Methods and applications in the management of heart and lung diseases: report on progress 2001-2006
My programme is focussed on applied and methodological issues in assessing effectiveness and cost-effectiveness in cardiothoracic surgery and medicine. This work can be split into 5 main strands: diagnostic methods, treatment of existing disease, modelling chronic disease pathways, end-stage disease therapies and statistical methodology. During the past 5 years our major achievements have been as follows. We have provided major modelling approaches to evaluation of Implantable Cardioverter Defibrillators (ICD) and Ventricular Assist Devices (VAD). These models have demonstrated that ICD use is only cost effective for patients with inducible arhythmias who are at high risk of sudden cardiac death, provided that costs of device acquisition and implantation are of the order of 10-15 thousand pounds, or if improvement in quality of life can be assumed. This does not have a strong evidence base. We demonstrated that widespread dissemination of a VAD implant service cannot be justified on cost-effectiveness grounds, and a restricted programme in a few specialised centres is the most efficient way of maintaining skills and monitoring the development of the technology. These two projects provided examples of how data from different sources could be combined. In a series of randomised controlled trials (RCTs) we have evaluated laser and other treatments for refractory angina. We have shown that the increased cost of surgical laser treatment does not justify the increased risk of death due to surgery, at least in the short term. The reduced risk for laser treatment delivered percutaneously is more convincing but remains expensive when evaluated over the first year of treatment. Further treatment options involving spinal cord stimulation are being investigated. We have contributed data to the British Thoracic Society's revision of guidelines for resection in patients with lung cancer. We showed that exclusion from surgery based on lung function and physiology should depend on test results that were expressed as a percentage of predicted rather than absolute values. Motivated by applications in transplant recipients we have developed statistical models and methods for chronic disease progression using irregularly measured markers of disease and where disease progression is heterogeneous between and within patients, where disease markers are either misclassified (discrete markers) or measured with error (continuous markers).
In both past and future research it has been our policy to work closely with clinicians and clinical scientists at Papworth Hospital, a leading international centre for research into cardiothoracic surgery and medicine. It has an enviable track record in attracting funding for substantive research projects and in completing those projects to the highest standards. The importance of maintaining academic contacts with the MRC is viewed by Papworth Hospital as fundamental to the success of this research. The hospital funds one band 2 and one band 4 post. Due to this financial commitment, the post-holders are expected to contribute to Papworth's grant applications, and to help to develop a high quality research culture at the hospital.
For patients with exercise tests suggestive of heart disease, the traditional method of diagnosis is angiography, which provides information on stenosis in major vessels. However, this test is expensive and invasive and does not give good information on cardiac function or problems in smaller peripheral vessels. As a result, up to 30% of patients have continued angina after revascularisation.
In recent years the potential value of echocardiography, cardiac magnetic resonance imaging and (metroxy-isobutol-isotrimitriale) MIBI nuclear scans for the assessment of cardiac function in patients with suspected heart disease has been recognised but evidence arises mainly from small observational studies. With colleagues in cardiology and radiology, and health economists at, Brunel University we secured a grant from the National Coordinating Centre for Health Technology Assessment (NCCHTA) to perform an RCT comparing these newer technologies with angiography. Recruitment of 900 patients was completed in September 2004 and patient follow up is ongoing. A paper on the feasibility, acceptability and predictive value of the 3 functional tests has been submitted [06.027] and further papers are planned. This trial is expected to influence policy at a national level and, because of NICE's international profile, to influence policy internationally also.
Implantable Cardioverter Defibrillators (ICDs):
Much of the last 2 years has been spent on a study of the use of ICDs for secondary prevention of malignant arrhythmias. With consultant cardiologists at Papworth and Liverpool, public health specialists Southampton), health economists at Brunel University and quality of life experts at Papworth hospital we developed a model of cost-effectiveness of ICDs, combining evidence from RCTs, patient registries and a new survey of quality of life in patients implanted in the UK. International links were established with health economists at McMaster University, Canada who supplied individual patient data from the Canadian RCT of ICDs. The project was commissioned by the NCCHTA and was recognised and used as the main source of evidence by the Decision Support Unit (DSU) of the National Institute for Clinical Excellence (NICE) in its recent appraisal of ICDs. The final version of the report is in press [06.025] and a paper has been submitted [06.103].
On the basis of the above work the Decision Support Unit of NICE commissioned development of the model to incorporate primary prevention. Although in the UK ICDs are used infrequently in patients who have not had a major arrhythmic event, practice is changing. We were able to identify patient groups for whom the technology is effective, and strategies for which it is cost-effective (NICE guidance on ICDs, 2005). In short, ICD use was only cost effective for patients with inducible arhythmias who are at high risk of sudden cardiac death, provided that costs of device acquisition and implantation are of the order of 10-15 thousand pounds, or if improvement in quality of life can be assumed. This does not have a strong evidence base.
