D.E. Matthews « V.T. Farewell Using and Understanding Medical Statistics 4th, completely revised and enlarged edition Vernon Todd Farewell B. Math, M. Math (Waterloo), PhD (London); Senior Scientist MRC Biostatistics Unit, Cambridge, UK The most common organizational structure for a trial is to have three pri- mary committees. The first is often called the Trial Management Committee or Team. This group of individuals is usually headed by the principal investigator(s) fer the trial, and is charged with the day-to-day running of the trial. The Trial Steering Committee, on the other hand, is chaired by an indi- vidual who is independent of the investigators who designed and are imple- menting the trial, in order to provide independent oversight of the study. The Steering Committee will have other independent representation, usually in- cluding statistical expertise, and often including lay individuals from either the general public or disease interest groups. Trial investigators may also sit on this committee. The Trial Steering Committee is vested with primary respon- sibility for the ethical running of the trial. The final committee is usually the Data Monitoring Committee (DMC). This is a group of individuals who are entirely independent of the trial, and who are charged with monitoring the trial from an ethical perspective manuscript are detailed below. The authors thank Professors Tom Meade, Anthony Pinching and Simon Wessely for advice about design and executicn. Trial Steering Committee (TSC) ‘The Trial Steering Committee (TSC) Is responsible for the independent oversight of the progress of the trial, Investigation of serious adverse events, and determining the future progress of the trial in the light of regular reports trom the OMEC. The TSC Is composed of: Professor Janet Darbyshire (Chair),Tony Johnson report on progress 2001-2006 contents Abstract Introduction Epilepsy National General Practice Study of Epilepsy in its early ‘Years (NGPSE) Multicentre Study of Early Epilepsy end Single Seizures (MESS) Longer-term clinical outcomes and cost-effectiveness of standard and new antiepileptic drugs (SANAD) Multicentre trial of infantile spasms (UKTSS) Dementia Controlled trial of a cholinesterase inhibitor in the -nanagenent of agitation in denentia that is unresponsive ‘to psychological intervention (CALM-AD Psychiatry Clinical Trials Unit (King's College London & Institute of Psychiatry at the Maudsley) Mental Health Research Network (NHRN) Adoptions Comittee Depression Neurotic Disorders Chronic Fatigue Syndrome (CFS) Transfusion Medicine Epideniology and survival ot transfusion recipients {EASTR) Transfusion alternatives preoperatively in sickle cell disease (TAPS Trial) Acknowledgement ‘Sumary of major achievenents Publications from this progranme Links Abstract T have initiated, developed, and collaborated in both clinical trials and epidemiological studies in four challenging medical specialties working with a large nunber of collaborators geographically dispersed throughout UK, Europe, and beyond. These have resulted in major advances in the understanding of denentia in the comunity (with Fiona Matthews), the ‘treatment of infantile spasns and epilepsy, the efficacy of cognitive therapy in both unipolar and bipoler affective disorder, and the long-term consequences of neurotic disorders. Over many years my progranme has contributed to the successtul completion of the three Largest clinical trials, all of major international importance, in epilepsy, as well as the development of a novel method for estimating years of Life Lost following diagnosis of seizures. My programme will be exploited in the future in further collaborations with the pharmaceutical industry that allow head-to-head comparisons of their new drugs. deleted T have enabled a successful collaboration Linking the research progranmes of this Unit with the HRC Clinical Trials Unit (MRC CTU) in London, that has resulted in the establishnent of a new Clinical Trials Unit dedicated to mental health and neurological sciences at the Institute of Psychiatry in London, and to the creation of a major research progranne in transfusion medicine, a specialty that currently lacks an evidence base, that has resulted in a multitude of clinical trials and other studies. The Linkage has enabled ny expertise in clinical trials to be extended to chronic fatigue syndrone and the setting-up of 2 major WRC study to evaluate the efficacy of four different interventions. ‘I have advised many clinical trialists on the setting-up of