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1.  An investigation of whether factors associated with short-term attrition change or persist over ten years: data from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) 
BMC Public Health  2006;6:185.
Factors associated with the loss of participants in long-term longitudinal studies of ageing, due to refusal or moves, have been discussed less than those with short term follow-up.
In a population-based study of cognition and ageing (the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS)), factors associated with dropout due to refusal and moving in the first follow-up period (over two years) are compared with factors associated with dropout over ten years. Participants at 10-year follow-up are compared with their age-standardised baseline contemporaries.
Some consistent trends are found over the longer term. Refusers tended to have poorer cognition, less years of education, not have a family history of dementia and be women. Characteristics of people who moved differed between waves, but the oldest and people in worse health moved more. When surviving and responding individuals at ten years are compared with those of the same age at baseline many differences are found. Individuals of lower social class, education, cognitive ability, in residential care, with sight/hearing problems and poor/fair self-reported health are less likely to be seen after 10 years of follow-up. Individuals report more health problems when they participate in multiple interviews.
The characteristics of refusers in the longer term are similar to those refusing to participate over the shorter term. Long-term follow-up studies will under represent the disadvantaged and disabled but represent full health status of participating individuals better. There are advantages and disadvantages to both short-term and long-term follow-up.
PMCID: PMC1538586  PMID: 16848886
2.  Hormone replacement therapy in general practice: a survey of doctors in the MRC's general practice research framework. 
BMJ : British Medical Journal  1991;302(6788):1317-1320.
OBJECTIVES--To survey current prescribing practice for hormone replacement therapy among general practitioners and to elicit their views on the role of hormone replacement therapy in the prevention of osteoporosis and cardiovascular disease; to determine whether they would participate in randomised controlled trials to evaluate the long term beneficial and adverse effects of hormone replacement therapy. DESIGN--Postal questionnaires to general practitioners throughout the United Kingdom. PARTICIPANTS--1268 general practitioners in the Medical Research Council's general practice research framework. RESULTS--1081 (85%) doctors in 220 (95%) practices responded. The doctors were currently prescribing hormone replacement therapy to an estimated 9% of their female patients aged 40 to 64, and 55% of doctors were prescribing opposed hormone replacement therapy (oestrogen plus progestogen) to more patients than a year previously. Over half the doctors would consider prescribing hormone replacement therapy for prevention of osteoporosis (670, 62%) and cardiovascular disease (611, 57%) to asymptomatic women. Overall, 79% of the doctors (851) would definitely or probably consider entering women who have had a hysterectomy into a randomised controlled trial comparing unopposed (oestrogen only) hormone replacement therapy with opposed hormone replacement therapy; 49% (524) would enter patients with a uterus into such a trial. Among a subsample, 85% (180/210) would consider entering patients without menopausal symptoms into a trial comparing hormone replacement therapy with no treatment (unopposed in patients who have had a hysterectomy, opposed in those with a uterus). CONCLUSION--There is considerable uncertainty among general practitioners as to the balance of beneficial and harmful effects of hormone replacement therapy in the long term, particularly relating to its use for prevention of osteoporosis and cardiovascular disease. Most of these doctors would be prepared to participate in randomised controlled trials to determine the long term effects of this increasingly widely used treatment.
PMCID: PMC1670009  PMID: 2059689
3.  Study protocol: delayed intervention randomised controlled trial within the Medical Research Council (MRC) Framework to assess the effectiveness of a new palliative care service 
Palliative care has been proposed to help meet the needs of patients who suffer progressive non-cancer conditions but there have been few evaluations of service development initiatives. We report here a novel protocol for the evaluation of a new palliative care service in this context.
Using the MRC Framework for the Evaluation of Complex Interventions we modelled a new palliative care and neurology service for patients severely affected by Multiple Sclerosis (MS). We conducted qualitative interviews with patients, families and staff, plus a literature review to model and pilot the service. Then we designed a delayed intervention randomised controlled trial to test its effectiveness as part of phase II of the MRC framework. Inclusion criteria for the trial were patients identified by referring clinicians as having unresolved symptoms or psychological concerns. Referrers were advised to use a score of greater than 8 on the Expanded Disability Scale was a benchmark. Consenting patients newly referred to the new service were randomised to either receive the palliative care service immediately (fast-track) or after a 12-week wait (standard best practice). Face to face interviews were conducted at baseline (before intervention), and at 4–6, 10–12 (before intervention for the standard-practice group), 16–18 and 22–24 weeks with patients and their carers using standard questionnaires to assess symptoms, palliative care outcomes, function, service use and open comments. Ethics committee approval was granted separately for the qualitative phase and then for the trial.
We publish the protocol trial here, to allow methods to be reviewed in advance of publication of the results. The MRC Framework for the Evaluation of Complex Interventions was helpful in both the design of the service, methods for evaluation in convincing staff and the ethics committee to accept the trial. The research will provide valuable information on the effects of palliative care among non-cancer patients and a method to evaluate palliative care in this context.
PMCID: PMC1615868  PMID: 17014714
4.  Prognostic features in the third MRC myelomatosis trial. Medical Research Council's Working Party on Leukaemia in Adults. 
British Journal of Cancer  1980;42(6):831-840.
This paper reports the prognostic significance of clinical and laboratory features recorded at presentation in 485 patients entered into the Medical Research Council's 3rd therapeutic trial in myelomatosis between July 1975 and August 1978. The data were complete up to 1 January 1980, with a median follow-up time of 36 months. The 3 major determinants of prognosis were the blood urea concentration (BUC), the haemoglobin concentration ([Hb]), and the clinical performance status. Three prognostic groups based on these determinants were specified. The groups contained 22%, 56% and 22% of the patients and gave 2-year survival probabilities of 76%, 50% and 9% respectively. Patients in the good-prognosis group had a BUC less than or equal to 8 mM. [Hb] greater than or equal to 100 g/l, and no or minimal symptoms. Those in the poor-prognosis group had either [Hb] less than or equal to 75 g/l or a BUC greater than 10 mM and restricted clinical activity. Patients who had combinations of the 3 determinant features which excluded them from these 2 groups were classified into an intermediate prognosis group.
