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School of Health and Related Research (ScHARR) The University of Sheffield Regent Court 30 Regent Street Sheffield, S1 4DA...
Health Economics and Decision Science (HEDS) <ul><li>The purpose of HEDS section within ScHARR is to promote excellence in...
Portfolio of specialities of HEDS 27/10/11 © The University of Sheffield
RESEARCH
Information resources Bayesian Statistics in Health Economics Evidence review and synthesis Health Economics and Outcomes ...
27/10/11 © The University of Sheffield Consultancy within HEDS Modelling alongside clinical trials Health related quality ...
Disease Areas <ul><li>Acute coronary syndrome </li></ul><ul><li>Age-related macular degeneration </li></ul><ul><li>Alcohol...
Innovation & Knowledge Transfer Contact details <ul><li>Further information about consultancy projects and research areas ...
Cost-effectiveness modelling to support Healthcare Decision Making 27/10/11 © The University of Sheffield
<ul><li>The Decision Analytic Modelling team is a leading healthcare modelling group internationally, with a wide ranging,...
In particular: <ul><li>Cost-effectiveness modelling to support HTA submissions </li></ul><ul><li>Budget impact modelling <...
Examples of cost-effectiveness studies conducted in HEDS 27/10/11 © The University of Sheffield
Evaluating the cost-effectiveness of diagnostic tests Dr Matt Stevenson Reader in Health Technology Assessment; NICE Appra...
Overview <ul><li>A brief description of how (and why) cost-effectiveness analyses are applied </li></ul><ul><li>A brief ov...
Cost-effectiveness analyses In the last 10 years there has a been a considerable increase in the importance of cost-effect...
Does a diagnostic test represent value for money? Diagnostic tests with high prices may be cost-effective (i.e. a worthwhi...
Cost-effectiveness analyses The goal of funding agencies is to provide the greatest amount of health for society within th...
Previous Diagnostic evaluations <ul><li>Whilst the majority of evaluations undertaken relate to pharmaceuticals, evaluatio...
Methods for evaluating diagnostic tests There have been, for some time, clear methods guide for undertaking evaluation of ...
Simplified Overview of the modelling required The following slides discuss the steps that would be required to generate an...
Estimating Test Accuracy The sensitivity and specificity of a diagnostic test must be estimated.  These values would be co...
Modelling the patient experience For each of the four groups defined, an estimation of the events that would occur to the ...
Modelling the patient experience Ultimately, an estimation of the life years, quality adjusted life years (QALYs*) and cos...
Calculating an ICER* Assume that post diagnosis, an average patient was expected to gain 10 QALYs at a cost of £20,000 und...
Calculating an ICER In this example, the ICER would be £2,000 per QALY gained (£2,000 / 1) This would be compared with an ...
Implications for diagnostic pricing Where a new diagnostic test has a large impact on mortality or on the utility of a pat...
Sequences and subgroups Note that sequences of tests and only incorporating tests on a subgroup of the population are poss...
Example of diagnostic algorithm Taken from Goodacre et al. QJM 2006; 99:377–388
Returning to the example of sepsis Current gold standard is blood culture, but this has poor sensitivity. A new test is av...
Estimating the cost-effectiveness of a Treat ©  and SeptiFast ©  diagnostic strategy <ul><li>For each Treat ©  category, t...
Estimating the cost-effectiveness of a Treat ©  and SeptiFast ©  diagnostic strategy Thus there will be a QALY gain (and c...
Additional complications with evaluating diagnostic tests There are reasons why evaluating diagnostic tests are more diffi...
Complicating Issues <ul><li>The need to understand the patient pathway </li></ul><ul><li>Data reporting </li></ul><ul><li>...
NICE Decision Support Unit <ul><li>Dr Paul Tappenden </li></ul><ul><li>Senior Research Fellow </li></ul><ul><li>Acting DSU...
Background to DSU <ul><li>Established in 2002. </li></ul><ul><li>Formal collaboration between the Universities of Sheffiel...
Main strands of work <ul><li>Appraisal-specific work </li></ul><ul><ul><li>Rapid evaluation of technical issues/analysis a...
Appraisal-specific work <ul><li>~7 appraisals per year </li></ul><ul><li>Analysis of additional evidence submitted as part...
The NICE Methods Guide for Technology Appraisal <ul><li>Setting the agenda for, organising and facilitating the NICE metho...
DSU Technical Support Documents (TSDs) <ul><li>Series of independent, non-prescriptive reports commissioned to support NIC...
Other DSU methods research <ul><li>Report and related publications demonstrating the feasibility of applying Value of Info...
Methods training   <ul><li>Bridge between NICE and the pharmaceutical industry in providing methods training </li></ul><ul...
Future updates <ul><li>Join our mailing list at : http://www.nicedsu.org.uk </li></ul>
Health economic modelling in bowel cancer <ul><li>Dr Paul Tappenden </li></ul><ul><li>Senior Research Fellow </li></ul><ul...
Health economics and cancer <ul><li>Key area of methodological expertise in ScHARR for >15 years </li></ul><ul><li>Key are...
Key areas of application <ul><li>Modelling interventions for the early detection / prevention of cancer </li></ul><ul><li>...
1. Modelling interventions for the early detection / prevention of cancer <ul><li>Methodological development in modelling ...
An example – screening for CRC 27/10/11 © The University of Sheffield
2. Modelling interventions for the treatment of diagnosed cancer <ul><li>Curative / palliative treatments for diagnosed ca...
An example – bevacizumab for MCRC 27/10/11 © The University of Sheffield
3. Whole Disease Modelling <ul><li>Usefulness of models is in part determined by the scope of the decision it is intended ...
A lot of effort so why bother? <ul><li>Consistent basis for economic evaluation across the pathway </li></ul><ul><li>Struc...
An example – Colorectal Cancer Whole Disease Model
From piecewise CPQ to constrained maximisation 27/10/11 © The University of Sheffield
Colorectal cancer screening : using mathematical modelling to inform policy decisions <ul><li>Dr Sophie Whyte </li></ul><u...
Contents <ul><li>Background </li></ul><ul><li>The current NHS Bowel Cancer Screening Programme </li></ul><ul><li>The flexi...
The current NHS Bowel Cancer Screening Programme <ul><li>Roll out commenced in 2006 and now screening covers the whole of ...
Flexible sigmoidoscopy(FS) screening trial* <ul><li>Trial reported in 2010 </li></ul><ul><li>170,432 persons aged 55-64 we...
Should the screening programme be changed in light of new evidence? <ul><li>Project for NHS cancer screening “Reappraisal ...
Methods: Possible screening scenarios <ul><li>Biennial screening with guaiac or immunochemical FOBT for ages 60-74 </li></...
