147 156

List of figures and photographs

Figures

No oF WP =

David Baum’s memo, November 1989

Children in Focus clinics: categories of measures (Jean Golding) Letter to Jean Golding from a Study child

Example page from Focus at 7 booklet

Example page from Focus at 7 booklet

Participants’ newsletter article

Inquiry into Human Genetic Databases consultees

Photographs

David Baum Michael Furmston Tim Chambers Jean Golding Gordon Stirrat Elizabeth Mumford David Jewell Marcus Pembrey

List of abbreviations

AELC ALEC ALSPAC

BCC BPA

CiF Co90s COREC

DfES ELSPAC

EPEG

ALSPAC Ethics and Law Committee ALSPAC Ethics and Law Committee Avon Longitudinal Study of Parents and Children, previously known as Avon Longitudinal Study of Pregnancy and Childhood

Bristol City Council

British Paediatric Association Children in Focus: research clinics for 10% subsample of ALSPAC

Children of the 90s (ALSPAC as known by the Study participants) Central Office for Research Ethics Committees

Department for Education and Skills European Study of Pregnancy and Childhood

Ethical Protection in Epidemiological Genetic Research: Participants’

Perspective

Ethics of Research Committee ALSPAC research clinics for participants at age seven, eight, nine, 10 and 11

HGC HV IRB LREC MRC NHS NSC ONS PIAG PIS RCP REC

Teen Focus 1

Teen Focus 1 fasttrack Teen Focus 2

Teen Focus 3

Teen Focus 4

TF1

TF1

TF2

LIST OF ABBREVIATIONS

ALSPAC research clinics for participants at age seven, eight, nine, 10 and 11

ALSPAC research clinics for participants at age seven, eight, nine, 10 and 11

Human Genetics Commission

Health Visitor

Institutional Review Board

Local Research Ethics Committee (NHS)

Medical Research Council

National Health Service

National Screening Committee

Office for National Statistics

Patient Information Advisory Group Participant Information Sheet

Royal College of Physicians

Research Ethics Committee (NHS) ALSPAC research clinic for participants at age 12

Briefer ALSPAC research clinic for participants at age 12

Briefer ALSPAC research clinic for participants at age 12

Vil

TF3 ALSPAC research clinic for participants at age 15

TF4 ALSPAC research clinic for participants at age 17

UOB University of Bristol

WHO World Health Organisation

WT Wellcome Trust

Vill

Authors and contributors, with current positions

Professor Richard Ashcroft e Professor of Bioethics, Queen Mary, University of London

e Member of the ALSPAC Ethics and Law Committee: September 1998 to March 2000

e ALSPAC collaborator and principle investigator on Wellcomefunded qualitative study: Ethical Protection in Epidemiological Genetic Research: Participants Perspectives (EPEG)

e Interviewed in Queen Mary, London, February 2013

Miss Karen Birmingham e Research Fellow, Centre for Child & Adolescent Health, University of Bristol

e Secretary of the ALSPAC Ethics and Law Committee: December 1999 to April 2013

Dr Tim Chambers e Consultant Paediatrician, retired

e Founding member of the ALSPAC Ethics and Law Committee: May 1990 to June 1997

e Interviewed in Barley House (University of Bristol), February 2013

Professor Michael Furmston e Professor of Law, Sunway University, Malaysia

e Emeritus Professor of Law, University of Bristol

e Chair of the ALSPAC Ethics and Law Committee from its initial meeting in April 1990 to September 2006

e Interviewed in his UK home in Bridgwater, Somerset, December 2012

Professor Jean Golding e Emeritus Professor of Paediatric & Perinatal Epidemiology, University of Bristol

e As Director of ALSPAC, in attendance at every ALSPAC Ethics and Law Committee meeting, almost without exception, from initial meeting in April 1990 to retirement in July 2005

e Interviewed at home in Clevedon, Somerset, December 2012

Dr David Jewell

= e General Practitioner, Bristol, retired

e Member of the ALSPAC Ethics and Law Committee: June 2000 to September 2013

e Chair of the ALSPAC Ethics and Law Committee: January 2010 to September 2013

e Interviewed in Barley House (University of Bristol), December 2012

Dr lan Lister Cheese e Senior Medical Officer, Department of Health, retired

e Founding member of the ALSPAC Ethics and Law Committee: April 1990 to July 2000

e Interviewed at home in Wantage, Oxfordshire, April 2013

AUTHORS AND CONTRIBUTORS

Mrs Elizabeth Mumford

Teaching Fellow in Law, University of Bristol

Secretary of the ALSPAC Ethics and Law Committee from initial meeting in April 1990 to December 1999