PMCID: PMC2010574  PMID: 7459218
5.  Differences in classification of COPD group using COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores: a cross-sectional analyses 
The GOLD 2011 document proposed a new classification system for COPD combining symptom assessment by COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores, and exacerbation risk. We postulated that classification of COPD would be different by the symptom scale; CAT vs mMRC.
Outpatients with COPD were enrolled from January to June in 2012. The patients were categorized into A, B, C, and D according to the GOLD 2011; patients were categorized twice with mMRC and CAT score for symptom assessment, respectively. Additionally, correlations between mMRC scores and each item of CAT scores were analyzed.
Classification of 257 patients using the CAT score vs mMRC scale was as follows. By using CAT score, 60 (23.3%) patients were assigned to group A, 55 (21.4%) to group B, 21 (8.2%) to group C, and 121 (47.1%) to group D. On the basis of the mMRC scale, 97 (37.7%) patients were assigned to group A, 18 (7.0%) to group B, 62 (24.1%) to group C, and 80 (31.1%) to group D. The kappa of agreement for the GOLD groups classified by CAT and mMRC was 0.510. The mMRC score displayed a wide range of correlation with each CAT item (r = 0.290 for sputum item to r = 0.731 for dyspnea item, p < 0.001).
The classification of COPD produced by the mMRC or CAT score was not identical. Care should be taken when stratifying COPD patients with one symptom scale versus another according to the GOLD 2011 document.
PMCID: PMC3680333  PMID: 23731868
COPD; CAT; mMRC scores
6.  Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease 
Thorax  1999;54(7):581-586.
BACKGROUND—Methods of classifying chronic obstructive pulmonary disease (COPD) depend largely upon spirometric measurements but disability is only weakly related to measurements of lung function. With the increased use of pulmonary rehabilitation, a need has been identified for a simple and standardised method of categorising disability in COPD. This study examined the validity of the Medical Research Council (MRC) dyspnoea scale for this purpose.
METHODS—One hundred patients with COPD were recruited from an outpatient pulmonary rehabilitation programme. Assessments included the MRC dyspnoea scale, spirometric tests, blood gas tensions, a shuttle walking test, and Borg scores for perceived breathlessness before and after exercise. Health status was assessed using the St George's Respiratory Questionnaire (SGRQ) and Chronic Respiratory Questionnaire (CRQ). The Nottingham Extended Activities of Daily Living (EADL) score and Hospital Anxiety and Depression (HAD) score were also measured.
RESULTS—Of the patients studied, 32 were classified as having MRC grade 3 dyspnoea, 34 MRC grade 4 dyspnoea, and 34 MRC grade 5 dyspnoea. Patients with MRC grades 1 and 2 dyspnoea were not included in the study. There was a significant association between MRC grade and shuttle distance, SGRQ and CRQ scores, mood state and EADL. Forced expiratory volume in one second (FEV1) was not associated with MRC grade. Multiple logistic regression showed that the determinants of disability appeared to vary with the level of disability. Between MRC grades 3 and 4 the significant covariates were exercise performance, SGRQ and depression score, whilst between grades 4 and 5 exercise performance and age were the major determinants.
CONCLUSIONS—The MRC dyspnoea scale is a simple and valid method of categorising patients with COPD in terms of their disability that could be used to complement FEV1 in the classification of COPD severity.

PMCID: PMC1745516  PMID: 10377201
7.  The Incidence of Dementia in England and Wales: Findings from the Five Identical Sites of the MRC CFA Study 
PLoS Medicine  2005;2(8):e193.
Although incidence of dementia is known to vary between nations, variation within country has not been explored because most incidence studies are single site or have insufficient numbers to compare sites. Few countries have conducted multisite incidence studies in order to facilitate national comparisons. This study aims to provide robust measures of the variation of the incidence of dementia across sites within England and Wales and produce overall estimates by age and sex.
Methods and Findings
The Medical Research Council Cognitive Function and Ageing Study used identical methodology in five diverse sites across the United Kingdom, each with different risk patterns and mortality rates. Incidence has been estimated using likelihood-based methods between the first two waves of interviews. Incidence rates rise with age, particularly above the age of 75 y, from 7.4 (95% confidence interval, 3.6–16.1) per 1,000 person years at age 65–69 y to 84.9 (95% confidence interval, 63.0–107.8) per 1,000 person years at age 85 y and above. The rate of increase for both sexes is marked, and continues into the oldest age groups. Hence, it is estimated that approximately 180,000 new cases of dementia occur in England and Wales each year. There is no convincing evidence of variation across sites, and incidence rates do not reflect the variations in the prevalence of possible risk factors in these sites.
There is no evidence, within England and Wales, of variation in dementia incidence across sites. Dementia incidence rates do not tail off at the oldest ages.
No evidence for variation in dementia incidence between areas with different vascular disease risk or between men and women, nor for reduced indidence amongst oldest age groups.
PMCID: PMC1188245  PMID: 16111436
8.  Three Decades of Research on Computer Applications in Health Care 
The Agency for Healthcare Research and Quality and its predecessor organizations—collectively referred to here as AHRQ—have a productive history of funding research and development in the field of medical informatics, with grant investments since 1968 totaling $107 million. Many computerized interventions that are commonplace today, such as drug interaction alerts, had their genesis in early AHRQ initiatives.
This review provides a historical perspective on AHRQ investment in medical informatics research. It shows that grants provided by AHRQ resulted in achievements that include advancing automation in the clinical laboratory and radiology, assisting in technology development (computer languages, software, and hardware), evaluating the effectiveness of computer-based medical information systems, facilitating the evolution of computer-aided decision making, promoting computer-initiated quality assurance programs, backing the formation and application of comprehensive data banks, enhancing the management of specific conditions such as HIV infection, and supporting health data coding and standards initiatives.
Other federal agencies and private organizations have also supported research in medical informatics, some earlier and to a greater degree than AHRQ. The results and relative roles of these related efforts are beyond the scope of this review.
PMCID: PMC344572  PMID: 11861630
9.  Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute Lymphoblastic leukaemia, 1980–2001 
Leukemia  2009;24(2):406-418.