Methods: Advantages of modelling <ul><li>The number of possible screening strategies is very large </li></ul><ul><li>To de...
Methods: Modelling challenges <ul><li>Considerable uncertainty surrounding values of some parameters essential for colorec...
Methods: Modelling challenges <ul><li>Uncertainty in screening test characteristics </li></ul><ul><li>Sensitivity to CRC o...
CRC natural history model structure 27/10/11 © The University of Sheffield
Methods: Modelling solutions 27/10/11 © The University of Sheffield Polyp detection rate at FS screening Polyp prevalence ...
Methods: Modelling solutions 27/10/11 © The University of Sheffield Probability of diagnosis of CRC (due to symptoms or ch...
Methods: Modelling solutions 27/10/11 © The University of Sheffield Parameter values are estimated by using a Bayesian app...
Results and conclusions <ul><li>CRC screening is generally cost-effective:  Tappenden et al found FS screening to be cost ...
Potential impact on policy decisions <ul><li>Results of work will allow us to advise NHS cancer screening on various aspec...
Calibration method <ul><li>The Metropolis-Hastings algorithm explores the multi-dimensional parameter space to generate mu...
<ul><li>Cost utility analysis of interventions to return employees to work following long term sickness absence </li></ul>...
Introduction <ul><li>Background </li></ul><ul><li>Project process </li></ul><ul><li>Modelling methodology </li></ul><ul><l...
Background <ul><li>People can apply for Incapacity Benefit after they have been on sick leave for >6 months. </li></ul><ul...
Process <ul><li>Effectiveness literature review </li></ul><ul><ul><li>Very limited evidence identified – only 3 UK papers ...
Model scope <ul><li>Population:  </li></ul><ul><li>A cohort of employed men & women that have been on between 1 week and 6...
Modelling methodology (1) <ul><li>Markov model which simulates the experience of a hypothetical cohort of employees who ar...
Modelling methodology (2) <ul><li>Costs and QALYs have been calculated for both cohorts starting at age 41 (average age of...
Quality of life <ul><li>Utility scores estimated based on data from the British Household Survey Panel (BHSP) </li></ul><u...
Costs State in the model Perspective NHS & PSS Societal Employer At work £0 £0 £0 1 wk to 6 months sick leave Cost of usua...
Key model assumptions (1) <ul><li>If an employee has not returned to work within 6 months given the intervention they are ...
Key model assumptions (2) <ul><li>The employee is assumed to receive 15 weeks on full pay and 16.4 weeks on half pay </li>...
Results: NHS/ Societal perspective (1) Cost per QALY gained = £2,758
Results: NHS/ Societal perspective (2)
Results: Employer perspective Cost per day on sick leave avoided = £0.34
One way sensitivity analysis <ul><li>If the difference in health utility between being at work and being on LTS is ≤0.02 t...
Conclusions <ul><li>The model suggests that interventions to return employees to work do not have to be very effective to ...
Model limitations <ul><li>Effectiveness data based on generally poor evidence carried out in non-UK countries </li></ul><u...
Further research <ul><li>Further research is required that: </li></ul><ul><ul><li>Is within the UK setting; </li></ul></ul...
Public health modelling: lessons learned from a contraception case study Hazel Squires, Jim Chilcott, Nick Payne, Lindsay ...
Introduction <ul><li>Outline methods & results of contraception case study </li></ul><ul><li>Discuss key issues in public ...
Aim of NICE contraceptive services project <ul><li>To assess the effectiveness and cost-effectiveness of interventions to ...
Model scope <ul><li>Population:   </li></ul><ul><ul><li>Young people aged between 14 & 16 years within secondary school wh...
Conceptual model 27/10/11 © The University of Sheffield Education/ employment impacts Impact on ‘unintended’ pregnancies I...
Methods <ul><li>Markov model developed within Excel. </li></ul><ul><li>Cohort of 100,000 14-year olds who have not had a b...
27/10/11 © The University of Sheffield Outcomes of teenage birth   Family, societal and individual characteristics Long te...
Literature review: long term outcomes <ul><li>Econometric literature review assessing long term consequences of a teenage ...
Model schematic 27/10/11 © The University of Sheffield t t+1 t+1 t Conception (may be mistimed or unwanted) No conception ...
Key model assumptions <ul><li>The negative impacts of a teenage birth include: </li></ul><ul><ul><li>4% more likely to rec...
Health outcomes <ul><ul><li>Usually increasing life years is considered to be a good thing. In this case, contraceptives a...
Cost-effectiveness decision rules 27/10/11 © The University of Sheffield More expensive Less effective More expensive More...
Results (excl. Benefits) Cohort of 100,000 14-year olds followed over a lifetime 27/10/11 © The University of Sheffield Ex...
Results (incl. Benefits) Cohort of 100,000 14-year olds followed over a lifetime 27/10/11 © The University of Sheffield Do...
Key issues in public health modelling <ul><li>Model scoping & granularity </li></ul><ul><li>Extrapolating outcomes over th...
Model scoping & granularity (1) <ul><li>Public health interventions & their settings are complex.  </li></ul><ul><ul><li>O...
Model scoping & granularity (2) <ul><ul><li>Formal OR problem structuring methods such as cognitive mapping could be used:...
Extrapolating outcomes over the long term <ul><li>Trials generally collect intermediate outcomes. </li></ul><ul><li>The re...
Valuing outcomes <ul><li>Within health economics, benefits are generally measured in terms of QALYs gained </li></ul><ul><...
Handling uncertainty <ul><li>Within health economics, uncertainty within model parameters is formally assessed using proba...
Conclusions <ul><li>Dispensing contraceptives within schools to 14 – 16 yr olds is likely to be cost-effective </li></ul><...
High dose lipid-lowering therapy  Is this strategy cost-effective? <ul><li>Roberta Ara </li></ul><ul><li>Senior Research F...
Background <ul><li>Statin therapy for secondary CVD should “ usually be initiated with a drug with a low acquisition cost ...
The decision problem To evaluate the cost-effectiveness of high dose statins (atorvastatin 80mg/d, rosuvastatin 40mg/d & s...
Markov health states
Clinical Data  Literature review: 28 RCTs > 12 week duration Benefit: LDL-c  Synthesis: MTC  Relationship: LDL-c & CV events
Mean Relative Risks (95% CI)   Atorvastatin 80mg/d Rosuvastatin 40mg/d Simvastatin 40mg/d Simvastatin 80mg/d Non-fatal MI ...
Adherence to therapies   Scenario A Scenario B   Yr 1 Yr 5 Yr 1 Yr 5 S40 ITT ITT ITT ITT A80 ITT ITT 95% 85% R40 ITT ITT 9...