Angina that does not respond to best medical therapy, and that cannot be addressed using established revascularisation procedures is a large and difficult problem. With colleagues at Papworth we have conducted a series of RCTs to investigate treatments for refractory angina, focusing on surgical (TMR) [01.012; 01.013] and percutaneous (PMR) [03.030; 05.013] therapy using laser technology and more recently spinal cord stimulation [06.074]. We have shown that the increased cost of surgical laser treatment does not justify the increased risk of death due to surgery, at least in the short term. The reduced risk for laser treatment delivered percutaneously is more convincing but remains expensive when evaluated over the first year of treatment. Further treatment options involving spinal cord stimulation are being investigated. Papworth has been the UK centre conducting these trials and has published extensively (see above publications and related references).
As a result of the European Work-time Directive, appropriately trained nurses are increasingly taking on responsibilities that were traditionally undertaken by doctors. Introduction of these changes in service delivery needs be evaluated to ensure patient safety, patient satisfaction and maintenance of clinical standards. We have been at the forefront of research into evaluation of nurse practitioners, with examples in intensive care units [02.098], bronchiectasis outpatient clinics [02.012; 02.083] and asthma outpatient management [05.071; 06.134]. Funding was secured from the NCCHTA for the bronchiectasis trial and from the NHS R&D regional funding scheme for the asthma trial. Through this work we have defined extended roles for nurse practitioners in a number of areas, resulting in reduced pressure on doctors' time and increased job satisfaction and career development options for senior nurses, whilst ensuring that patient management is not compromised.
Trials of new surgical techniques are emerging but methods are less well developed than for medical treatment. The traditional view has been that surgical procedures are life-saving and therefore trials are not necessary. Increasingly, surgical procedures are undertaken to relieve symptoms or improve functioning, so that the patient benefit is less compelling. Thus, the cost-benefit arguments are less obvious. With colleagues at Papworth we have been in the forefront of the argument for proper evaluation of surgical interventions and this has resulted in a number of trials, for example, of bioprothesis in aortic valve disease [06.079; 06.004] and lung volume reduction surgery for chronic obstructive pulmonary disease [01.606].
The clinical care component and the day-to-day management of the above trials take place at Papworth hospital. My role has been in supervising the design, conduct, analysis and interpretation of results. In particular, I have extensive input into the design phase of all major (non-commercial) trials at Papworth and am considered a key member of trial steering groups. I supervise data collection, working closely with trial managers and, with the principle investigator, take responsibility for drafting clinical and methodology papers arising from these trials.
Chronic disease modelling
The natural history of chronic diseases can be described using panel data, such as determinations of disease state or organ function at a series of clinic visits. In clinical practice these measurements are often made at irregular intervals and at different times post-intervention for each patient. In addition, due to limitations of measurement instruments, patients may be misclassified or may have inaccurate measurements. This causes some problems in estimating natural history and in assessing biomarkers for disease onset, progression and prognosis. Using novel methods (see section on Methodological Research) we have been able to make significant contributions to the understanding of the causes and features of some chronic diseases encountered after transplantation [02.042; 02.041; 03.080; 04.057]. For example, we have identified distinct modes of onset of obliterative bronchiolitis in lung transplant patients, resulting either from chronic rejection or from irreversible build up of fibrotic tissue following acute events [04.057]. This aids transplant clinicians to decide on appropriate treatment of decline in lung function. In collaboration with Simon Thompson and others, these methods were also applied to results from serial abdominal aortic aneurysm measurements [03.044].
End stage heart and lung disease
Transplantation is a complicated area and we have made a number of contributions to the field.
Due to the altruism involved in organ donation, and the imbalance in supply and demand, there is considerable pressure to demonstrate that the patient selection and management strategy is optimal and that maximum benefit is achieved. We have developed methods for quantifying the benefit attributable to transplantation in the absence of randomisation [02.015; 05.060; 05.059].
Post-transplant coronary artery vasculopathy (CAV) grade is imaged, with error, using angiography. Hidden Markov models have been developed to simultaneously estimate disease onset, progression, death rates and sensitivity and specificity of angiography [03.080; 06.116]. Covariates for disease onset and prognosis were also investigated. Reporting of these studies included a didactic description of the methodology.
With clinical colleagues at Papworth we continue to lead research into the mechanisms [05.093], micro-vascular changes [04.068; 06.064], risk factors [02.084; 03.047; 05.093] and treatment [05.093] of post-lung transplant obliterative bronchiolitis and its clinical manifestation bronchiolitis obliterans syndrome. Hidden Markov models [02.042; 02.041] and change point models [04.057] have provided a more precise representation of the natural history of this disease.
In addition to these substantial areas of work we have also contributed to the estimation of cost-effectiveness of transplantation, both in costing models [01.083; 01.084] and as a by-product of the evaluation of Ventricular Assist Devices (see below) [06.025]. We have also been involved in the following studies: evaluation of therapeutic drug monitoring [02.099], [03.028; 04.108]; donor optimisation and effects [02.090; 04.067; 05.062; 06.115]; recipient selection [01.087; 03.049; 05.071]; use of prophylaxis [03.048; 05.078]; markers and surrogate markers of acute phase dysfunction [02.409; 03.085; 05.108]; chronic dysfunction [02.003; 02.079; 04.003]. Recommendations for a national human embryonic stem cell donor bank were recently published in the Lancet [05.112].