organisational. structures including Steering and Data Monitoring Committees, and Management Groups, against a background of confusion partly engendered by recent European and UK legislation. Introduction I present my eighth and final Unit review report since joining MRC Neuropsychiatric Research Unit in 1968; @ period exceeding 37 years ‘during which I have been very privileged to engage fully in the research programes of MRC, be a co-editor for 18 years of the first major journal in medical statistics (Statistics in Medicine), found an international society (Society of Pharmaceutical Medicine), draft the Constitution for another (International Society for Clinical Biostatistics), and contribute to UK Government, European, and International working parties and committees. In view of my retirement in September 2068 I describe only ay research programme over the past five years without reference to the future but note that none of my projects will terminate in the near future, for they will be continued and expanded by others many of whom I have trained for that purpose. As I have worked within WRC Cognitive Function and Ageing Study since its inception, and line-managed Fiona Matthews from her appointment as statistician to this project in 1997, this section ends with a description of her research over the Last six years as well as her proposals for the next five. fy role within MRC changed radically in 2001, resulting in my switching from independent band 2 to core scientist, and with secondment (20%) to the Division Without Portfolio (DWP), now Division for Other Diseases, in deleted WRC CTU, London (Director: Janet Darbyshire). My expertise in clinical trials was needed to expand the activities of DWP into areas such as mental health, denentia, chronic fatigue, and transfusion medicine, all currently the focus of government health policy. The requirement to serve ‘two NRC Units Linking Cambridge and London has worked extremely well and T have not only fulfilled my expanded role within MRC CTU (as evidenced by their Unit review in 2604 and requests for an increased element of my time), but also through continuation and completion of the programme set out in this Unit's previous review report; this was achievable only by virtue of the capabilities of the staff 1 have supervised ‘and trained. Tn my expanded role T have engaged in many clinical trial consultation meetings especially to deal with the establishment of infrastructure, the complexities resulting from European and UK legislation, and the changing roles of Trial Steering Committees and Data Monitoring Committees over which there is currently great variation in practice, elated coupled with much confusion. In this report I present activities within both Units under the main headings of epilepsy, dementia, psychiatry, chronic fatigue, and transfusion medicine, highlighting only the principal studies ‘Epilepsy — ‘Epilepsy is the third most prevalent neurological disorder (about 1 in)200) ‘collaborations, started 36 years ago, include large clinical trials and epidemiological studies of international importance. In 2005 ny contributions were recognised by neurologists with the Epilepsy Lifetime Service Award for "a lifetime's contributions to Services to statistics and epilepsy" from International League Against Epilepsy UK Chapter; I am the third recipient of this avard and the first statistician. In 1996 I was appointed by the Secretary of State for Transport (Sir George Young) to his Honorary Medical Advisory Panel on Driving and Disorders of the Nervous System for a term of 5 years (the panel includes neurologists, neurosurgeons, neurophysiologists, and neuropsychologists as well as representatives from DVLA]; it advises first on driving regulations for both group I and group 11 licenses in specific disease categories, and on individual cases. My term was extended for a further 5 years in 2062, and T remain the only statistician appointed to any of the Minister's six advisory deleted panels. T describe four of my more important collaborations to epilepsy nal General Practice Study of Epilepsy in its early Years (NOPSE) (with S. Shorvon, 0.Cockerell, S. Lhatoo, B. MacDonald, J. Sander, 6. Bell (National Hospital, London), D.Goodridge (GP, Kent)) NGPSE remains the only large prospective cohort study of epilepsy ini the general population; it recruited 1268 patients during 1984-1988, with follow-up to 2001. 