Treatment costs   Annual cost Sensitivity analyses Atorvastatin 80mg/d £368 £92 Rosuvastatin 40mg/d £387 Simvastatin 40mg/...
Results <ul><li>C omparing with simvastatin 40mg/d: </li></ul>  Atorvastatin 80mg/d Rosuvastatin 40mg/d Simvastatin 80mg/d...
Results –  reduced cost for Atorvastatin simvastatin 40mg/d simvastatin 80mg/d atorvastatin 80mg/d rosuvastatin 40mg/d 0.0...
Summary & Conclusion <ul><li>Rosuvastatin 40mg/d is currently the most cost-effective alternative </li></ul><ul><li>Atorva...
A cost-effectiveness model of prostate cancer screening Matthew Mildred, Jim Chilcott, Silvia Hummel ScHARR, University of...
Contents <ul><li>Introduction to the project and topic </li></ul><ul><li>Disease natural history model </li></ul><ul><li>D...
The project <ul><li>Client:  </li></ul><ul><li>UK National Screening Committee </li></ul><ul><li>Purpose:  </li></ul><ul><...
Introduction to prostate cancer <ul><li>The prostate is a small gland in men behind the bladder. </li></ul><ul><li>The mos...
Aim of screening: <ul><li>Reduce cancer mortality, morbidity and treatment costs through early diagnosis and intervention....
Challenges: <ul><li>Effectiveness of different screening programmes unknown. </li></ul><ul><li>Scarce data around disease ...
Solution: <ul><li>Develop loosely parameterised cancer screening simulation model. </li></ul><ul><li>Calibrate unobservabl...
About the model: <ul><li>Disease natural history model (Simul8) </li></ul><ul><li>Calibration module (Excel, Visual Basic)...
Screening strategies investigated 05/04/2011 © The University of Sheffield No. Screens Screening Age (years) Screening Int...
Outputs: <ul><li>Age-specific incidence </li></ul><ul><li>Age-specific mortality </li></ul><ul><li>Prostate cancer stage d...
Definitions & terms used 05/04/2011 © The University of Sheffield PCa Onset Screen Detection PCa Mortality Clinical Diagno...
Disease natural history model 05/04/2011 © The University of Sheffield
Data 05/04/2011 © The University of Sheffield Data Source Age specific cancer incidence Office of National Statistics Canc...
Calibration process 05/04/2011 © The University of Sheffield
Total SSE during calibration 05/04/2011 © The University of Sheffield
Validation: Incidence 05/04/2011 © The University of Sheffield
Validation: PCa mortality 05/04/2011 © The University of Sheffield
Validation: BAUS 05/04/2011 © The University of Sheffield
Results: Incidence 05/04/2011 © The University of Sheffield
Results: Mortality 05/04/2011 © The University of Sheffield
Over-detection & Lead time: 05/04/2011 © The University of Sheffield Once at 50 50-74 every 4 years 50-74 every 2 years 50...
Conclusions: <ul><li>A minimal life gain is offset by the high levels of disease management and over-diagnosis: </li></ul>...
Have you heard our findings? 05/04/2011 © The University of Sheffield BBC News 06/12/2010 http://www.bbc.co.uk/news/health...
Acknowledgements: <ul><li>Dr Anne Mackie and Prof Julietta Patnick at the UK National Screening Committee </li></ul><ul><l...
Healthcare costs alone do not describe the total costs directly attributable to Ankylosing Spondylitis <ul><li>R. Ara 1 , ...
Introduction <ul><li>Ankylosing Spondylitis (AS) is a chronic, progressive disease and prognosis is often poor. In additio...
Objectives <ul><li>To explore the total costs directly attributable to AS patients attending rheumatological centres in th...
Methods <ul><li>Health care costs included:  medications, inpatient, GP/ outpatient, physiotherapy, hydrotherapy  </li></u...
Results (1) <ul><li>Healthcare Utilisation: </li></ul><ul><li>41% reported no health care resources </li></ul><ul><li>45% ...
Results (2) <ul><li>Total Costs: </li></ul><ul><li>The distribution of costs is heavily skewed with small number incurring...
Results (3) <ul><li>Absenteeism/ presenteeism </li></ul><ul><li>25% of working age reported not working or early retiremen...
Results (4) <ul><li>Using BASDAI & BASFI to predict AS disease costs </li></ul><ul><li>Model 1 :  </li></ul><ul><li>Probab...
Conclusion <ul><li>This study shows that direct healthcare costs alone do not describe the total costs associated with AS ...
The direct healthcare resource costs associated with Ankylosing Spondylitis patients attending a UK secondary care rheumat...
Introduction <ul><li>Anti-TNF inhibitors such as etanercept (ETN), are now licensed for treating patients with severe Anky...
Objectives <ul><li>To explore the direct healthcare resources utilised by AS patients attending a UK secondary care rheuma...
Methods <ul><li>Costs:   </li></ul><ul><li>Costs were assessed using a micro-costing approach starting with a detailed inv...
Results (1) <ul><li>Mean Annual Disease Costs </li></ul><ul><li>The mean total annual costs is estimated to be £1,837 (s.d...
Results (2) <ul><li>Using BASDAI & BASFI to predict AS disease costs </li></ul><ul><li>Both the BASDAI and BASFI measureme...
Discussion/Future Research <ul><li>The results of this costing study give an indication of the range of direct healthcare ...
A treatment option for patients with severe active Ankylosing Spondylitis:  the costs and benefits associated with etanerc...
Introduction <ul><li>Ankylosing Spondylitis (AS) is a progressive inflammatory disease that can cause irreversible skeleta...
Objective <ul><li>To explore the costs and benefits associated with etanercept (ETN) in patients with severe AS in the UK ...
Methods <ul><li>The model (written in Excel 2003) estimates the costs and benefits associated with ETN (2x 25mg/week) plus...
Assumptions <ul><li>Natural disease progression: BASFI increases at 0.7 units per annum </li></ul><ul><li>For responders t...
Base case results 27/10/11 © The University of Sheffield
Univariate sensitivity analyses <ul><li>The tornado diagram shows that the three variables that have the largest impact of...
Monte Carlo results <ul><li>Using a 25 year horizon and a £30k per QALY threshold, ETN would be considered a cost-effectiv...
Areas for future research <ul><li>Potential impact of radiological progression on long term disability </li></ul><ul><li>E...
An economic evaluation of etanercept in the treatment of patients with psoriatic arthritis <ul><li>RM Ara and R Rafia </li...
Introduction <ul><li>Psoriatic Arthritis (PsA) is a chronic, progressive disease and prognosis is often poor.  </li></ul><...
Objective <ul><li>To explore the costs and benefits associated  with  etanercept in the treatment for patients with psoria...