Continued as member of the ALSPAC Ethics and Law Committee until October 2011

Interviewed in Barley House (University of Bristol), February 2013

Professor Marcus Pembrey

Emeritus Professor of Paediatric Genetics, University College, London

ALSPAC Director of Genetics, not a member of the ALSPAC Ethics and Law Committee, but advised on genetic issues

Interviewed at home in Mersea Island, Essex, February 2013

Professor Gordon Stirrat

Emeritus Professor of Obstetrics and Gynaecology, University of Bristol

Founding member of the ALSPAC Ethics and Law Committee with a two-year break in membership when Dean of Faculty of Medicine Chair of the ALSPAC Ethics and Law Committee from September 2006 to December 2009

Interviewed in Barley House (University of Bristol), February 2013

Xl

Acknowledgements

My thanks to:

Jean Golding, none of which could have been achieved without her, not only for establishing and directing ALSPAC while maintaining an unwavering commitment to the ethical underpinning of the Study, but also for her constant and enthusiastic personal support, enabling the ALSPAC Ethics Archive to be created and this book to be written.

Michael Furmston for his inspiring chairmanship of the Committee for so many years and the other members of the Committee from whom I have learnt so much.

All those who agreed to be interviewed and have been extensively quoted throughout.

Hugh Barnes, Richard Jones and Elizabeth Mumford for their suggestions and perspective.

Linda Wilson, who spent many hours scanning the documents to create the ALSPAC Ethics Archive and Jill Kelly, who created some order from the initial mass of archival documents.

The Leverhulme Trust, which financed the process of creating the ALSPAC Ethics Archive.

The Brocher Foundation, which awarded me a visiting researcher post during September and October 2012, providing the facilities and peace and quiet to enable me to begin writing the book.

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ACKNOWLEDGEMENTS

The University of Bristol Alumni, which financed the brief oral histories through the Dean of the Faculty of Medicine and Dentistry Award.

The Wellcome Trust, which financed both scoping (Grant ref 096605/Z/11/Z) and cataloguing (Grant ref 106783/Z/15/Z) of the ALSPAC Administrative Archive, including the ALSPAC Ethics Archive, by the University of Bristol Library Special Collections. The Wellcome Trust also, alongside the UK Medical Research Council (Grant ref: 102215/2/13/2) and the University of Bristol, continue to provide core support for ALSPAC.

All the families who took part in the Study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.

The current ALSPAC Executive Committee has read and is happy to endorse this book.

XIII

Foreword

It was a privilege to have the opportunity of initiating and directing the Avon Longitudinal Study of Parents and Children (ALSPAC), even though when times were particularly tough, it seemed like a self-imposed treadmill. Such times were more to do with raising enough money to keep the Study going rather than the Study itself, which was exciting and rewarding in itself. As will be seen from this book, the Study was pioneering in many ways, and the Ethics Committee was vital in guiding it. It was the late, and much missed, Professor David Baum whose idea it was to have such a committee, and it was he who had the foresight to suggest Michael Furmston as the Chair. Both ideas were inspirational. As will be seen from this volume, the way in which the Committee worked derived largely from that choice of Chair. To put the Study in context, Britain was famous for its longitudinal birth cohort studies, especially the three previous national surveys of births in 1946, 1958 and 1970. Having worked on the last two of these, I was aware of the advantages and defects in such studies — the advantages being that they were population-based, with high response rates, the disadvantages being that they lacked the depth that could have been found with more frequent contacts and observations. I therefore developed a design in the 1980s based on the latest (at that time) ideas as to what was known and what was not known. Surprisingly little was known about the ways in which different features of the environment influenced the health and development of the child but evidence from the study of malformations and childhood leukaemia showed that pregnancy was an important time, and that factors such

XIV

FOREWORD as medications (for example thalidomide) and infections (for example rubella) could have profound effects. What was not known was how such features might have more subtle influences that would not be apparent until mid-childhood or later. Added to this was the possibility that there were subtle genetic effects that may have direct influences on development, or that may only have influences in the presence of specific environments.