1 was responsible for the design and have undertaken analysis in a series of major papers published since 1996. We found an unexpected excess mortality [01.050] and exploited the yearly decline in SRS trom diagnosis by Using a Weibull survival model to estimate annual death rates by sex, age, and seizure type; these were superimposed on ‘the English Life table to estimate reductions in Life expectancy [04.043]. As far as I am aware, this methodology is original and the paper attracted a bursary avard fromthe Anerican Epilepsy Association for the first author to attend their 57th Annual Meeting in Boston in 2063; the Lancet editorial on the paper connented that ‘the authors have expressed earlier knowledge in a new form which serves to refine our understanding of an important prognostic aspect of epilepsy" (Tomson, 2665). Modelling of seizure recurrence using multi-state, discrete tine, Markov chain and other uence transitions epsy) states. Further follow-up of the NGPSE cohort is planned. deleted entre Study of Early Epilepsy and Single Seizures (ess) Geith hadwick, When and whether to start drug treatment following a seizure is|uncertain We have now resolved this issue in the MRC funded MESS| trial that randomised 1443 patients fron 13 countries to inmediate or delayed drug treatment. Lois Kim's analysis demonstrated reduction of seizure occurrence with imnediate drug treatment but no long-term effect on emergence of chronic epilepsy; Lois Kim also produced a simple prognostic model using the nethods developed by Royston and Saverbrei (2004) to estimate risks ot seizure recurrence under the two treatment policies that can be readily used in clinical practice. Results were published in Lancet [05.067] and Lancet Neurology [96.061], and attracted an editorial (NcIntosh and Berkovic, 2005). Longer-term clinical outcones and cost-effectiveness of standard and new antiepileptic drugs (SANAD) (with D. Chadwick, A. Jacoby, C. Tudor Smith, P. Williamson (Liverpoot)) There is a substantial difference in costs of drugs introduced in the early 19905 and the standard first-line treatments, carbanazepine and sodiun valproate, available from the 1969s. The HTA-Tunded SANAD trial evaluates 5 new drugs for cost-effectiveness by conparison with the two standard ones in an original design that allows drugs from different pharmaceutical companies to go head-to-head; it conpleted randomisation of nearly 2500 patients by mid-2004 with minimum follow-up for an additional year; results were presented in March 2086 and are of major importance. I advised on design and analysis and chaired the Data Monitoring Committee. The success of this study design will be exploited in a new trial comparing the best treatments) from SANAD with @ further generation ot drugs licensed in the late 1990s. Multicentre trial of infantile spasms (UKTSS) (with J. Osborne, 5. Edwards, E, Hancock, A. Lux, F. O'Callaghan (Bath), C. Kennedy (Southampton), R. Newton’ (Nanchester), C. Verity (Department of Paedi jenbrooke's Hospital, Canbridge)) ‘Infantile spasms are a rare form of devastating epilepsy in childhood that is difficult to control and associated with Learning disabilities, severe Psychonotor retardation, and death. Just two forms of treatment, drugs (vigabatrin) and hormones, are available, and we have compared these in the UKISS trial that recruited 197 infants throughout UK; I advised on trial design and did the analysis. Results published in Lancet [04.969] demonstrate that hormones provide better early control of spasms, while ‘those published in Lancet Neurology [05.063] indicate no longer term differences up to age 14 months, but as conjectured suggest that better initial control of spasms in those with no identified underlying aetiology may lead to improved development with hormones. The design of this study will now be exploited in a new Randomised Controlled Trial (RCT) comparing combined hormone and vigabatrin treatment with hormones alone. Dementia Part of my activity in dementia has been within the MRC Coanitive deletedFunction and Ageing Study Co-operative (CFAS) of which I have been a member since its inception in 1988. Fiona Matthews was appointed as CFAS statisticion in 1997 and, since my role is now mainly advisory, this part of my programme is summarised separately under her name. Fiona Natthews's achievements in understanding the full complexities of this study, developing the necessarily complex techniques for analysis within deleted her PhO, organising a thriving research team of 15 staff thereby demonstrating her abilities of leadership, and coordinating the publication of over 38 papers, indicate her capability for managing CFAS within the Unit. Tan