Ventricular Assist Devices (VADs):
Due to the chronic shortage of organ donors, and with an eye to future treatment of heart failure in those not listed for transplantation, there has been considerable interest in the use of VADs. Papworth and Harefield are the leading centres in the UK for implantation of these devices and with colleagues at Brunel University and Papworth I hold the grant for the national evaluation of the programme of device use as a bridge to transplantation. VAD data were gathered from Papworth, Harefield and Newcastle and we were responsible for the statistical models of effectiveness and cost-effectiveness and for producing the report that will inform national policy. Data from UK activity was combined with published evidence in a statistical model. This work builds on previous studies of transplant listing policies and cost models. The challenge in these models was the construction of a plausible comparison group in the absence of controlled experiments. We demonstrated that widespread dissemination of a VAD implant service cannot be justified on cost-effectiveness grounds, and a restricted programme in a few specialised centres is the most efficient way of maintaining skills and monitoring the development of the technology. The final report is in press [06.104] and several papers are in preparation.
The British Thoracic Society has published guidelines for selection of lung cancer patients for surgery, the treatment which affords the greatest chance of success. There is some evidence that the guidelines are too strict and were derived from older research studies including exclusively men. We have collected data on a relatively large (n=150) series of lung cancer cases in order to re-assess the guidelines using a more-recent and stronger evidence base. Some descriptive papers have already been written [05.128; 05.129; 05.130; 06.133] and a substantive paper on the guidelines is in preparation. More inclusive decision rules based on test results expressed as percentage predicted for age, sex and size were provided.
Mesothelioma is a growing problem and treatments for sufferers have rarely been the subject of research. I am involved in two RCTs, one based at Papworth as trial statistician and one based at Leicester as statistician to the Trial Steering Committee/Data Monitoring and Ethics Committee. Preliminary work for the Papworth trial has been published (Halstead, 2002). Other lung cancer studies have considered the agreement between patients and clinician perception of performance [03.010].
Much of the methodological research undertaken is motivated by work from, and embedded in, applied studies. Interests concentrate on: methods for combining different sources of evidence in effectiveness and cost-effectiveness studies to inform policy, methods in assessing institutional performance, describing natural history and assessing prognostic features in chronic diseases. Specifically:
Although RCTs and meta-analysis of RCTs are the gold-standard for evaluating new treatments, they tend to provide only short- to medium-term outcomes. Cost-effectiveness assessment usually requires (quality-adjusted) life-years gained over the lifetime of treated patients. A major interest is extrapolation of RCT results and survival to lifetime models for cost-effectiveness analysis. We have made recommendations for good practice in specific examples (VADs, [06.104], ICDs [06.025]). Also, we have developed general methods for extrapolation of survival curves using information from Government census data to estimate the expected pattern of survival [05.018]. In this work we showed how national age-specific death rates could be used to estimate the shape of survival experience. Contrasting these death rates with those from short-term clinical trial data, we can estimate relative or additive hazards that are accurate in the short-term. Combining estimates of the shape of the survival curve, with these relative/additive hazards, we can extrapolate patient survival, and thus have an estimate of life-years gained over the whole lifetime of the patient group. Clearly, this approach involves making a number of assumptions about the long-term behaviour of absolute and relative hazards, but has the advantage of making these assumptions explicit so that they can be subject to sensitivity analyses.
Methods in assessing institutional performance:
Motivated by work when statistical advisor to the UK Transplant Support Service Agency and from Papworth studies [02.091; 03.065; 04.045; 05.109], David Ohlssen, David Spiegelhalter and I have submitted a tutorial-style paper drawing together the main methods for assessing unusual performance into a unified modelling framework [06.087]. In addition, to address the problem of identifying clusters of unusual centres we have produced flexible non-parametric multi-level models based on truncated Dirichlet process priors [06.088]. With modifications, these models can be applied to other hierarchical-structured data, for example those arising from meta-analysis and cluster randomised trials.
As described above (see section on Chronic disease modelling) general Markov, semi-Markov and hidden Markov models have been developed to describe chronic dysfunction in a number of applications [02.041; 03.044; 04.057]. Multistate models are a convenient way of modelling the natural history of chronic diseases when they manifest as a series of discrete states. In medical applications these models are complicated by the following features: clinical constraints can result in observations of disease states at irregular intervals, so that continuous time models are necessary; transition rates are often not constant over time (within patient heterogeneity); there is heterogeneity between patients so that covariate effects need to be estimated; diagnostic tools are imperfect so that disease states may be misclassified. Realistic models that incorporate these features are intractable for all but the simplest of cases, and must be solved numerically. We have described general models which are flexible enough to incorporate these features, and we have produced general software for estimation of these models (msm functions in R).
Stochastic epidemic modelling:
Nikolaos Demiris completed a PhD at Nottingham University on probabilistic models for disease spread among heterogeneous populations. Since he has been at the Unit I have encouraged him to continue to work on these research interests within my programme, in order to further his own professional development, and since this work is consistent with the MRC's aims. Briefly, statistical methods for epidemic models that incorporate the heterogeneous nature of 'at risk' populations will provide more accurate estimates of disease transmission and the burden on public health resources, such as vaccination programmes. Methods for disease spread in populations with a general structure have been published [05.019]. Approximate inference for stochastic epidemic models in which the population is partitioned into groups (such as households) has been addressed [05.020] and some exact and asymptotic properties of these models are to appear [06.032].