Between 1980 and 2001, the United Kingdom Medical Research Council Childhood Leukemia Working Party has conducted 4 clinical trial in acute lymphoblastic leukemia, which have recruited a total of 6516 patients. UKALL VIII examined the role of daunorubicin in induction chemotherapy, and UKALL X examined the role of post-induction intensification. Both resulted in major improvement in the outcomes. UKALL XI examined the efficacy of different methods of CNS-directed therapy and the effects of an additional intensification. ALL97, which was initially based on the UKALL X D template (two intensification phases), examined the role of different steroids in induction and different thiopurines through continuing chemotherapy. A reappraisal of results from UKALL XI compared to other cooperative group results led to a redesign in 1999, which subsequently resulted in a major improvement in outcomes. Additionally, ALL97 and 97/99 demonstrated a significant advantage for the use of dexamethasone rather than prednisolone; although the use of 6-thioguanine resulted in fewer relapses, this advantage was offset by an increased incidence of deaths in remission. Over the era encompassed by these four trials there has been a major improvement in both event-free and overall survival for children in the UK with ALL.
PMCID: PMC2820452  PMID: 20010621
acute leukemia; therapy; clinical trial
10.  Prescriptions for medical research. I--Management within the Medical Research Council. 
BMJ : British Medical Journal  1993;306(6893):1668-1672.
In their submission to the government in advance of the white paper on science policy in the United Kingdom the Medical Research Council commends the MRC's own approach to managing directly funded research. But a series of semi-structured interviews with the directors of some of the MRC's units suggests a gap between the MRC's model of managed research and the reality. Although such units are theoretically managed from MRC head office (and units are charged an overhead for this), in practice each unit runs its own affairs. Between major reviews average contact time with the head office contact person is seven hours a year. The first paper argues that a purchaser-provider split would recognise the benefits of decentralisation and allow units to bid for research funds from several sources, the successful ones guaranteeing their survival through a rolling series of research programmes. The second paper criticises the MRC's cumbersome peer review system. Reliance on outside experts atrophies the scientific skills of head office staff and builds delays into decision making. A purchaser-provider model would allow the head office scientific staff to act like commercial research and development managers, commissioning research, and using the outcome, rather than peer review, as a criterion for continued funding.
PMCID: PMC1678049  PMID: 8324441
11.  Routine neonatal screening for phenylketonuria in the United Kingdom 1964-78. Medical Research Council Steering Committee for the MRC/DHSS Phenylketonuria Register. 
From 1964 to 1968, despite a general policy of routine neonatal screening for phenylketonuria that was usually carried out using the Phenistix nappy test, half to one-quarter of all cases reported to the register had been missed in the screening programme and had not been detected before the age of 4 months. In about two-thirds of the "missed" cases no screening test had been carried out, and in one-third a urine test had been performed but had given a false-negative result. In 1968-9 the screening programme was reorganised according to recommendations made in a Government circular (HM (69) 72), which proposed that a specimen of blood should be obtained by heel prick from all newborn infants between the 6th and 14th day of life and be tested in a central laboratory for the presence of raised blood phenylalanine concentrations. The senior medical officers of the various regions were made responsible for ensuring that all infants were tested. By 1974 only 1 to 2% of surviving infants were not being tested for phenylketonuria in the neonatal period, and only five of the 357 cases born between 1974 and 1978 and notified to the register had been diagnosed after the age of 3 months.
PMCID: PMC1505602  PMID: 6786433
12.  An MRC prospective randomised trial of radiotherapy versus surgery for operable squamous cell carcinoma of the oesophagus. 
The objective of the trial was to determine whether there was any difference in survival rates after operable cases of squamous cell carcinoma of the oesophagus were treated by radiotherapy or surgery. It was designed as a prospective, randomised, multicentre trial in the United Kingdom, after staging as potentially operable, and it was planned to enter 100 patients per annum for 4 years, with a minimum follow-up of 5 years, after pre-entry staging of patients under 75 years of age by barium swallow, chest radiographs, oesophagoscopy, biopsy, bronchoscopy and CT scanning. The protocol was published in July 1986; the trial started in January 1987 and was stopped in June 1988 when only 31 patients from 16 centres were entered, although 30 centres had ethical committees' approval and were willing to start the trial. Interventions were to be as follows: 1. Surgery. According to the practice of that particular surgeon and classified as (a) curative resection if the surgeon considered that no macroscopic tumour was left behind, and (b) palliative if incompletely resected. 2. Radiotherapy. (a) Prescribed minimum corrected tumour dose of 5000 cGy with daily dose of 250 cGy in 20 fractions over 4 weeks. (b) Prescribed minimum corrected tumour dose of 6000 cGy with daily dose of 200 cGy in 30 fractions over 6 weeks. The endpoint was to be survival at 1, 2 and 5 years. The trial was discontinued after 18 months because of lack of recruitment and thus the question whether operable squamous cell cancer of the oesophagus, staged before treatment with CT scanning, is to be treated by radiotherapy or surgical resection remains unanswered.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC2499354  PMID: 1996871
13.  Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. 
BMJ : British Medical Journal  1992;304(6824):405-412.
To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke, coronary heart disease, and death.
Randomised, placebo controlled, single blind trial.
226 general practices in the MRC general practice research framework.
4396 patients aged 65-74 randomised to receive diuretic, beta blocker, or placebo. Patients had mean systolic pressures of 160-209 mm Hg and mean diastolic pressures less than 115 mm Hg during an eight week run in and were not taking antihypertensive treatment.
Patients were randomised to atenolol 50 mg daily; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily; or placebo. The regimens were adjusted to achieve specified target pressures. Mean follow up was 5.8 years.
Strokes, coronary events, and deaths from all causes.
Both treatments reduced blood pressure below the level in the placebo group. Compared with the placebo group, actively treated subjects (diuretic and beta blocker groups combined) had a 25% (95% confidence interval 3% to 42%) reduction in stroke (p = 0.04), 19% (-2% to 36%) reduction in coronary events (p = 0.08), and 17% (2% to 29%) reduction in all cardiovascular events (p = 0.03). After adjusting for baseline characteristics the diuretic group had significantly reduced risks of stroke (31% (3% to 51%) p = 0.04), coronary events (44% (21% to 60%), p = 0.0009), and all cardiovascular events (35% (17% to 49%), p = 0.0005) compared with the placebo group. The beta blocker group showed no significant reductions in these end points. The reduction in strokes was mainly in non-smokers taking the diuretic.