a member of the team led by Martin Rossor (University College, London) and Ian Mckeith (Newcastle) that presented our bid to become the Co-ordinating Centre for the UK Denentias and Neurodegenerat ive Diseases Research Network at the Department of Health (DK); we competed successtully against two other teams and were awarded 726m. deleted Controlled trial of se inhibitor in the managenent of agitation in denentia that is unresponsive stitute of Psychiatry, London), C. Ballard (Newcastle) ‘Lock (Swindon), A.Burns (Manchester), (. Holmes (Southampton), R. Jacoby, E. Juszczak (Oxford), M. Knapp (London), J. Lindesay (Leicester), J. O'Brien (Newcastle), S. Nally &S. Tebbs (MRC CTU)) Tan a principal investigator (PI) for this MRC-funded trial that was designed to compare donepezil, risperidone, and placebo in thercontrol ot agitation in denentia, and I guided other investigators on design, managenent, and analysis, as well as supervising a half-time data manager within MRC CTU. CALM-AD suffered major problens with a delayed start due to extended negotiation of indemnity agreenents vith deleted sponsors, opposition to the trial by a pharmaceutical conpany, withdrawal of risperidone by Committee on Satety of Medicines 3 months after its start, and expiry of the shelf-Life of placebo. Despite these setbacks the trial was remarkably successful in randomising its target of 190 patients 6 months before the scheduled end of recruitment; at my suggestion the chief investigator applied for, and NRC awarded, an additional 740,000 to enable continuation of recruitment resulting in 272 patients randomised; deleted results will be disclosed in Nay 2086. The research team and infrastructure brought together by this trial will be maintained in a further trial (DOMINO) comparing donepezil, menantine, and their conbination, in Alzheiner's disease, the outline proposal having been accepted recently by MRC. Psychiatry my long-running programe in psychiatry has continued with the successful conclusion of two trials in depression, a series of papers|ifrom ‘the Nottingham neurotic disorders cohort, engagement in the MRC Co-operative Group for the Evaluation of Interventions to Inprove Mental Health in Primary and Secondary Care (succeeding Simon ‘Thonpson) wherein T supervised their statistician (Ula Nur), and membership of Steering Committees and Data Monitoring Committees. I have declined to _ deleted be an applicant on several grant proposals as a result of overload but have nonetheless provided statistical advice. I have revised ny chapter in the Royal College of Psychiatrists’ book on research methodology to be published (3rd edition) this year [66.496] and will update my survey oF clinical trials in psychiatry (Johnson, 1998) to include 2606. Clinical Trials Unit (King's College London & Institute of Psychiatry at the Maudsley) (with S.Wessely, R. Kerwin, R. Walwyn, S. Lee, (Institute of Psychiatry, London)) A Long needed Clinical Trials Unit (CTU) dedicated to RCTs in psychiatry ‘and the neurosciences has been established with an ambitious remit to advise, initiate, design, conduct, analyse, present and publish clinical trials in mental health. I have acted as a link between this CTU and MRC CTU, Provided guidance as @ member of its Steering and Management Comnittees, and provided supervision and managenent of its statisticians geleted (Rebecca Walwyn & Sally Lee) on a monthly basis. I have attempted to guide the CTU towards critical mass and in addition to two statisticians it now has @ Manager, Database Manager, and secretary. Difficulties with appointing a successor to Brian Everitt as Chair of Biostatistics or a senior lecturer within that department, posts that were intended to provide sone management and supervision of statisticians within the CTU, have led to my fulfilling these roles as well as providing advice to grant applicants at ‘the Institute of Psychiatry (IoP) and King's with inevitable requests, necessarily usually declined, to becone a co-applicant. Nental Health Research Network (NHRN) Adoptions Comittee (chair: T. Wykes (Institute of Psychiatry, London)) In March 2005, I succeeded Janet Darbyshire as a menber of this important independent subcommittee of MHRN that decides on the suitability of projects to run on the UK network provided that they have service user input, are in Line with national mental health policy, are free of major ethical and design flaws, require multiple centres, and demonstrate feasibility to run on the network. T have guided the conmittee towards acceptance of larger