In all these areas I have been particularly interested in realistic modelling which can be performed in standard and freely available software. For example, former PhD student Chris Jackson and I provided a suite of functions (named msm) for the freely available statistical package R which can be used to fit multistate models with covariates and misclassification [03.044]. These functions are now included in the R software core libraries and we have received favourable comments and feedback from numerous researchers around the world. Similarly, flexible random effects distributions have been derived for use in intercentre comparisons using WinBUGS and programs are currently being assessed for inclusion in the core WinBUGS examples [06.088]. Finally, WinBUGS programs for survival extrapolation are freely available and have been downloaded from the Unit's website.
We have contributed to a range of collaborative research projects, mainly with clinicians and researchers at Papworth, [01.054; 01.002; 01.051; 02.016; 02.030; 02.050; 02.076; 02.102; 03.047; 03.049; 03.048; 04.066; 04.052; 04.051; 04.070; 05.084; 06.102; 06.130; 06.136; 06.008; 06.093; 06.094]
I retain an interest in repeated events data [03.059] and the evaluation and use of health-related, quality of life measurement instruments.
Teaching and dissemination
As Director of Studies I provide academic direction of the PhD programme in the Unit. In recent years we have attracted and developed some world class, young, academic statisticians. These students have gone on to make names for themselves in a variety of fields.
I direct and partly teach the Papworth Hospital Research Skills Course (which attracts medical researchers nationally) and workshops on preparing grant applications, statistical analysis and critical appraisal of literature.
Summary of major achievements
The major contributions/achievements of this programme include:
- Improved treatment for acute and chronic heart disease patients;
- Better classification and therefore better management decisions for heart and lung transplant recipients and other chronic disease sufferers;
- More effective and cost-effective use of implantation technologies in heart disease;
- More available methodologies for establishing disease progression, understanding disease pathways and formally monitoring and managing patients;
- General software for fitting multi-state models, flexible random effects models and survival extrapolation;
- More accurate pinpointing of institutions where clinical performance needs to be improved
Publications from this programme
Publications - 2001
||Bala DV, Patel DD, Duffy SW, Charman SC, Patel PS, Trivedi J, Pinaki P, Pandey P, Patel R. Role of Dietary Intake and Biomarkers in Risk of Breast Cancer: A Case Control Study. Asian Pacific Journal of Cancer Prevention 2001; 2: 123-130.
||Burns SM, Brown S, White CA, Tait S, Sharples LD, Schofield PM. Quantitative analysis of myocardial perfusion changes with transmyocardial laser revascularization. American Journal of Cardiology 2001; 87: 861-867.
||Campbell HE, Tait S, Buxton MJ, Sharples LD, Caine N, Schofield PM, Wallwork J. A UK trial-based cost-utility analysis of transmyocardial laser revascularization compared to continued medical therapy for treatment of refractory angina pectoris. European Journal of Cardio-Thoracic Surgery 2001; 20: 312-318.
||Kiely DG, Ansari S, Davey WA, Mahadevan V, Taylor GJ, Seaton D. Bedside tracer gas technique accurately predicts outcome in aspiration of spontaneous pneumothorax. Thorax 2001; 56: 617-621.
||Lim E, Barlow CW, Hosseinpour AR, Wisbey C, Wilson K, Pidgeon W, Charman SC, Barlow JB, Wells FC. Influence of atrial fibrillation on outcome following mitral valve repair. Circulation 2001; 104: I59-I63.
||Mahadeva R, Sharples LD, Ross-Russell RI, Webb AK, Bilton D, Lomas DA. Association of alpha(1)-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis. Thorax 2001; 56: 53-58.
||Nashef SA, Carey F, Charman SC. The relationship between predicted and actual cardiac surgical mortality: impact of risk grouping and individual surgeons. European Journal of Cardio-Thoracic Surgery 2001; 19: 817-820.
||Satchithananda DK, Stoica SC, White PA, Charman SC, Luckraz H, Schofield PM, Wallwork J, Parameshwar J, Redington AN, Large SR. Systolic right ventricular dysfunction in 'good' donor hearts - a normal finding? Journal of Heart and Lung Transplantation 2001; 20: 243.
||Sharples LD, Taylor GJ, Karnon J, Caine N, Buxton M, McNeil K, Wallwork J. A model for analyzing the cost of the main clinical events after lung transplantation. Journal of Heart and Lung Transplantation 2001; 20: 474-482.
||Sharples LD, Taylor GJ, Faddy M. A piecewise-homogeneous Markov chain process of lung transplantation. Journal of Epidemiology and Biostatistics 2001; 6: 349-355.
||Stoica SC, Satchithananda DK, Charman SC, Smith S, Redington AN, Tsui S, Wallwork J, Large SR. Swan Ganz catheter assessment of donor hearts - outcome of organs with borderline haemodynamics. Journal of Heart and Lung Transplantation 2001; 20: 250.