Hydrochlorothiazide and amiloride reduce the risk of stroke, coronary events, and all cardiovascular events in older hypertensive adults.
PMCID: PMC1995577  PMID: 1445513
14.  The Registration of Medical Graduates from Eastern European Union Countries with the General Medical Council (GMC) and the Medical Council, Ireland. 
The Ulster Medical Journal  2013;82(2):71-74.
The purpose of this study was to identify the number of medical graduates registered with the General Medical Council (GMC) between 1990 and 2005, whose initial training was in Eastern Europe and who came from universities which have subsequently developed an “English Parallel” course and are now within the European Union (EU). A similar exercise was undertaken with graduates registered with the Medical Council, Ireland.
Between 1990 and 2005 one thousand six hundred and fourteen (1614) doctors, who had trained in the selected universities from Eastern Europe, registered with the General Medical Council (GMC) in the United Kingdom (Table 1). The Register of Medical Practitioners for Ireland as at 1st July 2005 was also scanned manually to identify graduates from these countries who were registered in Ireland. Sixty four such graduates were identified of whom 6 qualified before 1990 and 5 were in their internship year. The study suggests that since 2000 younger graduates who sought training in Central and Eastern Europe are returning to the UK shortly after graduation to register and start clinical training.
PMCID: PMC3756861  PMID: 24082282
15.  A Medical Research Council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma 
British Journal of Cancer  2000;83(12):1623-1629.
The UK Medical Research Council conducted this trial of carboplatin chemotherapy in advanced seminoma to compare single agent carboplatin with a standard combination of etoposide with cisplatin. The use of single agent carboplatin was expected to be associated with reduced toxicity. A total of 130 patients with advanced seminoma were randomly assigned to treatment with either single agent carboplatin (C) at a dose of 400 mg/m2 to be corrected for glomerular filtration rate outside the range 81–120 ml min–1 and to be administered on day 1 of a 21 day cycle to a total of 4 cycles or to etoposide + platinum (EP). The trial was designed as an equivalence study aiming to exclude a reduction in the 3-year progression-free survival in patients allocated to carboplatin of between 10 and 15%, requiring initially a target accrual of 250 patients (90% power significance level 5% (one-sided)). The trial closed after 130 patients had been randomized following recommendation by an independent data monitoring committee. At a median follow-up time of 4.5 years, 81% of patients had been followed up for at least 3 years and 19 patients have died. The estimated PFS rate (95% Confidence Intervals (CI)) at 3 years was 71% (60–82%) in patients allocated C and 81% (71–90%) in those allocated EP; the 95% CI for the difference in 3 year PFS was – 6% to +19%. The hazard ratio of 0.64 (95% CI 0.32–1.28) favoured EP but the difference was not statistically significant (log rank chi-squared = 1.59 P = 0.21). The 3-year survival rate was 84% (75–92%) in those allocated C, and 89% (81–96%) in those allocated EP. The hazard ratio for survival was 0.85 with 95% CI, 0.35–2.10, log rank chi-squared = 0.12, P = 0.73. The trial has not demonstrated statistically significant differences in the major survival endpoints comparing single agent carboplatin with a combination of etoposide + cisplatin. This cannot be taken as an indication of equivalence since the limited size of this trial rendered it unable to exclude a 19% lower progression-free survival and survival in those treated with single agent carboplatin which would be important clinically. Standard initial chemotherapy for advanced seminoma should be based on cisplatin combinations and the role of carboplatin awaits the outcome of further studies. © 2000 Cancer Research Campaign
PMCID: PMC2363456  PMID: 11104556
seminoma; germ cell tumour; chemotherapy; cisplatin; carboplatin; randomized control trial
16.  Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial 
Lancet  2011;377(9783):2103-2114.
In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.
In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.
1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3–29·2] in the control group vs 17·0 months [9·4–30·1] in the cetuximab group; HR 1·04, 95% CI 0·87–1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0–12·5] in the control group vs 8·6 months [5·1–13·8] in the cetuximab group; HR 0·96, 0·82–1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5–27·4); KRAS mutant, 14·4 months (8·5–24·0); all wild-type, 20·1 months (11·5–31·7).
This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.
Cancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.
PMCID: PMC3159415  PMID: 21641636
17.  Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US 
PLoS Medicine  2006;3(10):e342.
Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case.
Methods and Findings
A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible vCJD contamination in the UK, contributed to a greater sense of urgency and a speedier implementation of regulations in that country. Third, while the results of scientific studies played a prominent role in the construction of regulations in both nations, this role was shaped by existing social and professional networks. In the UK, early focus on a European study implicating B-lymphocytes as the carrier of prion infectivity in blood led to the introduction of a policy that requires universal leukoreduction of blood components. In the US, early focus on an American study highlighting the ability of plasma to serve as a reservoir of prion infectivity led the FDA and its advisory panel to eschew similar measures.
The results of this study yield three important theoretical insights that pertain to the global management of emerging infectious diseases. First, because the perception and management of disease may be shaped by previous experience with disease, especially catastrophic experience, there is always the possibility for over-management of some possible routes of transmission and relative neglect of others. Second, local specificities within a given nation may influence the temporality of decision making, which in turn may influence the choice of disease management policies. Third, a preference for science-based risk management among nations will not necessarily lead to homogeneous policies. This is because the exposure to and interpretation of scientific results depends on the existing social and professional networks within a given nation. Together, these theoretical insights provide a framework for analyzing and anticipating potential conflicts in the international management of emerging infectious diseases. In addition, this study illustrates the utility of qualitative methods in investigating research questions that are difficult to assess through quantitative means.
A qualitative study of US and UK governmental policy statements on the topic of vCJD and blood transfusion transmission identified factors responsible for differences in the policies adopted.