Given this background, it was obvious that the design of the Study should be to collect as much information as possible on the environment of the parents up until the time of pregnancy and to continue to monitor this, and that of the child, thereafter. The obvious time to start collecting data was as early in pregnancy as possible. This was the first way in which ALSPAC differed from other British birth cohorts. The second unique feature concerned the decision to collect data using self-completion questionnaires rather than by interview; this we considered important for two reasons — it was cheaper but, more importantly, the participants would have the advantage of having time to find answers (such as by looking at diaries or asking a family member) and thus provide more accurate information. Third, the Study was innovative in collecting biological samples as a means of identifying exposures to chemicals, as well as providing the opportunity to extract DNA and assay levels of hormones and metabolites of various sorts. Fourth, and equally importantly, it was innovative in its approach to ethics and the creation of its own ethics committee.

None of the previous cohorts had felt the need to consider the ethics of what they were doing until the mid-1980s, when Neville Butler decided that the plans for the medical examination included in the 16-year-old sweep of the 1970 birth cohort should be considered by a Local Research Ethics Committee. However, it was unique to have an ethics committee attached to a Study. This proved to be a major asset to the Study and to me in particular.

As Director of the Study, I was acutely aware of the responsibilities entailed. My husband had been in the army during the Second World War and was particularly keen on asking “Where does the buck stop?”. Obviously, it stopped with me. Any breach of confidentiality,

XV any error in the science and any difficulty with the financial probity of the Study would ultimately fall on me. As Karen has documented so well in this volume, as time went on, it became apparent that the majority of participants had complete trust in our ability to protect their anonymity, and to treat their contributions appropriately. Although the Ethics Committee could not take over the responsibility, it provided me with the overall advice and support that was needed regarding the running of the Study. It was a group of experts from a variety of backgrounds to whom I could take my worries and uncertainties, and get considered and wise opinions. Nowadays, it is assumed that ethics committees need to be independent — I am not sure why. If the aim is to ensure that a study is carried out ethically, surely the optimum is to work with the study to derive solutions to ethical dilemmas, rather than being a jury stating ‘yes’ or ‘no’?

The Study has succeeded, in spite of all odds. This is due to the amazing staff who were involved and were particularly important in making sure that the Study ran smoothly and within appropriate ethical limits, as well as the members of the Ethics Committee who had major beneficial impacts on the ways in which the data were collected and used. When persuading Karen to write this book, I asked her to ensure that she considered the triumphs and failures ‘warts and all’ — she has done so admirably (as anticipated). It was important to document where it could have been improved and where it fulfilled its aims so that others may learn from both. This document tells the story of this pioneering, informative and rewarding enterprise.

Jean Golding Bristol, August 2017

XVI

Preface

The Avon Longitudinal Study of Parents and Children (ALSPAC), also known as ‘Children of the 90s’, is an internationally renowned longitudinal birth cohort study, based within the University of Bristol in South-West England. ALSPAC’s main goal, in collaboration with local, national and international scientists, is to understand the ways in which the physical and social environment interact, over time, with genetic inheritance to affect health, behaviour and development. Over 14,000 pregnant women were enrolled during 1991—92 and these mothers, with their partners and children and, more recently, others from their extended families, continue to give vast amounts of data: physical, psychological, social, educational, environmental, biological and genetic. The collection and analysis of these unique, diverse and complex data sets raised many ethical concerns, and from the outset, it became clear that sound ethical and legal advice would be necessary to guarantee appropriate protection for the Study participants, including those yet to be born.

At the time ALSPAC was established, there were no guidelines for the ethical governance of such longitudinal studies and no other ethics committees dealing with these issues, so ALSPAC founded its own pioneering ethics committee — the ALSPAC Ethics and Law Committee. This was the first ethics committee attached to a longitudinal study and the first to deal with the ethical issues arising from the collection of genetic material from a population sample. This aspect of the study design was a research methodology not used before; genetic studies had previously been preoccupied with ‘pedigrees’ and

XVII individual inheritance. ALSPAC was also the first comprehensive birth cohort to enrol participants in utero and to include fathers or partners in the Study from the outset.