Publications - 2002
||Akhlaghi F, Jackson CH, Parameshwar J, Sharples LD, Trull AK. Risk factors for the development and progression of dyslipidemia after heart transplantation. Transplantation 2002; 73: 1258-1264.
||Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, Hodgkins D, Bilton D. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic. Health Technology Assessment 2002; 6: 1-71.
||Charman SC, Sharples LD, McNeil KD, Wallwork J. Assessment of survival benefit after lung transplantation by patient diagnosis. Journal of Heart and Lung Transplantation 2002; 21: 226-232.
||Chung DA, Sharples LD, Nashef SA. A case-control analysis of readmissions to the cardiac surgical intensive care unit. European Journal of Cardio-Thoracic Surgery 2002; 22: 282-286.
||Convey P, Pugh PJA, Jackson CH, Murray AW, Ruhland CT, Xiong FS, Day TA. Response of antarctic terrestrial microarthropods to long-term climate manipulations. Ecology 2002; 11: 3130-3140.
||Guo X, Kuzumi E, Charman SC, Vuylsteke A. Perioperative melatonin secretion in patients undergoing coronary artery bypass grafting. Anesthesia and Analgesia 2002; 94: 1085-1091.
||Jackson CH, Sharples LD. Hidden Markov models for the onset and progression of bronchiolitis obliterans syndrome in lung transplant recipients. Statistics in Medicine 2002; 21: 113-128.
||Jackson CH, Sharples LD, McNeil K, Stewart S, Wallwork J. Acute and chronic onset of bronchiolitis obliterans syndrome (BOS): are they different entities? Journal of Heart and Lung Transplantation 2002; 21: 658-666.
||Lim E, Ali ZA, Barlow CW, Hosseinpour AR, Wisbey C, Charman SC, Wells FC, Barlow JB. Determinants and assessment of regurgitation after mitral valve repair. Journal of Thoracic and Cardiovascular Surgery 2002; 124: 911-917.
||Rhydwen GR, Charman SC, Schofield PM. Influence of thrombolytic therapy on the patterns of ventricular septal rupture after acute myocardial infarction. Postgraduate Medical Journal 2002; 78: 408-412.
||Satchithananda DK, Parameshwar J, Sharples LD, Taylor GJ, McNeil K, Wallwork J, Large SR. The incidence of end-stage renal failure in 17 years of heart transplantation: a single center experience. Journal of Heart and Lung Transplantation 2002; 21: 651-657.
||Sharples LD, Edmunds J, Bilton D, Hollingworth W, Caine N, Keogan M, Exley A. A randomised controlled crossover trial of nurse practitioner versus doctor led outpatient care in a bronchiectasis clinic. Thorax 2002; 57: 661-666.
||Sharples LD, McNeil K, Stewart S, Wallwork J. Risk factors for bronchiolitis obliterans: a systematic review of recent publications. Journal of Heart and Lung Transplantation 2002; 21: 271-281.
||Stoica SC, Satchithananda DK, Charman SC, Sharples LD, King R, Rozario C, Dunning J, Tsui SS, Wallwork J, Large SR. Swan-Ganz catheter assessment of donor hearts: outcome of organs with borderline hemodynamics. Journal of Heart and Lung Transplantation 2002; 21: 615-622.
||Stoica SC, Sharples LD, Ahmed I, Roques F, Large SR, Nashef SA. Preoperative risk prediction and intraoperative events in cardiac surgery. European Journal of Cardio-Thoracic Surgery 2002; 21: 41-46.
||Tripp C, Screaton M, Sharples LD, Kearsley N, Caine N. Development and evaluation of the critical care practitioner role. Nursing in Critical Care 2002; 7: 227-234.
||Trull A, Hughes V, Cooper D, Wilkins M, Gimson A, Friend P, Johnston A, Sharples LD, Park G. Influence of albumin supplementation on tacrolimus and cyclosporine therapy early after liver transplantation. Liver Transplantation 2002; 8: 224-232.
||Venkateswaran RV, Charman SC, Goddard M, Large SR. Lethal mesenteric ischaemia after cardiopulmonary bypass: a common complication? European Journal of Cardio-Thoracic Surgery 2002; 22: 534-538.
Publications - 2003
||Blagden SP, Charman SC, Sharples LD, Magee LRA, Gilligan D. Performance status score: do patients and their oncologists agree? British Journal of Cancer 2003; 89: 1022-1027.
||Brown PJ, Warmington V, Laurence M, Prevost AT. A methodology for the functional comparison of coding schemes in primary care. Informatics in Primary Care 2003; 11: 145-148.
||Gee I, Trull AK, Charman SC, Alexander GJ. Sirolimus inhibits oxidative burst activity in transplant recipients. Transplantation 2003; 76: 1766-1768.
||Gray TJ, Burns SM, Clarke SC, Tait S, Sharples LD, Caine N, Schofield PM. Percutaneous myocardial laser revascularisation in patients with refractory angina pectoris. American Journal of Cardiology 2003; 91: 661-666.