studies, documentation and monitoring of Load on the network within individual hubs, by disease areas, and by patient recruitment requirements. Depression (with 6 Paykel, R Abbott, H Hayhurst (Departnent of Psychiatry, University of Cambridge), F Bentall (Manchester), P Kinderman, R Morris (Liverpool), Glasgow, ffectiveness of cognitive therapy (CT) or usual treatment for people with residual (unipolar) depression followed up for 18 months in which advised on design and deleted Supervised analysis. We have now extended follow-up to 6 years and denonstrated (using exponential and Weibull survival models) that the effects of CT in preventing relapse were not lost until 31/2 years; we also identified a need to evaluate the efficacy of booster CT around 2 years [95.077]. We have extended the methods and infrastructure developed in this trial to conduct @ similar RCT in people with bipolar disorder. I wrote comprehensive analysis strategy prior to exatining any tril deta thet has Gateted become a template for trials in psychiatry, and beyond, and supervised those doing the analysis (Hazel Hayhurst & Rosemary Abbott), Results indicate that by contrast to unipolar depression, CT was of Little use in bipolar disorder but suggested benefit in patients with few prior episodes With Giles Newton-Howes and Peter Tyrer (Imperial College, London)|i have produced a najor meta-analysis of the association between deleted personality disorder and outcome of depression incorporating every study that we could find in the Literature irrespective of measures used, and employing the methods of whitehead et al. (Whitehead et al, 1999), to enable inclusion of both dichotonised and continuous outcones. This is an area of major controversy over a long period and we have denonst rated clearly that co-morbid personality disorder with depression is associated with a doubLing of the risk of poor outcone for depression irrespective of ‘type of outcome criterion, or treatment (drugs, psychotherapy, or both) (05.089). lieurotic Disorders (with P. Tyrer, U. Nur, G. Knerer (London), H. Seivewright (Nottingham) ) ‘The Nottingham study of neurotic disorders started as 2 community-based 10-week RCT of 201 patients allocated to three treatments and then continued as a cohort study with follow-up to 5 years. We have now completed a further follow-up at 12 years achieving 98% response by using (to my mind the fully justified method of) cold-calling. The study is' unique and has produced a series of papers on the ethics of cold-calling, changes in personality status, ‘hymia, ial_functioni delted Chronic Fatigue Syndrome (CFS) (with P. white, T. chalder (London ), M. Sharpe (Edinburgh) CFS is currently the most controversial area of medical research characterised by vitriolic articles and websites nainta:ned by the More Geleteg extreme charities supported by some patient groups, journalists, Members “deletes of Parliament, and others, who have little time for research investigations. were funded end have started despite active canpaigns’to halt then. Tam dalated part of the PACE study, a multi-centre RCT comparing cognitive behaviour therapy, graded exercise training, and) pacing in addition to standardised specialist medical care (SSMC), with SSMC alone in 600 patients; it is funded by MRC, Chief Scientist's office (Scotland), DH, and Department of Work and Pensions at an estimated cost of 72.7m. I have been fully engaged in providing advice about design of PACE and I ana menber ot © deleted both Trial Managenent Group and Trial Steering Committee. T am not a PT because of familial involvenent with one of the charities, a perspective that has enabled ne to play a vital role in ensuring that all involved in PACE naintain absolute neutrality to all trial treatments in presentation, docunentation, and assessment. Transfusion Medicine (with National Blood Service (NBS) Clinical Studies Unit (CSU, Cambridge), A casbard (MRC CTU) Transfusion medicine is one of the newer specialties of medicine and covers all aspects of the use of blood products and components. Since the evidence base for current practice is very Limited with few high quality RCTs, NBS established in 2001 a CSU in Cambridge, supporting a deleted dedicated statistician within MRC CTU, to initiate new trials and other studies. T moved into this area through involvement in MRC CTU and have supervised the statistician (Angela Casbard) supported by the NBS grant (initially 3 years but now permanent). Location of the CSU in Cambridge has enabled my close collaboration with excellent