The aim of this book is to describe the innovative work carried out by the ALSPAC Committee in its early years, particularly how the core ethical principles were established and then how the policies evolved as the Study progressed and became more complex as the children grew up and as the interest and understanding of the ethics of such studies developed and advanced in academia, politics and beyond. This book should be of interest to all those curious about the development of ethical protection for participants within longitudinal studies, not only ethicists, epidemiologists, historians and other academics, but also professionals and lay members of research ethics committees and any individual who is, or has been, a participant in longitudinal epidemiological research.

The book is enlivened by quotes from Committee members that have been interviewed recently, who reflect not only on the pioneering work of the Committee, but also on the unusual style and inspirational leadership of the first Committee Chair, Professor Michael Furmston. The first part of the book documents this unusual style, the changing status of the Committee as research governance developed within the University and the National Health Service (NHS), and, with it, the sometimes difficult relationship with these other official bodies.

The second part of the book describes policy development, with separate chapters detailing:

e Confidentiality and anonymisation: the complexities of providing a secure system when it was essential to link individual participants’ ongoing sequential data. Deductive disclosure was a particular concern in such a localised study.

e Informed consent: the practical considerations of all aspects of consent and assent, including implied, withdrawal, proxy, dual (parent and child), sole (child only) and, most controversial, ‘broad’ consent for the use of genetic material. Too much information was considered as detrimental as too little.

XVIII

PREFACE

Child protection: the principle of non-intervention that was inherent in the design of ALSPAC was soon challenged as child protection concerns arose when Study families were visited at home, attended ALSPAC research clinics or imparted worrying information when interviewed or answering questionnaires. Intervention could also involve breaking the guarantee of anonymity so essential for the carefully nurtured trust of the participants. Disclosure of results: the Committee’s general position of non-disclosure was also challenged with the detection of treatable conditions either foreseen (such as anaemia) or incidental (such as tumours).

Disclosure of individuals’ results on request: the Committee reviewed all requests on a case-by-case basis but despite conflicting legal opinions and considerable pressure, they never felt an individual’s circumstances warranted disclosure and, with it, the risks of breaking the guarantee of anonymity.

Requests for help by individual participants: requests for help, sometimes quite harrowing, were also reviewed on a case-by-case basis and, very occasionally, the guarantee of anonymity was broken on compassionate grounds.

Linkage to third-party databases: opt-out consent was initially acceptable but this became inadequate over time as more comprehensive protection of patients became obligatory and complex procedures had to be negotiated.

Although these chapters cover familiar concepts within the now well-established discipline of medical ethics, the ALSPAC Committee was at the forefront of ethical thinking in regard to genetic epidemiology and longitudinal studies. How much the Committee’s work contributed to the current debates on these issues, evident in the abundance of journals and publications on the ethics of research, is debatable and references within this book have been limited to the few with obvious relevance.

The Committee had to work from first principles and grapple with the real ethical dilemmas that emerged as the Study progressed and became ever more complex. Many of the policies arising from these

XIX deliberations are considered standard practice within medical research now, others remain controversial. Nevertheless, these principles and policies have served ALSPAC well, with the integrity of the Study never compromised.

The final part of the book describes the broader remit of the Committee when deliberating on the ethical issues that arose when endeavouring to reduce attrition rates with appropriate incentives or collaborating with commercial companies. The Committee also had unique oversight of the whole of ALSPAC as it reviewed in detail all that was asked of participants. Finally, the wider influence of the Committee is discussed, not only in a formal advisory capacity for other institutions, such as a House of Lords Science and Technology Sub-Committee and the European Society of Human Genetics, but also as an exemplar for other longitudinal studies, a research methodology that has become increasingly popular since ALSPAC began. These interventions and the importance of the Committee’s work beyond that of protecting the Study participants have not been documented previously, although some references can be found scattered within the Committee minutes. The extensive influence of the Committee should provide weight to those considering the Committee’s work in the light of their own.