||Jackson CH, Sharples LD, Thompson SG, Duffy SW, Couto E>. Multi-state markov models for disease progression with misclassification error. The Statistician 2003; 52: 193-209.
||Lim E, Ali ZA, Barlow CW, Jackson CH, Hosseinpour AR, Halstead JC, Barlow JB, Wells FC. A simple model to predict coronary disease in patients undergoing operation for mitral regurgitation. Annals of Thoracic Surgery 2003; 75: 1820-1825.
||Luckraz H, Sharples LD, McNeil K, Wreghitt T, Wallwork J. Cytomegalovirus antibody status of donor/recipient does not influence the incidence of bronchiolitis obliterans syndrome in lung transplantation. Journal of Heart and Lung Transplantation 2003; 22: 287-291.
||Luckraz H, Charman SC, Wreghitt T, Wallwork J, Parameshwar J, Large SR. Does cytomegalovirus status influence acute and chronic rejection in heart transplantation during the ganciclovir prophylaxis era? Journal of Heart and Lung Transplantation 2003; 22: 1023-1027.
||Luckraz H, Parameshwar J, Charman SC, Firth J, Wallwork J, Large S. Short- and long-term outcomes of combined cardiac and renal transplantation with allografts from a single donor. Journal of Heart and Lung Transplantation 2003; 22: 1318-1322.
||Luckraz H, Murphy F, Bryant S, Charman SC, Ritchie AJ. Vacuum-assisted closure as a treatment modality for infections after cardiac surgery. Journal of Thoracic and Cardiovascular Surgery 2003; 125: 301-305.
||Metcalfe C, Thompson SG, Cowie MR, Sharples LD. The use of hospital admission data as a measure of outcome in clinical studies of heart failure. European Heart Journal 2003; 24: 105-112.
||Petrou M, Rocques F, Sharples LD, Kinsman R, Keogh B, Carey F, Nashef SAM. The risk model of choice for coronary surgery in the United Kingdom. Heart 2003; 89: 98-99.
||Sharples LD, Jackson CH, Parameshwar J, Wallwork J, Large SR. Diagnostic accuracy of coronary angiography and risk factors for post-heart-transplant cardiac allograft vasculopathy. Transplantation 2003; 76: 679-682.
||Stoica SC, Satchithananda DK, Atkinson C, Charman SC, Goddard M, Large SR. Heat shock protein, inducible nitric oxide synthase and apoptotic markers in the acute phase of human cardiac transplantation. European Journal of Cardiothoracic Surgery 2003; 24: 932-939.
Publications - 2004
||Atkinson C, Horsley J, Rhind-Tutt S, Charman SC, Phillpotts CJ, Wallwork J, Goddard MJ. Neointimal smooth muscle cells in human cardiac allograft coronary artery vasculopathy are of donor origin. Journal of Heart and Lung Transplantation 2004; 23: 427-435.
||Barnett GC, Charman SC, Sizer B, Murray PA. Information given to patients about adverse effects of radiotherapy: a survey of patients' views. Clinical Oncology (Royal College of Radiologists (Great Britain)) 2004; 16: 479-484.
||Goldstone AR, Callaghan CJ, Mackay J, Charman SC, Nashef SAM. Should surgeons take a break after an intraoperative death? Attitude survey and outcome evaluation. British Medical Journal 2004; 328: 379-382.
||Groves AM, Win T, Charman SC, Wisbey C, Pepke-Zaba J, Coulden RA. Semi-quantitative assessment of tricuspid regurgitation on contrast-enhanced multidetector CT. Clinical Radiology 2004; 59: 715-719.
||Haworth CS, Selby PL, Webb AK, Martin L, Elborn S, Sharples LD, Adams JE. Inflammatory related changes in bone mineral content in adults with cystic fibrosis. Thorax 2004; 59: 613-617.
||Jackson CH, Sharples LD. Models for longitdinal data with censored change-points. Applied Statistics 2004; 53: 149-162.
||Lim E, Cornelissen J, Routledge T, Kirtland S, Charman SC, Bellm S, Munday H, Khan O, Masood I, Large S. Clopidogrel did not inhibit platelet function early after coronary bypass surgery: A prospective randomized trial. Journal of Thoracic and Cardiovascular Surgery 2004; 128: 432-435.
||Luckraz H, Charman SC, Parameshwar J, Tsui SS, Dunning J, Wallwork J, Large SR. Are non-brain stem-dead cardiac donors acceptable donors? Journal of Heart and Lung Transplantation 2004; 23: 330-333.
||Luckraz H, Goddard M, McNeil K, Atkinson C, Charman SC, Stewart S, Wallwork J. Microvascular changes in small airways predispose to obliterative bronchiolitis after lung transplantation. Journal of Heart and Lung Transplantation 2004; 23: 527-531.
||Mackay JH, Powell SJ, Charman SC, Rozario C. Resuscitation after cardiac surgery: are we ageist? European Journal of Anaesthesiology 2004; 21: 66-71.
||Trull AK, Akhlaghi F, Charman SC, Endenberg S, Majid O, Cornelissen J, Steel L, Parameshwar J, Wallwork J, Large S. Immunosuppression, eotaxin and the diagnostic changes in eosinophils that precede early acute heart allograft rejection. Transplant Immunology 2004; 12: 159-166.