Methods <ul><li>The model compares ciclosporin to anti-TNF agents (etanercept, adalimumab, infliximab) and it is assumed t...
Relationship between  HAQ and HrQoL <ul><li>Relationship estimated from PRESTA trial for the base case: </li></ul><ul><li>...
Relationship between  HAQ and Direct health care Costs <ul><li>Health care costs include both primary and secondary care r...
Base case results
Uncertainty in results <ul><li>The model results were sensitive to both the magnitude of the rebound of HAQ after withdraw...
Conclusion <ul><li>While this evaluation provides evidence on the potential cost-effectiveness of etanercept compared to o...
Evidence Review and Synthesis 27/10/11 © The University of Sheffield
Extensive experience of systematic review and evidence synthesis work for <ul><ul><li>National Institute for Health and Cl...
Systematic review of clinical evidence <ul><li>High quality systematic reviews for submissions to  key reimbursement bodie...
Generalised evidence synthesis  <ul><li>Classical and Bayesian meta analysis, including  network meta analysis </li></ul><...
Examples of Systematic reviews conducted in HEDS 27/10/11 © The University of Sheffield
PET and MRI for the assessment of axillary lymph node metastases in early stage breast cancer <ul><li>A Systematic review ...
Background <ul><li>Axillary staging is important for breast cancer staging and treatment planning </li></ul><ul><li>Curren...
Diagnostic pathway <ul><li>NICE diagnostic pathway </li></ul><ul><li>*Either fine needle aspiration cytology (FNAC) or cor...
HTA report <ul><li>National Institute for Health Research Health Technology Assessment (HTA) programme commissioned resear...
Methods <ul><li>Searched eleven databases  </li></ul><ul><li>Inclusion criteria:  </li></ul><ul><ul><li>Assessed diagnosti...
Diagnostic accuracy studies <ul><li>Patients are classified against a reference standard (eg ALND or SLNB) as true positiv...
Results 27/10/11 © The University of Sheffield
PET results <ul><li>Quality generally acceptable, though some problems with patient spectrum, blinding, availability of re...
PET results – forest plots
PET sensitivity analyses
MRI results <ul><li>Quality generally good. Some problems with patient spectrum, availability of relevant clinical informa...
MRI results – forest plot 27/10/11 © The University of Sheffield
MRI results <ul><li>Criteria for positivity varied across studies, including variables of size, morphology and uptake. Upt...
Adverse effects <ul><li>No adverse effects were reported for PET </li></ul><ul><li>Mild to moderate adverse effects report...
Discussion <ul><li>PET, PET-CT and MRI have lower sensitivity and specificity than ALND, SLNB and 4-NS </li></ul><ul><li>P...
Discussion (2) <ul><li>Based on these estimates, if PET or MRI are used to replace SLNB/4-NS in the diagnostic pathway, mo...
PET results – ROC plot 27/10/11 © The University of Sheffield All PET studies, showing ROC curve (solid line), mean sensit...
MRI results – ROC plot 27/10/11 © The University of Sheffield All MRI studies, showing ROC curve (solid line), mean sensit...
Systematic reviews of relevant data Myfanwy Lloyd Jones Senior Research Fellow ScHARR, University of Sheffield Email: m.ll...
More specifically <ul><li>Drawing on the experience of the pilot diagnostics project, how do systematic reviews of diagnos...
The review question <ul><li>Is there a bigger difference between the overall project question and the question that forms ...
Therapeutic intervention <ul><li>Research question defined in the protocol:  </li></ul><ul><li>To establish the clinical a...
In PICOS terms <ul><li>Population: postmenopausal women with osteoporosis, with or without prior fracture </li></ul><ul><l...
Diagnostic intervention <ul><li>Decision problem defined in the protocol:  </li></ul><ul><li>Will using non-invasive liver...
In PICOS terms: population & intervention <ul><li>Population: patients suspected of having liver fibrosis related to alcoh...
In PICOS terms: the comparator <ul><li>The current UK decision-making process?  </li></ul><ul><ul><li>What the NICE team w...
In PICOS terms: outcomes <ul><li>Test accuracy compared with the reference standard </li></ul><ul><li>Number of test failu...
In PICOS terms: study design <ul><li>Protocol: “The best available level of evidence will be included, with priority given...
Population (1) <ul><li>Therapeutic intervention:  </li></ul><ul><ul><li>reasonable match between review question and study...
Population (2) <ul><li>In diagnostic studies, if the reference standard is invasive (eg liver biopsy) or particularly expe...
Intervention   <ul><li>Therapeutic intervention: </li></ul><ul><li>Description and other useful data from EMEA and BNF </l...
Comparator: what is it? <ul><li>Therapeutic intervention: </li></ul><ul><li>No active intervention (placebo or no treatmen...
Comparator: issues <ul><ul><li>Studies of diagnostic test accuracy assume that the reference standard has 100% sensitivity...
Outcomes: therapeutic intervention <ul><li>Primary outcome: fracture </li></ul><ul><ul><li>Clinical relevance clear </li><...
Outcomes: diagnostic intervention <ul><li>Primary outcome: subject of debate </li></ul><ul><ul><li>Test accuracy? </li></u...
Reporting of outcomes: therapeutic intervention (1) <ul><li>The Consort statement says that “for each outcome, study resul...
Reporting of outcomes: therapeutic intervention (2) <ul><li>1 </li></ul>27/10/11 © The University of Sheffield Number (%) ...
Reporting of outcomes: therapeutic intervention (3) <ul><li>Vertebral fracture: </li></ul><ul><ul><li>SOTI trial reported ...
Reporting of outcomes: diagnostic intervention (1) <ul><li>The STARD (Standards for Reporting of Diagnostic Accuracy) guid...
Reporting of outcomes: diagnostic intervention (2) 27/10/11 © The University of Sheffield Reference standard positive Refe...
Reporting of outcomes: diagnostic intervention (3) 27/10/11 © The University of Sheffield
Reporting of outcomes: diagnostic intervention (4) <ul><li>NILTs produce results on a continuous scale, but liver biopsy r...
Study design <ul><li>Therapeutic intervention: </li></ul><ul><li>Only RCTs included </li></ul><ul><li>Diagnostic intervent...
Meta-analysis (1) <ul><li>Therapeutic intervention: </li></ul><ul><li>Generally straightforward using Review Manager </li>...
Meta-analysis (2) <ul><li>Not appropriate  if studies have heterogeneous populations, and in diagnostic studies that heter...
Systematic reviews of relevant data Myfanwy Lloyd Jones Senior Research Fellow ScHARR, University of Sheffield Email: m.ll...
The aim of the assessment <ul><li>To answer the research question: Will using the specified non-invasive liver assessment ...