Editors' Summary
In 1996 in the UK, a new type of human prion disease was seen for the first time. This is now known as variant Creutzfeldt-Jakob disease (vCJD). Prion diseases are rare brain diseases passed from individual to individual (or between animals) by a particular type of wrongly folded protein, and they are fatal. It was suspected that vCJD had passed to humans from cattle, and that the agent causing vCJD was the same as that causing bovine spongiform encephalopathy (or “mad cow disease”). Shortly after vCJD was recognized, authorities in many countries became concerned about the possibility that it could be transmitted from one person to another through contaminated blood supplies used for transfusion in hospitals. Even though there wasn't any evidence of actual transmission of the disease through blood before December 2003, authorities in the UK, US, and elsewhere set up regulations designed to reduce the chance of that happening. At this early stage in the epidemic, there was little in the way of scientific information about the transmission properties of the disease. Both the UK and US, however, sought to make decisions in a scientific manner. They made use of evidence as it was being produced, often before it had been published. Despite this, the UK and US decided on very different changes to their respective regulations on blood donation. Both countries chose to prevent certain people (who they thought would be at greater risk of having vCJD) from donating blood. In the UK, however, the decision was made to remove white blood cells from donated blood to reduce the risk of transmitting vCJD, while the US decided that such a step was not merited by the evidence.
Why Was This Study Done?
This researcher wanted to understand more clearly why the UK and US ended up with different policies: what role was played by science, and what role was played by non-scientific factors? She hoped that insights from this investigation would also be relevant to similar challenges in the future—for example, as many countries try to work out how to control the threat of avian flu.
What Did the Researcher Do and Find?
The researcher searched for all relevant official government documents from the US and UK, as well as scientific papers, published between the time vCJD was first identified (March 1996) and the first instance of vCJD carried through blood (December 2003). She also interviewed people who knew about vCJD management in the US and UK—for example, members of government agencies and the relevant advisory committees. From the documents and interviews, the researcher picked out and grouped shared ideas. Although these documents and interviews suggested that policy making was rooted in scientific evidence, many non-scientific factors were also important. The researcher found substantial uncertainty in the scientific evidence available at the time. The document search and interviews showed that policy makers felt guilty about a previous experience in which people had become infected with HIV/AIDS through contaminated blood and were concerned about repeating this experience. Finally, in the UK, the possibility of blood contamination was seen as a much more urgent problem than in the US, because BSE and vCJD were found there first and there were far more cases. This meant that when the UK made its decision about whether to remove white blood cells from donated blood, there was less scientific evidence available. In fact, the main study that was relied on at the time would later be questioned.
What Do These Findings Mean?
These findings show that for this particular case, science was not the only factor affecting government policies. Historical and social factors such as previous experience, sense of urgency, public pressure, and the relative importance of different scientific networks were also very important. The study predicts that in the future, infectious disease–related policy decisions are unlikely to be the same across different countries because the interpretation of scientific evidence depends, to a large extent, on social factors.
Additional Information.
Please access these Web sites via the online version of this summary at
National Creutzfeldt-Jakob Disease Surveillance Unit, Edinburgh, UK
US Centers for Disease Control and Prevention pages about prion diseases
World Health Organization variant Creutzfeldt-Jakob disease fact sheet
US National Institute of Neurological Disorders and Stroke information about prion diseases
PMCID: PMC1621089  PMID: 17076547
18.  Ventricular extrasystoles during thiazide treatment: substudy of MRC mild hypertension trial. 
One short term and one long term study of the relation between ventricular extrasystoles and thiazide treatment were carried out during the Medical Research Council's mild hypertension trial. In the short term study 110 patients were randomly assigned to one of three treatment groups, bendrofluazide with or without potassium supplements, or placebo. They were studied before starting treatment and nine to 10 weeks later while still taking their randomly assigned drugs. No significant increase in the number of ventricular extrasystoles was associated with short term thiazide treatment, although serum potassium concentrations changed as expected. In the long term study 214 patients who had completed an average of two years' treatment with randomly assigned bendrofluazide or a placebo were studied while continuing to take their trial tablets; the 214 included 20 people who had been randomised at entry to the bendrofluazide group and who had a subsequent history of hypokalaemia. These 20 patients were studied before and after being further randomised to two groups, one continuing treatment without change and one continuing with bendrofluazide and also taking potassium supplements. Counts of ventricular extrasystoles were significantly higher (p = 0.025) in those receiving long term thiazide treatment than in their controls; however, there was no significant association between the number of ventricular extrasystoles and serum potassium concentrations in this group, although the correlation between number of extrasystoles and serum urate concentrations was significant (p = 0.035). Pooled data for both studies showed a highly significant correlation between number of ventricular extrasystoles, and serum potassium concentrations (r = -0.185; p = 0.003), but the correlation with serum urate concentrations was of similar strength (r = 0.178; p = 0.004). These biochemical changes may be acting merely as markers of thiazide intake, and the explanation of the association between thiazide treatment and ventricular extrasystolic activity therefore remains uncertain.
PMCID: PMC1549726  PMID: 6196073
19.  Ghost Authorship in Industry-Initiated Randomised Trials 
PLoS Medicine  2007;4(1):e19.
Ghost authorship, the failure to name, as an author, an individual who has made substantial contributions to an article, may result in lack of accountability. The prevalence and nature of ghost authorship in industry-initiated randomised trials is not known.
Methods and Findings
We conducted a cohort study comparing protocols and corresponding publications for industry-initiated trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg in 1994–1995. We defined ghost authorship as present if individuals who wrote the trial protocol, performed the statistical analyses, or wrote the manuscript, were not listed as authors of the publication, or as members of a study group or writing committee, or in an acknowledgment. We identified 44 industry-initiated trials. We did not find any trial protocol or publication that stated explicitly that the clinical study report or the manuscript was to be written or was written by the clinical investigators, and none of the protocols stated that clinical investigators were to be involved with data analysis. We found evidence of ghost authorship for 33 trials (75%; 95% confidence interval 60%–87%). The prevalence of ghost authorship was increased to 91% (40 of 44 articles; 95% confidence interval 78%–98%) when we included cases where a person qualifying for authorship was acknowledged rather than appearing as an author. In 31 trials, the ghost authors we identified were statisticians. It is likely that we have overlooked some ghost authors, as we had very limited information to identify the possible omission of other individuals who would have qualified as authors.