Personal perspective

In describing the early days of the Committee, a completely objective perspective was not possible as I have not been a detached observer. As a recent and thoroughly sleep-deprived mother, I joined Jean Golding’s Unit of Paediatric and Perinatal Epidemiology in 1988 as a medical coder when ALSPAC was being planned. As with all staff within ALSPAC in the early days, I had a variety of simultaneous roles, mainly related to my nursing background. In 1998, Jean asked me to complete the local NHS Research Ethics Committee form for approval for the first all-cohort research clinic, and so began my involvement with the ethical issues within ALSPAC. A year later, I was asked to take the minutes for the Committee, and soon after that, I became the Committee Secretary and then the ALSPAC Ethics Manager. For

XX

PREFACE over 14 years I worked closely with the Committee, some members have become friends and I continue to work with Jean Golding. Other than verbatim quotes from recorded interviews and extracts from the Committee minutes, opinions and any errors remain my own. There have been three main sources used when writing this document:

1. Minutes and accompanying documents of the Committee between its establishment in 1990 and July 2005, when the retirement of Jean Golding was formally acknowledged by the Committee. Ethical approval was given for the deposit of this material as a public resource in the University of Bristol ALSPAC Administrative Archive held by the Library’s Special Collections (Committee reference E201301, July 2015).

2. Papers during the same period from: Jean Golding; Michael Furmston, Chair of the Committee throughout this period; Elizabeth Mumford (née Roberts), Secretary of the Committee for the first 10 years; and myself, Secretary of the Committee for the following 14 years.

3. Brief oral histories recorded by me during 2012-13 from eight members of the Committee, as well as Professor Marcus Pembrey, ALSPAC’s Director of Genetics, who was central to the inclusion of genetics from the outset in ALSPAC’s design and provided essential information and advice to the Committee.

These documents have been indexed and will be archived along with the videotaped oral histories in the University of Bristol Special Collections as the ALSPAC Ethics Archive, a subset of the main ALSPAC Administrative Archive that provides a rich resource for further research into the origins and complex methodology of this extraordinarily ambitious and successful study.

Karen Birmingham August 2017

XXI

The Avon Longitudinal Study of Parents and Children (ALSPAC) was part of a European consortium of longitudinal birth cohorts, designed by Jean Golding, who had extensive knowledge and experience of such studies from working on the previous UK national birth cohorts. It was an immensely ambitious study that uniquely included genetics in its methodology and was supported by a Steering Committee who believed, unlike many people, that Jean’s vision could be achieved. They also believed that it was vital for the Study to be beyond criticism not only scientifically, but also ethically, and promoted the novel concept of an ethics committee attached to the Study itself - the ALSPAC Ethics and Law Committee. To insist on such thorough and ongoing ethical review was exceptional at a time when research governance was minimal and ethical scrutiny not obligatory. ALSPAC’s frequent and detailed data collections from diverse sources (self-completion questionnaires, interviews, hands-on measurements, biological samples and environmental measures) provided a unique and complex resource for scientists of many disciplines but also created numerous ethical issues not encountered previously. It would be the Committee’s task to identify the principles and design the policies that would provide comprehensive protection of the Cohort throughout the Study.

The Avon Longitudinal Study of Parents and Children is known to the scientific community as ALSPAC and to the Study participants and public as ‘Children of the 90s’.! ALSPAC was based in the UK city of Bristol and the surrounding area but was part of a multicentre European consortium (the European Study of Pregnancy and Childhood [ELSPAC]) (Golding, 1989a), which was initiated after a meeting in Moscow in 1985 convened by the World Health

Organisation. Jean Golding was the initial Director of both ELSPAC and ALSPAC and brought with her a resolute belief in the value of longitudinal birth cohorts, based substantially on her previous work on the 1958 and 1970 UK national birth cohorts.”

The aims of ALSPAC were exceptionally ambitious: to identify the ways in which to optimise the health and development of children.’ Not only were detailed and frequent data collections planned, but several innovative components were also included: to collect genetic data from the outset; to recruit women in pregnancy; and to collect data from both the mothers and their partners. George Davey Smith, Professor of Clinical Epidemiology, who took over from Jean Golding as Scientific Director of ALSPAC when she retired, has frequently talked about his first reaction to ALSPAC. In August 1989, he noticed a brief paragraph by Jean Golding in the back of the Lancet (Golding, 1989b) describing ALSPAC and asking for potential collaborators to make contact. He considered the project an impossible undertaking, dismissed it out of hand and, not yet knowing Jean Golding personally, thought it sounded implausibly ambitious. If studying children was not ambitious enough, ALSPAC rapidly expanded to include adults and, to reflect this, in 1999, the meaning of the acronym ALSPAC was adapted from ‘Pregnancy and Childhood’ to the current ‘Parents and Children’.