The specified tests <ul><li>Three patented blood tests: </li></ul><ul><ul><li>The Enhanced Liver Fibrosis (ELF) test </li>...
Outcomes of interest: <ul><li>Diagnostic test accuracy (including numbers of test failures) </li></ul><ul><li>Number of pa...
Reference standard tests <ul><li>Liver biopsy </li></ul><ul><li>Also used in some studies </li></ul><ul><ul><li>Hepatic ve...
Systematic review of clinical effectiveness <ul><li>Population: patients with suspected alcohol-related liver fibrosis  </...
Included studies: ELF test <ul><li>Rosenberg 2004: patients with chronic liver disease (subgroup with ALD); test accuracy ...
Included studies: FibroTest (1) <ul><ul><li>2 studies specifically in patients with known or suspected alcohol-related liv...
Included studies: FibroTest (2) <ul><li>3 studies in mixed aetiology liver disease: </li></ul><ul><ul><li>1 study in patie...
Included studies: FibroMAX <ul><li>No relevant studies identified </li></ul>
Included studies: FibroScan (1) <ul><li>6 studies specifically in patients with known or suspected alcohol–related liver d...
Included studies: FibroScan (2) <ul><li>3 studies in mixed aetiology liver disease: </li></ul><ul><ul><li>1 study in patie...
AUROCs from key studies: test vs liver biopsy Test Degree of fibrosis Study AUROC (95% CI) ELF ‘ Moderate/severe’ Rosenber...
Sensitivity and specificity: ELF Test (subgroup with ALD) Degree of fibrosis Study  Threshold  score Sensitivity Specifici...
Sensitivity and specificity: FibroTest (all patients ALD) Degree of fibrosis Study  Threshold score Sensitivity  Specifici...
Sensitivity and specificity: FibroScan (all patients ALD, all biopsied) Degree of fibrosis Study Threshold score Sensitivi...
Sensitivity and specificity: FibroScan (all patients ALD, only subset biopsied) Degree of fibrosis Study  Threshold score ...
FibroScan: exclusion of patients with laboratory signs of ASH  Degree of fibrosis No of patients AUROC Threshold score Sen...
Evidence re outcomes of interest (1) <ul><li>Diagnostic test accuracy: NILTs appear to have reasonable accuracy, but the e...
Evidence re outcomes of interest (2) <ul><li>Numbers of patients giving up or significantly reducing alcohol consumption f...
Liver biopsy: an imperfect reference standard <ul><li>Diagnostic studies assume that the reference standard has 100% sensi...
Liver biopsy: ethical aspects affect study design <ul><li>Adverse events: </li></ul><ul><ul><li>Minor adverse events: 9.39...
How much homogeneity is required for meta-analysis? <ul><li>The studies of FibroTest and FibroScan included in this review...
Health Economics and Outcomes Research 27/10/11 © The University of Sheffield
Areas of Particular Strength <ul><li>Quality of life and outcomes measurement, wellbeing and equity </li></ul><ul><li>Prim...
Research centre <ul><li>Centre for Well-being in Public Policy (CWiPP) </li></ul><ul><li>The goals of the centre are to co...
For example: <ul><li>HEDS in collaboration of the Department of Economics, University of Sheffield run a number of joint r...
Examples of health outcome studies conducted in ScHARR 27/10/11 © The University of Sheffield
Developing and testing condition-specific preference-based measures: Lessons learnt and policy implications John Brazier, ...
Acknowledgements <ul><li>COSMeQ team: John Brazier 1 , Aki Tsuchiya 1 , Ifigeneia Mavrazenouli 1,2 , Tracey Young 1 , Yali...
Economic evaluation <ul><li>Economic evaluation using cost utility analysis (CUA) increasingly used to inform resource all...
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
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ScHARR, ISPOR Presentation, Madrid, November, 2011
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ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
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ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
ScHARR, ISPOR Presentation, Madrid, November, 2011
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  • PDG &amp; literature to derive
  • Switching from atorvastatin (10/20mg) to generic simvastatin (20/40mg) saves approx £1,000/patient over 5 years (Moon 2006) SEARCH
  • Scenario A: Adherence in clinical trials reported 80-90% - results represent cost-effectiveness for individuals who tolerate potent doses AND adhere to treatment Scenario B: Scenario C: assumed individuals who didn’t tolerate potent statins received simvastatin 40mg/d
  • For Scenario B, For Scenario A &amp; C: All potent doses would be considered cost-effective For Scenario B: Rosuvastatin would be considered cost-effective, Simvastatin 80mg/d would not
  • Alcohol consumption (? within the last 2 months) affects the results of several of the tests used in ELF and FibroTest, and causes inflammation which influences FibroScan results. FibroMAX may be less affected as it combines FibroTest with additional tests for steatosis (SteatoTest), non-alcoholic steatohepatitis (NashTest), and severe alcoholic steatohepatitis (AshTest). In patients with risk factors for ALD, it simultaneously presents the FibroTest, SteatoTest and AshTest results. 42
  • Lack of clarity about numbers of patients with ALD; lack of independence of test manufacturer
  • Naveau: patients hospitalised for alcoholism or complications of cirrhosis; test accuracy (biopsy) (2005); survival at 5 and 10 years (2009) Nguyen-Khac 2008: patients requiring alcohol detoxification/rehabilitation; test accuracy (biopsy) – this is the only FT study which seems independent of the manufacturer Excluded Foucher 2006a: alcoholic patients (not further defined) because test accuracy (biopsy) in subset only, and criteria for biopsy not clear
  • Excluded Thabut 2003 HVPG comparison in patients with patients with chronic liver disease as data relating specifically to patients with ALD neither published nor available from study authors
  • Kim 2009: patients with ALD; test accuracy (biopsy) Mueller 2010: patients with ALD; test accuracy (biopsy) Nahon 2008: patients with suspected ALD; test accuracy (biopsy) Nguyen-Khac 2008: patients requiring alcohol detoxification/ rehabilitation; test accuracy (biopsy) Janssens 2010: patients requiring alcohol detoxification/ rehabilitation; test accuracy (biopsy, HPVG) assessed only in those with scores indicating severe fibrosis Melin 2005: patients treated for alcohol withdrawal; test accuracy (biopsy) only in subset with FS score &gt;13 kPa Foucher 2006a: alcoholic patients (not further defined); test accuracy (biopsy) in subset only, criteria for biopsy not clear, therefore study excluded
  • Foucher 2006b excluded because population overlapped with 2006a
  • Key studies – ie the only study of ELF, even though it is only a subgroup analysis of a mixed population, and the studies of FibroTest and FibroScan which focused on patients with known or suspected ALD, and biopsied all patients.