Ghost authorship in industry-initiated trials is very common. Its prevalence could be considerably reduced, and transparency improved, if existing guidelines were followed, and if protocols were publicly available.
Of 44 industry-initiated trials, there was evidence of ghost authorship in 33, increasing to 40 when a person qualifying for authorship was acknowledged rather than appearing as an author.
Editors' Summary
Original scientific findings are usually published in the form of a “paper”, whether it is actually distributed on paper, or circulated via the internet, as this one is. Papers are normally prepared by a group of researchers who did the research and are then listed at the top of the article. These authors therefore take responsibility for the integrity of the results and interpretation of them. However, many people are worried that sometimes the author list on the paper does not tell the true story of who was involved. In particular, for clinical research, case histories and previous research has suggested that “ghost authorship” is commonplace. Ghost authors are people who were involved in some way in the research study, or writing the paper, but who have been left off the final author list. This might happen because the study “looks” more credible if the true authors (for example, company employees or freelance medical writers) are not revealed. This practice might hide competing interests that readers should be aware of, and has therefore been condemned by academics, groups of editors, and some pharmaceutical companies.
Why Was This Study Done?
This group of researchers wanted to get an idea of how often ghost authorship happened in medical research done by companies. Previous studies looking into this used surveys, whereby the researchers would write to one author on each of a group of papers to ask whether anyone else had been involved in the work but who was not listed on the paper. These sorts of studies typically underestimate the rate of ghost authorship, because the main author might not want to admit what had been going on. However, the researchers here managed to get access to trial protocols (documents setting out the plans for future research studies), which gave them a way to investigate ghost authorship.
What Did the Researchers Do and Find?
In order to investigate the frequency and type of ghost authorship, these researchers identified every trial which was approved between 1994 and 1995 by the ethics committees of Copenhagen and Frederiksberg in Denmark. Then they winnowed this group down to include only the trials that were sponsored by industry (pharmaceutical companies and others), and only those trials that were finished and published. The protocols for each trial were obtained from the ethics committees and the researchers then matched up each protocol with its corresponding paper. Then, they compared names which appeared in the protocol against names appearing on the eventual paper, either on the author list or acknowledged elsewhere in the paper as being involved. The researchers ended up studying 44 trials. For 31 of these (75% of them) they found some evidence of ghost authorship, in that people were identified as having written the protocol or who had been involved in doing statistical analyses or writing the manuscript, but did not end up listed in the manuscript. If the definition of authorship was made narrower, and “ghost authorship” included people qualifying for authorship who were mentioned in the acknowledgements but not the author list, the researchers' estimate went up to 91%, that is 40 of the 44 trials. For most of the trials with missing authors, the ghost was a statistician (the person who analyzes the trial data).
What Do These Findings Mean?
In this study, the researchers found that ghost authorship was very common in papers published in medical journals (this study covered a broad range of peer-reviewed journals in many medical disciplines). The method used in this paper seems more reliable than using surveys to work out how often ghost authorship happens. The researchers aimed to define authorship using the policies set out by a group called the International Committee of Medical Journal Editors (ICMJE), and the findings here suggest that the ICMJE's standards for authorship are very often ignored. This means that people who read the published paper cannot always accurately judge or trust the information presented within it, and competing interests may be hidden. The researchers here suggest that protocols should be made publicly available so that everyone can see what trials are planned and who is involved in conducting them. The findings also suggest that journals should not only list the authors of each paper but describe what each author has done, so that the published information accurately reflects what has been carried out.
Additional Information.
Please access these Web sites via the online version of this summary at
Read the Perspective by Liz Wager, which discusses these findings in more depth
The International Committee of Medical Journal Editors (ICMJE) is a group of general medical journal editors who have produced general guidelines for biomedical manuscripts; their definition of authorship is also described
The Committee on Publication Ethics is a forum for editors of peer-reviewed journals to discuss issues related to the integrity of the scientific record; the Web site lists anonymized problems and the committee's advice, not just regarding authorship, but other types of problems as well
Good Publication Practice for Pharmaceutical Companies outlines common standards for publication of industry-sponsored medical research, and some pharmaceutical companies have agreed to these
PMCID: PMC1769411  PMID: 17227134
20.  Cohort differences in disease and disability in the young-old: findings from the MRC Cognitive Function and Ageing Study (MRC-CFAS) 
BMC Public Health  2007;7:156.
Projections of health and social care need are highly sensitive to assumptions about cohort trends in health and disability. We use a repeated population-based cross-sectional study from the Cambridgeshire centre of the UK Medical Research Council Cognitive Function and Ageing Study to investigate trends in the health of the young-old UK population
Non-overlapping cohorts of men and women aged 65–69 years in 1991/2 (n = 689) and 1996/7 (n = 687) were compared on: self-reported diseases and conditions; self-rated health; mobility limitation; disability by logistic regression and four-year survival by Cox Proportional Hazards Regression models, with adjustments for differences in socio-economic and lifestyle factors.
Survival was similar between cohorts (HR: 0.91, 95% CI: 0.62 to 1.32). There was a significant increase in the number of conditions reported between cohorts, with more participants reporting 3 or more conditions in the new cohort (14.2% vs. 10.1%). When individual conditions were considered, there was a 10% increase in the reporting of arthritis and a significant increase in the reporting of chronic airways obstruction (OR: 1.36, 95% CI: 1.04 to 1.78).
This study provides evidence of rising levels of ill-health, as measured by the prevalence of self-reported chronic conditions, in the newer cohorts of the young-old. Though changes in diagnosis or reporting of disease cannot, as yet, be excluded, to better understand whether our findings reflect real increases in ill-health, investment should be made into improved population-based databases, linking self-report and objective measures of health and function, and including those in long-term care.
PMCID: PMC1947964  PMID: 17629910
21.  Neglect of Medical Evidence of Torture in Guantánamo Bay: A Case Series 
PLoS Medicine  2011;8(4):e1001027.
Vincent Iacopino and Stephen Xenakis review case records of nine individuals imprisoned at Guantánamo Bay which indicate that medical personnel assigned to the US Department of Defense neglected and/or concealed medical evidence of torture.