working relationships. Transfusion is a challenging area because ot the small number of clinicians working in this specialty, and their lack of involvenent in RCTS, ‘and also because this is a fast moving area where practices change deleted rapidly with the issuing of new guidelines; also there are no charities in transfusion. Problens are illustrated by @ review of all RCTs of prophylactic perioperative transfusion of fresh frozen plasma in) patients undergoing cardiac surgery; Just six were found, all small, of poor quality, with variable follow-up periods and outcomes [04.020]. Statistically this specialty is interesting because the outcones of transfusion are known within a short period (48 hours, a week, or at most a month) with just one or two of Prinary importance, and consequently there is scope to use the neglected (group) sequential designs. Despite the problems identified above, the CSU has been successful in stinuloting applications for over thirty RCTS and other major studies, some of which have been funded; two examples. deleted follow. records 0 the donor source, processing, and destination of every iten of every product they stock. By contrast very Little is known of exactly what happens at the level of patients with regard to requirenents and outcome. To renedy this NBS set up 2 national survey in England to establish the major uses of fresh frozen plasma, red blood cells, and platelets, and the survival of patients following transfusion. a pilot study was conducted in 5 hospitals using two months data fron early 2001 (4351 trensfusion episodes in 2468, recipients) to establish feasibility of Linking records manually from blood bank and hospital computers, and to classify major reasons for transfusionusing standard ICD-10 diagnoses and Office for Population Censuses and Surveys (OPCS) procedures; the pilot study report provided a wealth of important information on the main diseases and operative procedures for which the three components were required [02.410; 04.466]. The full survey of 29 hospitals (stratified by size and region) and surveying the period from October 2601 to September 2062 by random sampling of ‘transfusion recipients (stratified by product and month) but with complete annual use of blood products over that period, was allowed to proceed in 2065 after long delays induced by the Patient Information Advisory Group as we have reported [@4.972]. Information has been obtained from a larger sample than expected. This study is unique and is already the target for requests for infornation about specific patient groups; data collection, editing, and classification are complete, and I ax supervising the analysis Transfusion alternatives preoperatively in sickle cell disease (TAPS Trial) Patients with sickle cell disease (SCD) often have a blood transfusion before surgery, the efficacy of which is questionable. To ascertain whether pre-operative transfusion increases or decreases problens arising after Surgery we have set up a multi-centre group sequential RCT with one month follow-up to recruit 480 patients with SCO in UK and USA, thereby establishing the first major UK-USA collaboration in transfusion medicine TAPS has been funded by NBS and will start later this year. Acknowledgement At the end of this my final report I gratefully acknowledge the support T have received fron MRC over a very long period, the help and encouragenent I have received from seven very eninent Unit Directors (or deleted Derek Richter, Professor Sir Richard Doll, Dr Robert Balazs, Dr Ian Sutherland, Professor Nicholas Day, Professor Simon Thonpson, and Professor Janet Darbyshire), and the pleasure and privilege of working with hundreds of clinicians, statisticians, and other researchers scattered around the world. © pay particular tribute to all the Unit staff both past and present whose companionship, advice, and encouragement have made my career so enjoyable and revarding. ‘Summary of major achievements Successful integration of diverse research progranmes across two NRC Units; Providing young statisticians with confidence and expertise to function independently; Completion of major trials and epidemiological studies in difficult medical specialties; Inproving understanding of psychiatric and neurological diseases and their treatment; Lifetine achievenent avard for research in epilepsy. Publications from this programme Peer-reviewed publications Books, book chapters and reports Editorials and commissioned articles Letters and commentaries Other non-peer-reviewed publications ieee deleted