From her experience with other longitudinal studies, Jean Golding knew of the difficulties of analysing and interpreting large longitudinal data sets that lack sufficient detail to obtain robust results. This, combined with a chance meeting in Athens in 1988 with Professor Marcus Pembrey (Overy et al, 2012, p 11), Professor of Paediatric Genetics at the Institute of Child Health in London, resulted in ALSPAC being designed to incorporate genetic data as well as the detailed and frequent physical, psychological, social, educational, environmental and biological measures originally planned. Marcus Pembrey reflected on the significance and context of this methodology when interviewed in 2013:

“Tt was fairly clear that by 1988, it [the Human Genome Project’ was going to happen.... So, I knew that the big challenge — which no one really knew what the hell was going on — was these common diseases, the genetic component of asthma, allergy, diabetes, you name it.... It seemed a good plan.” (Marcus Pembrey, Oral History Interview, 2013)

A good plan indeed, also described as an “audacious plan”? by the late Professor David Baum, the charismatic Head of the Department of Child Health at the University of Bristol at the time and a stalwart supporter of ALSPAC from the very beginning. David Baum was “a man who had a hundred ideas a day”, as described by his friend and colleague Dr Timothy Chambers, also interviewed in 2013, who went on to Say:

“I don’t think David Baum had had a major focus on epidemiology ... I think David came under the influence of Jean [Golding], quite rightly. David being David, once he was seized with something would then take the very big view ... Jean had had the idea, it wouldn’t have taken much for David to be galvanised by it and to use his influence alongside hers to promote it.... Who could not be fired up with enthusiasm for David's breathtaking visions?” (Tim Chambers, Oral History Interview, 2013)

David Baum

The description of ALSPAC as audacious was baffling to Dr David Jewell, ALSPAC Ethics and Law Committee Chair from 2010 to 2013 but a member of the Committee for 10 years previously, who admitted when interviewed that it took over a decade to understand why the Study could be considered audacious:

“T didn’t quite understand why [audacious], but it [ALSPAC] now seems both farsighted as well as everything else.... The genetics looked just about possible but a long way into the future and it now is becoming apparent that it has happened a lot quicker than anyone ever expected, so other studies now are trying to emulate what ALSPAC had built into its own ‘genes’ at the very beginning.” (David Jewell, Oral History Interview, 2012)

The Study planned to enrol as many pregnant women as possible over a period of one year within the defined catchment area of three Avon Health Districts.° Follow-up of these mothers, their Study children and their partners with detailed data collections was anticipated for at least seven years. As the Study progressed, so the design expanded. Over 14,000 mothers were recruited during 1990-92, a longer enrolment period than first anticipated, with data collected from five main sources: self-completion postal questionnaires; hands-on measurements; biological samples; third-party sources, such as hospital and educational records; and environmental monitoring, such as air quality. The longitudinal aspect of the Study became inestimable; seven years became lifelong and 650 of the children’s children have (as of August 2017) been recruited to a third-generational study. The mothers received four questionnaires during pregnancy and by the time Jean Golding retired, 80 different questionnaires had been sent to Study participants. These questionnaires could be up to 60 pages long. The hands-on measurements began with ‘Children in Focus’, involving approximately 1,400 children who attended research clinics, initially at the age of four months and then nine more times in their first five years. This expanded to annual half-day clinics for all Cohort children from the age of seven to 13 years, with over 8,000 children seen at seven years and just over 6,000 at 13 years. Annual clinics overlapped as the Cohort comprised mothers whose births were due over a 21-month period. The collection of biological samples included placentas, blood, saliva, urine, hair, nails and teeth; DNA was extracted and cell lines eventually created, enabling infinite supplies of DNA. This has become a unique, internationally recognised resource used by thousands of collaborators from a multitude of disciplines.