In the wake of the September 11, 2001 attacks on the US, the government authorized the use of “enhanced interrogation” techniques that were previously recognized as torture. While the complicity of US health professionals in the design and implementation of US torture practices has been documented, little is known about the role of health providers, assigned to the US Department of Defense (DoD) at the US Naval Station Guantánamo Bay, Cuba (GTMO), who should have been in a position to observe and document physical and psychological evidence of torture and ill treatment.
Methods and Findings
We reviewed GTMO medical records and relevant case files (client affidavits, attorney–client notes and summaries, and legal affidavits of medical experts) of nine individuals for evidence of torture and ill treatment and documentation by medical personnel. In each of the nine cases, GTMO detainees alleged abusive interrogation methods that are consistent with torture as defined by the UN Convention Against Torture as well as the more restrictive US definition of torture that was operational at the time. The medical affidavits in each of the nine cases indicate that the specific allegations of torture and ill treatment are highly consistent with physical and psychological evidence documented in the medical records and evaluations by non-governmental medical experts. However, the medical personnel who treated the detainees at GTMO failed to inquire and/or document causes of the physical injuries and psychological symptoms they observed. Psychological symptoms were commonly attributed to “personality disorders” and “routine stressors of confinement.” Temporary psychotic symptoms and hallucinations did not prompt consideration of abusive treatment. Psychological assessments conducted by non-governmental medical experts revealed diagnostic criteria for current major depression and/or PTSD in all nine cases.
The findings in these nine cases from GTMO indicate that medical doctors and mental health personnel assigned to the DoD neglected and/or concealed medical evidence of intentional harm.
Please see later in the article for the Editors' Summary
Editors' Summary
Torture has been used throughout history for interrogation, coercion, and punishment. Ingenious methods have been devised to inflict severe physical or mental pain or suffering intentionally on an individual to obtain a confession or information, or to punish, intimidate, or coerce. Nowadays, torture is prohibited under international law and under the domestic law of most countries, and is considered to be a violation of human rights. Article 5 of the United Nations (UN) Universal Declaration of Human Rights, which was adopted in December 1948, states: “No one should be subjected to torture or to cruel, inhuman or degrading treatment or punishment.” Similarly, signatories of the Geneva Conventions, which provide protection for people who fall into enemy hands during conflicts, have agreed not to torture prisoners. Torture is also prohibited by the UN Convention against Torture and Other Cruel, Inhuman or Degrading Treatment or Punishment, which came into force in June 1987. Implementation of this Convention by participating states is monitored the UN Committee against Torture.
Why Was This Study Done?
After the September 11, 2001 attacks on the United States, the US government redefined acts such as waterboarding (simulated drowning), sleep deprivation, and prolonged isolation as “safe, legal, ethical, and effective” “enhanced interrogation” techniques (EITs). These EITs were previously recognized as torture by the UN Committee against Torture. US health professionals are known to have been complicit in the design and implementation of EITs. For example, the US Central Intelligence Agency (CIA) and Department of Defense (DoD) designated “non-clinical” health professionals to monitor the use of EITs at the US detainee facility at the US Navy Base at Guantánamo Bay, Cuba (GTMO), and the active role of these individuals during interrogations has been documented. Much less is known, however, about the role of health professionals assigned to the DoD to provide medical and mental health care to the GTMO detainees. Specifically, it is not known whether these health professionals accurately documented physical and psychological evidence of torture and ill treatment among the detainees. In this case series, the researchers review GTMO medical records and case files of nine detainees for evidence of documentation of ill treatment and torture by medical personnel.
What Did the Researchers Do and Find?
The researchers—non-governmental medical experts retained by legal representatives of GTMO detainees alleging torture and ill treatment—reviewed the medical records, client affidavits, attorney–client notes, and legal declarations of medical experts of nine GTMO detainees. In each case, the detainee alleged abusive interrogation methods consistent with torture as defined by the UN Convention against Torture. The researchers report that the medical affidavits for all the cases indicate that the allegations of torture and ill treatment were consistent with physical and psychological evidence of torture and ill treatment documented in the medical records and in evaluations by non-governmental experts. However, the medical personnel responsible for the detainees' routine medical and mental health care failed to inquire about and/or document the causes of the physical injuries and psychological symptoms that they observed. Instead, they attributed psychological symptoms to “personality disorders” and “routine stressors of confinement”. Moreover, psychotic symptoms such as hallucinations did not prompt consideration of abusive treatment. Importantly, psychological assessments conducted by non-governmental experts revealed diagnostic criteria for current major depression and/or post-traumatic stress disorder (PTSD, a common outcome of torture or ill treatment) in all the cases.
What Do These Findings Mean?
These findings indicate that health professionals assigned to the DoD to provide medical and mental health care to GTMO detainees neglected and/or concealed evidence of intentional harm. Because only nine cases are included in this case series, these findings may not be generalizable to other GTMO detainees. The findings are also limited by their reliance on medical records and case files that were sometimes heavily edited and on psychological assessments based on questionnaires rather than on direct examination. Nevertheless, these findings reveal new information about the potential extent of medical complicity in US torture practices, and they highlight the need for a thorough and impartial investigation of all the available information, including relevant classified information.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in the April 2011 PLoS Medicine Editorial
Wikipedia has pages on torture, and on the Guantánamo Bay detention camp note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The Office of the UN High Commissioner for Human Rights provides information about the UN Convention against Torture and other Cruel, Inhuman or Degrading Treatment or Punishment and the UN Committee against Torture (in several languages)
Physicians for Human Rights is a non-profit organization that mobilizes health professionals to advance health, dignity and justice, and promotes the right to health for all. Its Campaign against Torture seeks to restore the US commitment against torture
Amnesty International provides information about the Guantánamo Bay detention camp
PMCID: PMC3084605  PMID: 21559073
22.  Asthma in Black African, Black Caribbean and South Asian adolescents in the MRC DASH study: a cross sectional analysis 
BMC Pediatrics  2010;10:18.
Ethnic differences in the prevalence of asthma among children in the UK are under-researched. We aimed to determine the ethnic differences in the prevalence of asthma and atopic asthma in children from the main UK ethnic groups, and whether differences are associated with differential distributions in social and psychosocial risk factors.