Publications - 2005
||Campbell HE, Tait S, Sharples LD, Caine N, Gray TJ, Schofield PM, Buxton MJ. Trial-based cost-utility comparison of percutaneous myocardial laser revascularisation and continued medical therapy for treatment of refractory angina pectoris. European Journal of Health Economics 2005; 6: 288-297.
||Demiris N, Sharples LD. Bayesian evidence synthesis to extrapolate survival estimates in cost-effectiveness studies. Statistics in Medicine 2005; published online.
||Demiris N, O'Neill PD. Bayesian inference for stochastic multitype epidemics via random graphs. Journal of the Royal Statistical Society, Series B 2005; 67: 731-745.
||Demiris N, O'Neill PD. Bayesian inference for epidemics with two levels of mixing. Scandinavian Journal of Statistics 2005; 32: 265-280.
||Halstead JC, Lim E, Venkateswaran RM, Charman SC, Goddard M. Improved survival with VATS pleurectomy-decortication in advanced malignant mesothelioma. European Journal of Surgical Oncology 2005; 31: 314-320.
||Lim E, Ali Z, Ali A, Motalleb-Zadeh R, Jackson CH, Ong SL, Halstead J, Sharples LD, Parameshwar J, Wallwork J, Large SR. Comparison of survival by allocation to medical therapy, surgery, or heart transplantation for ischemic advanced heart failure. Journal of Heart and Lung Transplantation 2005; 24: 983-989.
||Luckraz H, Sharples LD, Charman SC, Tsui SS, Wallwork J, Parameshwar J, Large SR. Does heart transplantation confer survival benefit in all risk groups? Journal of Heart and Lung Transplantation 2005; 24: 1231-1234.
||Luckraz H, Goddard M, Charman SC, Wallwork J, Parameshwar J, Large SR. Early mortality after cardiac transplantation: should we do better? Journal of Heart and Lung Transplantation 2005; 24: 401-405.
||Luckraz H, White P, Sharples LD, Hopkins P, Wallwork J. Short- and long-term outcomes of using pulmonary allograft donors with low Po2. Journal of Heart and Lung Transplantation 2005; 24: 470-473.
||Nathan JA, Sharples LD, Exley AR, Sivasothy P, Wallwork J. The outcomes of lung transplantation in patients with bronchiectasis and antibody deficiency. Journal of Heart and Lung Transplantation 2005; 24: 1517-1521.
||Perreas KG, McNeil K, Charman SC, Sharples LD, Wreghitt T, Wallwork J. Extended ganciclovir prophylaxis in lung transplantation. Journal of Heart and Lung Transplantation 2005; 24: 583-587.
||Randall DC, Cafferty FH, Shneerson JM, Smith IE, Llewelyn MB, File SE. Chronic treatment with modafinil may not be beneficial in patients with chronic fatigue syndrome. Journal of Psychopharmacology 2005; 19: 647-660.
||Scott AI, Sharples LD, Stewart S. Bronchiolitis obliterans syndrome: risk factors and therapeutic strategies. Drugs 2005; 65: 761-771.
||Stoica SC, Atkinson C, Satchithananda DK, Charman SC, Goddard M, Redington AN, Large SR. Endothelial activation in the transplanted human heart from organ retrieval to 3 months after transplantation: an observational study. Journal of Heart and Lung Transplantation 2005; 24: 593-601.
||Stoica SC, Cafferty FH, Kitcat J, Baskett R, Goddard M, Sharples LD, Wells F, Nashef S. Octogenarians undergoing cardiac surgery outlive their peers - a case for elective referral. Heart 2005; published online.
||Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA. Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 2005; 366: 2019-2025.
||Win T, Jackson A, Sharples LD, Groves AM, Wells FC, Ritchie AJ, Laroche CM. Cardiopulmonary exercise tests and lung cancer surgical outcome. Chest 2005; 127: 1159-1165.
||Win T, Jackson A, Sharples LD, Groves AM, Wells FC, Ritchie AJ, Laroche CM. Relationship between pulmonary function and lung cancer surgical outcome. European Respiratory Journal 2005; 25: 594-599.
||Win T, Sharples LD, Wells FC, Ritchie AJ, Munday H, Laroche CM. The effect of lung cancer surgery on quality of life. Thorax 2005; 60: 234-238.