  • Low threshold: high sensitivity (in this case, all patients with moderate/severe fibrosis have a positive test result – no false negatives) but low specificity (ie lot of patients without moderate/severe fibrosis have a positive result – false positives) High threshold: lower sensitivity (ie some patients with moderate/severe fibrosis have false negative test results) but high specificity (ie no patients without moderate/severe fibrosis have a positive result – no false positives)
  • Janssens found that the threshold scores recommended for Hepatitis C (9.6 kPa for F3-F4, and 12.5 kPa for F4) had a poor PPV in patients with ALD (65% for F3-F4) (presumably because of the effect of alcohol-related liver inflammation), so looked at the effect of different thresholds.
  • Alcoholic steatohepatitis: Mueller et al found that diagnostic accuracy improved when patients with laboratory signs of ASH (GOT &gt;100 U/L) were excluded; exclusion of patients with mildly elevated GOT (&gt;50 U/L) improved accuracy re F3-F4 fibrosis, but not cirrhosis alone) – the specificity is affected more than the sensitivity (ie fewer false positives)
  • Either the whole study population is unrepresentative because of the disease severity (eg recruited from patients already scheduled for biopsy) Or the whole population is more representative, but biopsy is only performed in the subset with a NILT result suggesting severe disease
  • Naveau et al follow-up study of FibroTest found that only 21% were abstinent during follow-up period; 50% not abstinent, 29% unknown. No indication what the impact of the test result was. Some evidence that the ELF test and FibroTest may have some prognostic value, but without information about post-test drinking habits this is open to confounding
  • There are two major problems relating to the use of liver biopsy as the reference standard to assess the diagnostic accuracy of non-invasive liver tests. The first is the fact that it is an imperfect reference standard, and the second relates to ethical issues.
  • Because of the level of AEs, it would not be ethical to biopsy the full range of people with suspected ALD, including those who are unlikely to have fibrosis. So, the evidence clusters towards one end of the range, and we have much more evidence of the accuracy of the non-invasive tests in correctly identifying people who have severe fibrosis than in correctly identifying people who don’t have severe fibrosis
  • Care and management of dementia increasing concern
  • This is the development process that the team in Sheffield have developed and applied to a range of condition specific measures to create a health state classification system that is subsequently valued using a preference elicitation technique such as TTO
  • Why EFA
  • This is the development process that the team in Sheffield have developed and applied to a range of condition specific measures to create a health state classification system that is subsequently valued using a preference elicitation technique such as TTO
  • Sample size for DEMQOL-U was larger as the classification system describes more states and had a larger selected study design. using the AFD Names and Numbers version 3.1.25 database ( AFD Software Limited, Ramsey, UK) . The sample was balanced to the UK population according to geo-demographic profiles.
  • in which respondents valued states from one of the classification systems determined using a card block system. Interviewers worked systematically through blocks; odd and even blocks contained DEMQOL-U and DEMQOL-Proxy-U states respectively. This approach was used to try and ensure that there were no systematic differences across the geo-demographic profiles of the samples for each classification system. and this was done to help familiarise them with the classification system as there are concerns that naming the condition can affect elicited utility values (8). Face to face interviews This rank task further familiarised respondents with the classification system and the health states to be later valued using time trade-off (TTO).
  • 18 to 78 observations with 306 and worst states. The range of mean values was 0.954 to 0.184 One or more states with mean value lower than worst state. There were a large proportion of TTO values at 1 for both measures (26.9% for DEMQOL-U the distribution of the data was negatively skewed)
  • 287 valued worst states. The range of mean values was 0.961 to 0.331 (smaller than DEMQOL) one state with mean value lower than the worst state two states with a mean value higher than the best state. These apparent contradictions are most likely observed due to the much smaller number of observations for some states in comparison to worst state and best state 28.8% of values at 1 and distribution negatively skewed
  • Predicted range similar to observed range
  • Predicted range similar to observed range
  • Condition-specific preference-based measures have been derived from existing measures for Asthma quality of life questionnaire, overactive bladder questionnaire, EORTC-QOQ-C30, Sexual quality of life questionnaire etc. We are also nearing completion of measures for common mental health problems, epilepsy, dementia (using both self-report and proxy-report measures), and diabetes. This involves 3 stages. Firstly dimensions and items are selected using a combination of psychometric, factor and Rasch analysis. Secondly a sample of health states are valued by members of the general population, using, say, the time trade-off valuation techniques (primary data collection). Thirdly values are modelled using regression analysis to produce utility values for every health state defined by the measure. We’ve recently completed an MRC/NIHR funded study examining the methodology of the process and the HTA report is forthcoming. We have developed a measure suitable for children aged 7-11 years, the CHU-9D. (Current utility weights are from adults but work is ongoing to obtain preference weightings from children). This measure is being used in many studies in UK and Australia. AMD project involved primary data collection of HUI, SF-6D, EQ-5D utility values from approx 1000 patients with AMD in order to estimate the relationship between visual acuity and the generic measures to populate a cost-effectiveness model. We have recently undertaken many reviews examining whether EQ-5D is appropriate (assessing validity, responsiveness) for a range of conditions including...
  • Condition-specific preference-based measures have been derived from existing measures for Asthma quality of life questionnaire, overactive bladder questionnaire, EORTC-QOQ-C30, Sexual quality of life questionnaire etc. We are also nearing completion of measures for common mental health problems, epilepsy, dementia (using both self-report and proxy-report measures), and diabetes. This involves 3 stages. Firstly dimensions and items are selected using a combination of psychometric, factor and Rasch analysis. Secondly a sample of health states are valued by members of the general population, using, say, the time trade-off valuation techniques (primary data collection). Thirdly values are modelled using regression analysis to produce utility values for every health state defined by the measure. We’ve recently completed an MRC/NIHR funded study examining the methodology of the process and the HTA report is forthcoming. We have developed a measure suitable for children aged 7-11 years, the CHU-9D. (Current utility weights are from adults but work is ongoing to obtain preference weightings from children). This measure is being used in many studies in UK and Australia. AMD project involved primary data collection of HUI, SF-6D, EQ-5D utility values from approx 1000 patients with AMD in order to estimate the relationship between visual acuity and the generic measures to populate a cost-effectiveness model. We have recently undertaken many reviews examining whether EQ-5D is appropriate (assessing validity, responsiveness) for a range of conditions including...
  • ADHD project involves (ongoing) primary data collection of patients with ADHD and is an observation study examining the wider effects of ADHD on the patient and the family. AMD project involved primary data collection of HUI, SF-6D, EQ-5D utility values from approx 1000 patients with AMD in order to estimate the relationship between visual acuity and the generic measures to populate a cost-effectiveness model. Can move beyond the NHS perspective to societal perspective and take into account wider effects such as carer and productivity effects. Are currently involved in research for DH on value based pricing, as this is going to be used in the UK from 2014 onwards... Literature reviews can also be used to obtain values from the literature for use in the cost-effectiveness model and we have also undertaken research looking at synthesising utility values from multiple sources.