6,643 pupils aged 11-13 years, 80% ethnic minorities. Outcomes were asthma/wheeze with (atopic) and without hay fever/eczema. Risk factors examined were family history of asthma, length of residence in the UK, socioeconomic disadvantage, tobacco exposure, psychological well-being, and body mass index (BMI).
There was a pattern of lower prevalence of asthma in Black African boys and girls, and Indian and Bangladeshi girls compared to White UK. The overall prevalence was higher in Mixed Black Caribbean/White boys, with more atopic asthma in Black Caribbean boys and Mixed Black Caribbean/White boys due to more hayfever. Poor psychological well-being and family history of asthma were associated with an increased risk of asthma within each ethnic group. UK residence for ≤ 5 years was protective for Black Caribbeans and Black Africans. Increased BMI was associated with an increased reporting of asthma for Black Africans. Adjustments for all variables did not remove the excess asthma reported by Black Caribbean boys (atopic) or Mixed Black Caribbean/White boys.
The protective effect of being born abroad accounted for ethnic differences in some groups, signalling a role for socio-environmental factors in patterning ethnic differences in asthma in adolescence.
PMCID: PMC2851680  PMID: 20334698
23.  Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial 
Lancet  2010;375(9715):641-648.
In metastatic renal cell carcinoma combinations of interferon alfa-2a, interleukin-2, and fluorouracil produce higher response rates and longer progression-free survival than do single agents. We aimed to compare overall survival in patients receiving combination treatment or interferon alfa-2a.
RE04/30012 was an open-label randomised trial undertaken in 50 centres across eight countries. 1006 treatment-naive patients diagnosed with advanced metastatic renal cell carcinoma were randomly allocated (1 to 1) by minimisation to receive interferon alfa-2a alone or combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil. Treatment was not masked. The primary endpoint was overall survival. Treatment groups were compared with a non-stratified log-rank test. Analysis was by intention to treat. This study is registered, number ISRCTN 46518965.
502 patients were randomly assigned to receive interferon alfa-2a and 504 to receive combined treatment. Median follow-up was 37·2 months (24·8–52·3). Median overall survival was 18·8 months (17·0–23·2) for patients receiving interferon alfa-2a versus 18·6 months (16·5–20·6) for those receiving combination therapy. Overall survival did not differ between the two groups (hazard ratio 1·05 [95% CI 0·90–1·21], p=0·55; absolute difference 0·3% (−5·1 to 5·6) at 1 year and 2·7% (−8·2 to 2·9) at 3 years). Serious adverse events were reported in 113 (23%) patients receiving interferon alfa-2a and 131 (26%) of those receiving combined treatment.
Although combination therapy does not improve overall or progression-free survival compared with interferon alfa-2a alone, immunotherapy might still have a role because it can produce remissions that are of clinically relevant length in some patients. Identification of patients who will benefit from immunotherapy is crucial.
UK Medical Research Council.
PMCID: PMC2835851  PMID: 20153039
24.  A semi-competing risks model for data with interval-censoring and informative observation: An application to the MRC cognitive function and ageing study 
Statistics in Medicine  2010;30(1):1-10.
Semi-competing risks data occur frequently in medical research when interest is in simultaneous modelling of two or more processes, one of which may censor the others. We consider the analysis of semi-competing risks data in the presence of interval-censoring and informative loss-to-followup. The work is motivated by a data set from the MRC UK Cognitive Function and Ageing Study, which we use to model two processes, cognitive impairment and death. Analysis is carried out using a multi-state model, which is an extension of that used by Siannis et al. (Statist. Med. 2007; 26:426–442) to model semi-competing risks data with exact transition times, to data which is interval-censored. Model parameters are estimated using maximum likelihood. The role of a sensitivity parameter k, which influences the nature of informative censoring, is explored. Copyright © 2010 John Wiley & Sons, Ltd.
PMCID: PMC3443364  PMID: 21204119
multi-state models; semi-competing risks; Weibull models; interval-censored data
25.  Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial 
Lancet  2009;373(9666):811-820.
Preoperative or postoperative radiotherapy reduces the risk of local recurrence in patients with operable rectal cancer. However, improvements in surgery and histopathological assessment mean that the role of radiotherapy needs to be reassessed. We compared short-course preoperative radiotherapy versus initial surgery with selective postoperative chemoradiotherapy.
We undertook a randomised trial in 80 centres in four countries. 1350 patients with operable adenocarcinoma of the rectum were randomly assigned, by a minimisation procedure, to short-course preoperative radiotherapy (25 Gy in five fractions; n=674) or to initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-fluorouracil) restricted to patients with involvement of the circumferential resection margin (n=676). The primary outcome measure was local recurrence. Analysis was by intention to treat. This study is registered, number ISRCTN 28785842.
At the time of analysis, which included all participants, 330 patients had died (157 preoperative radiotherapy group vs 173 selective postoperative chemoradiotherapy), and median follow-up of surviving patients was 4 years. 99 patients had developed local recurrence (27 preoperative radiotherapy vs 72 selective postoperative chemoradiotherapy). We noted a reduction of 61% in the relative risk of local recurrence for patients receiving preoperative radiotherapy (hazard ratio [HR] 0·39, 95% CI 0·27–0·58, p<0·0001), and an absolute difference at 3 years of 6·2% (95% CI 5·3–7·1) (4·4% preoperative radiotherapy vs 10·6% selective postoperative chemoradiotherapy). We recorded a relative improvement in disease-free survival of 24% for patients receiving preoperative radiotherapy (HR 0·76, 95% CI 0·62–0·94, p=0·013), and an absolute difference at 3 years of 6·0% (95% CI 5·3–6·8) (77·5% vs 71·5%). Overall survival did not differ between the groups (HR 0·91, 95% CI 0·73–1·13, p=0·40).
Taken with results from other randomised trials, our findings provide convincing and consistent evidence that short-course preoperative radiotherapy is an effective treatment for patients with operable rectal cancer.
Medical Research Council (UK) and the National Cancer Institute of Canada.
PMCID: PMC2668947  PMID: 19269519

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