Publications - 2006
||Ali A, Halstead J, Cafferty FH, Sharples LD, Lee E, Coulden R, Dunning J, Argano V, Tsui S. Are stentless valves superior to modern stented valves? Circulation 2006; in press.
||Ali A, Halstead JC, Cafferty FH, Sharples LD, Lee E, Dunning J, Argano V, Tsui S. Early clinical and hemodynamic outcomes following stented and stenless aortic valve replacement: results from a randomized controlled trial. Journal of Heart Valve Disease 2006; in press.
||Baskett RJF, Cafferty FH, Powell SJ, Keogh BE, Kinsman R, Nashef SAM. Total arterial revasularisation is safe: Multicentre ten-year analysis of 71,470 isolated CABG cases. Annals of Thoracic Surgery 2006; submitted.
||Buxton MJ, Caine N, Connelly D, Grace AA, Jackson CJ, Parkes J, Sharples LD. A review of the evidence on the effects and costs of Implantable Cardioverter Defibrillator (ICD) therapy in different patient groups, and modelling of cost-effectiveness and cost-utility for these groups in a UK context. Health Technology Assessment 2006; in press.
||CeCat trial investigators, Sharples LD, Hughes V, Patel R, Stone D. The feasibility, acceptability and predictive value of functional cardiac testing in diagnosis and management of coronary heart disease: preliminary results from a randomised controlled trial of Echocardiography, Magnetic Resonance Imaging or SPECT as the primary test compared with Angiography. Heart 2006; submitted.
||Demiris N, O'Neill PD. Computation of final outcome probabilities for the generalised stochastic epidemic. Statistics and Computing 2006; submitted.
||Luckraz H, Goddard M, McNeil K, Atkinson C, Sharples LD, Stewart S, Wallwork J. Obliterative bronchiolitis following lung transplantation results from the loss of the microvascular blood supply to small airways. Annals of Thoracic Surgery 2006; in press.
||McNab D, Khan SN, Sharples LD, Ryan JY, Freeman C, Tait S, Caine N, Hardy I, Schofield PM. An open label, single-centre, randomised trial of Spinal Cord Stimulation (SCS) versus Percutaneous Myocardial Laser Revascularisation (PMR) in patients with Refractory Angina Pectoris: the SPiRiT trial. European Heart Journal 2006; in press.
||Nathan JA, Pearce L, Field C, Dotesio-Eyres N, Sharples LD, Cafferty FH, Moore CM. A randomised controlled trial of follow up of patients discharged from hospital following acute asthma: best performed by specialist nurse or doctor? Chest 2006; in press.
||Ohlssen D, Sharples LD, Spiegelhalter DJ. A hierarchical model framework for identifying unusual performance. Journal of the Royal Statistical Society, Series A 2006; submitted.
||Ohlssen D, Sharples LD, Spiegelhalter DJ. Flexible random-effects models using Bayesian semi-parametric models: applications to institutional comparisons. Statistics in Medicine 2006; submitted.
||Pauriah M, Kitcat J, Sharples LD, Tasker A, Schofield PM. Femoral artery pseudoaneurysm post cardiac catheterisation: Risk factors, incidence, management and outcome. Catheterization and Cardiovascular Diagnosis 2006; in press.
||Randall DC, Cafferty FH, Shneerson JM, Smith IE, Llewelyn MB, File SE. A comparison of the effects of repeated cognitive testing on mood and cognitive performance in patients with narcolepsy and chronic fatigue syndrome. Journal of Psychiatry and Neuroscience 2006; submitted.
||Randall DC, Cafferty FH, Shneerson JM, Smith IE, File SE. Chronic treatment with modafinil may have beneficial effects on spatial planning and mood in patients with narcolepsy: findings from a pilot study. Journal of Psychopharmacology 2006; submitted.
||Shah AR, Solanki RN, Shah K, Sharples LD. Double-blind, randomised, controlled trial to assess the effect of adding Theophylline or Montelukast to therapy compared to high dose steroid inhalation in bronchial asthma. Respiration 2006; published online.
||Sharples LD, Jackson CH, Buxton MJ, Caine N, Parkes J, Connelly DT, Grace A. Cost effectiveness of implantable cardioverter defibrillators used in secondary prevention in patients with low ejection fraction in the UK. Lancet 2006; submitted.
||Sharples LD, Buxton M, Caine N, Cafferty FH, Demiris N, Dyer M, Freeman C. Evaluation of Ventricular Assist Device Programme in the United Kingdom (EVAD). Health Technology Assessment 2006; in press.
||Stoica SC, Satchithananda DK, White PA, Parameshwar J, Sharples LD, Redington AN, Large SR. Brain death leads to abnormal contractile properties of the human donor right ventricle. Journal of Thoracic and Cardiovascular Surgery 2006; in press.
||Stoica SC, Cafferty FH, Prabhu M, Taylor C, Sharples LD, Wallwork J, Large SR, Parameshwar J. The cumulative effect of acute rejection on the development of cardiac allograft vasculopathy. Journal of Heart and Lung Transplantation 2006; in press.
||White V, Kitcat J, Hellyer P, Sharples LD, Nashef SAM. Sun, sea and surgery: the effect of leave on surgical outcomes. Lancet 2006; submitted.
||Win T, Jackson A, Groves AM, Sharples LD, Charman SC, Laroche CM. A comparison of shuttle walk with measured peak oxygen consumption in patients with operable lung cancer. Thorax 2006; 61: 57-60.
||Win T, Pearce L, Nathan J, Cafferty FH, Laroche C. Use of the AQ 20 Airway Questionnaire to detect changes in quality of life (QOL) following a hospital admission for acute asthma. Thorax 2006; submitted.
||Yagdi T, Sharples LD, Tsui S, Large S, Parameshwar J. Malignancy after heart transplantation: analysis of 24-year experience at a single centre. Transplantation 2006; submitted.