  • Jigsaw method to find out about key types evidence Into 4 groups. Each of you is going to become an expert (in 10 mins) on a particular level of evidence. Going to give you some information relating to one type of evidence. Read through it and digest the key points. Try to establish a clear definition and the pros and cons of using this type of evidence. You are then going to get together with fellow experts . Your task is to teach your fellow group members about the evidence you have been resesearching. 3 mins to get them up to speed. Your fellow group members will help you to prepare the key facts for your 3 min teaching session. You will each get a turn in your groups to be the expert, teaching the other group members about your evidence. Aim at the end – all group members informed about the key sources of evidence in very short space of time. So, 10 mins to digest your information. Then 15 mins with your fellow experts to plan your feedback session Then return to your groups and take turns to teach each other. Group members need to listen attentively and ask questions if they are unclear. At end, we are going to ask each group to feedback on what they have learned.
  • Jigsaw method to find out about key types evidence Into 4 groups. Each of you is going to become an expert (in 10 mins) on a particular level of evidence. Going to give you some information relating to one type of evidence. Read through it and digest the key points. Try to establish a clear definition and the pros and cons of using this type of evidence. You are then going to get together with fellow experts . Your task is to teach your fellow group members about the evidence you have been resesearching. 3 mins to get them up to speed. Your fellow group members will help you to prepare the key facts for your 3 min teaching session. You will each get a turn in your groups to be the expert, teaching the other group members about your evidence. Aim at the end – all group members informed about the key sources of evidence in very short space of time. 10 mins to digest your information. Then 10 mins with your fellow experts to plan your feedback session Then return to your groups and take turns to teach each other. 3 minute teaching session each person Group members need to listen attentively and ask questions if they are unclear. At end, we are going to ask each group to feedback on what they have learned
  • Supporting the Health Researcher of the Future In addition to supporting the key roles of basic education and continuing professional development health libraries are increasingly occupying an essential position in providing support to those involved in health research. Whereas previously such a role involved stocking a few key journals in a discipline and providing access to a much wider selection of peer reviewed articles through well-utilised interlibrary loan networks the emphasis has now shifted to a service “beyond the library walls”. Indeed the challenge faced by many libraries is that of warding off increasing invisibility as researchers become accustomed to accessing resources from their own desktops. Faced with such a challenge what can a health library that aims to meet the needs of its research community seek to do? One possibility is to reengineer the library&apos;s presence through a range of tailored services and virtual resources. This presentation will describe how a health library can utilise free or low cost technologies to deliver a suite of services that are based around the needs of particular programmes, projects or even individual researchers. It will describe the activities of the School of Health and Related Research at the University of Sheffield in moving forward its research support services through the use of wikis, RSS feeds, blogs and portals. The team will share lessons learnt and pointers for any other libraries seeking to extend its outreach to health researchers beyond the four walls of the library.
  • Supporting the Health Researcher of the Future (30 mins) The Context of Research Support (5 mins) The Potential of Web 2.0 (5 mins) Some Examples of Good Practice (4 mins) What we are doing in ScHARR/Y&amp;H (9 mins) The Way Forward? (2 mins) Questions (5 mins)
  •     Are you all familiar with CCs? Basically bibliographies identifying the key books in Health Subject areas to help librarians  in Collection Development - either when setting up a collection from scratch or to help prioritise budgets which in new era is particularly pertinent.   The process in updating these had however become very timeconsuming: - Difficult for people to meet - Diffcult to get people to contribute. - It was felt that an online version was now needed.   So in this presentation I&apos;ll take you through some of the and the issues we needed to address, Helen will explain her scoping of various Web 2.0 tools and how we piloted the use of Library Thing with the Mental Heath CC and then we&apos;ll do a live demonstration to try and entice you all to go away and contribute to the new Medical CC! Have to begin with a disclaimer - we are not experts in Web 2.0 technologies.  I for one work in an NHS Trust where frustratingly anything innovative is often firewalled,  So we will be deferring all technical queries at the end to Frank  
  • Core Collections have a long and fruitful history - over 17 years MIWP developed and when the group was disbanded, HLG took on the role of updating these in partnership with Tomlinsons.   But the process had become very timeconsuming.  When the issue of revising the CCs at one HLG committee meeting with a call out for volunteers, there was a definite tumbleweed moment.. We therefore set up a working group to look at alternative ways of revising these    
  •   HELEN         Idea of using Web 2.0 application   Not actually one but  3 challenges Team across the country Resource would be richer with more contributors Felt a need for the final lists to be available online     These challenges need different solutions - I&apos;m going to look at the last two and how Library Thing provided a full or part solution.
  • Consider 2nd challenge     Increasing collaboration - we needed to make it easier and quicker for people to suggest titles for the collection.    Considered 3 tools
  • HELENE     We decided to pilot the use of Library Thing with the Mental Health CC which was the smallest of the collections and also the one in most dire need of updating - the first edition had been published in 1999.  It had been produced by one library service, so had had limited ... A Library was set up on LT with the data from the last edition for people to comment on.   A briefing paper was sent out to librarians working in mental health via as many channels as possible and they were encourgaged toget clinicians and university lecturers in their areas involved.    People were encouraged to  comment on the books - w
  • We created a Mental Health collection on LT and loaded all the books from the last edition onto LT, Tomlinsons having checked for new edtions.  
  • Each book was assigned a tag, or subject term, making it easier for people to select the specific subjects they were interested in focusing on. As I said, we sent out some publicity and guidance to mental heatlh librarians via as many communication channels as possibe (e-mail discussion lists, the PLCS scheme etc) and asked them to contribute by commenting on the books already on the system, either to endorse them or to suggest that they should be removed and to suggest new books.  They were also encouraged to try to get health professionals and lecturers in their area to contribute.
  • Excellent feedback received, LT facilitated discussion - people in some cases arguing as to why a particular book should still be included despite its date for example. People commented on whether books were on reading lists, how popular they were with their users, etc.
  • The Mental Health CC was published in December 2009. The Nursing CC, which Lori Harvard has co-ordinated is literally hot off the press - collect your copy from Tomlinsons stand today if you haven&apos;t already.   Lori was involved in the complilation of the 3rd and 4th edition - doing it through LibraryThing made it all so much easier.
  • And Online version is available - either via the HLG website where we have a read-only version of the Collection on LT or via a new website which Tomlinsons have produced.
  • If you do contribute, your name will be included in the printed version of the 6th ed.
  • Sign in
  • Please don&apos;t delete anything!
  • Please add a brief comment to explain why you think the book is important and your name.
  • Transcript of "ScHARR, ISPOR Presentation, Madrid, November, 2011"

    1. 1. School of Health and Related Research (ScHARR) The University of Sheffield Regent Court 30 Regent Street Sheffield, S1 4DA Website: www.sheffield.ac.uk/scharr
    2. 2. Health Economics and Decision Science (HEDS) <ul><li>The purpose of HEDS section within ScHARR is to promote excellence in national and international healthcare resource allocation decisions, through applied and theoretical research funded by the public and private sector; and supporting the effective implementation of the results of such research through education, training and management interventions </li></ul>27/10/11 © The University of Sheffield
    3. 3. Portfolio of specialities of HEDS 27/10/11 © The University of Sheffield
    4. 4. RESEARCH
    5. 5. Information resources Bayesian Statistics in Health Economics Evidence review and synthesis Health Economics and Outcomes Research Cost-effectiveness modelling to support Healthcare Decision Making Main Focus of Research Areas
    6. 6. 27/10/11 © The University of Sheffield Consultancy within HEDS Modelling alongside clinical trials Health related quality of life Clinical Trial Simulation Health Economics Modelling Evidence Synthesis Costing studies Systematic reviewing
    7. 7. Disease Areas <ul><li>Acute coronary syndrome </li></ul><ul><li>Age-related macular degeneration </li></ul><ul><li>Alcohol </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Ankylosing spondylitis </li></ul><ul><li>Asthma </li></ul><ul><li>Back pain </li></ul><ul><li>Breast cancer </li></ul><ul><li>Cardiovascular conditions </li></ul><ul><li>Colon cancer </li></ul><ul><li>Colorectal cancer </li></ul><ul><li>Dementia </li></ul><ul><li>Depression </li></ul><ul><li>Dyskaryosis </li></ul><ul><li>Epilepsy </li></ul><ul><li>Flushing </li></ul><ul><li>Foot ulcers </li></ul><ul><li>Immune thrombocytopenic purpura </li></ul><ul><li>Incontinence </li></ul><ul><li>Influenza </li></ul><ul><li>Irritable bowel syndrome </li></ul><ul><li>Leg ulcers </li></ul><ul><li>Lymph node metastases </li></ul><ul><li>Menopause </li></ul><ul><li>Mental health problems </li></ul><ul><li>Multiple sclerosis </li></ul><ul><li>Overactive bladder </li></ul><ul><li>Prostate cancer </li></ul><ul><li>Psoriatic arthritis </li></ul><ul><li>Pulmonary hypertension </li></ul><ul><li>Renal disease </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Schizophrenia </li></ul><ul><li>Sexual health </li></ul><ul><li>Surgical procedures in sex reassignment </li></ul><ul><li>Type 1 and Type 2 diabetes </li></ul><ul><li>Vaccination scheduling </li></ul><ul><li>Venous ulcers </li></ul>
    8. 8. Innovation & Knowledge Transfer Contact details <ul><li>Further information about consultancy projects and research areas is available at: </li></ul><ul><li>http://www.sheffield.ac.uk/scharr/consultancy </li></ul><ul><li>For an informal chat, contact the HEDS programme director, Roberta Ara: </li></ul><ul><li>Email: [email_address] </li></ul>
    9. 9. Cost-effectiveness modelling to support Healthcare Decision Making 27/10/11 © The University of Sheffield
    10. 10. <ul><li>The Decision Analytic Modelling team is a leading healthcare modelling group internationally, with a wide ranging, high impact programme of methodological and applied research. </li></ul><ul><li>Research focuses on Operational Research modelling including both health technology assessment modelling and supporting service organisation and delivery. </li></ul>
    11. 11. In particular: <ul><li>Cost-effectiveness modelling to support HTA submissions </li></ul><ul><li>Budget impact modelling </li></ul><ul><li>Systematic reviews & critique of cost-effectiveness literature </li></ul><ul><li>Critique / validate existing model </li></ul><ul><li>Country adaptations </li></ul><ul><li>Model adaptations </li></ul>
    12. 12. Examples of cost-effectiveness studies conducted in HEDS 27/10/11 © The University of Sheffield
    13. 13. Evaluating the cost-effectiveness of diagnostic tests Dr Matt Stevenson Reader in Health Technology Assessment; NICE Appraisal Committee Member; Contributor to the NICE Diagnostic Assessment Programme manual
    14. 14. Overview <ul><li>A brief description of how (and why) cost-effectiveness analyses are applied </li></ul><ul><li>A brief overview of the analyses required to model diagnostic tests in sepsis </li></ul><ul><li>A very brief description of the reasons why diagnostic evaluations are more difficult than pharmaceutical evaluations </li></ul>
    15. 15. Cost-effectiveness analyses In the last 10 years there has a been a considerable increase in the importance of cost-effectiveness analyses. This was due to the relatively fixed budget and a combination of ageing populations and emerging expensive interventions. This has led to the formation of funding agencies in England and Wales, Scotland, Australia and Canada.
    16. 16. Does a diagnostic test represent value for money? Diagnostic tests with high prices may be cost-effective (i.e. a worthwhile use of a limited budget). Conversely, diagnostic tests with low prices may not be cost-effective. The ‘gold standard’ approach for determining whether the price of a diagnostic test is justified is through an economic evaluation, or cost-effectiveness analysis.
    17. 17. Cost-effectiveness analyses The goal of funding agencies is to provide the greatest amount of health for society within the budget, and thus opportunity cost is a key principle. That is, what health would be lost if money was diverted from one intervention in order to fund another. The process is typically to estimate the cost-effectiveness of an intervention through modelling, and comparing this result with a value assumed to represent opportunity cost.
    18. 18. Previous Diagnostic evaluations <ul><li>Whilst the majority of evaluations undertaken relate to pharmaceuticals, evaluations of diagnostic tests have been conducted: </li></ul><ul><li>Carotid Artery Imaging - Wardlow et al. HTA </li></ul><ul><li>Thrombophilia Testing - Simpson et al. HTA </li></ul><ul><li>BMD Scanning (Strontium Ranelate) – Stevenson et al HTA </li></ul><ul><li>Diagnostic strategies for DVT – Goodacre et al HTA </li></ul><ul><li>Diagnostic pathways for minor head injuries – Pandor et al. HTA </li></ul><ul><li>Non-Invasive Liver Testing – Stevenson et al HTA (in press) </li></ul>
    19. 19. Methods for evaluating diagnostic tests There have been, for some time, clear methods guide for undertaking evaluation of pharmaceutical interventions. Recently NICE has set up a Diagnostic Assessment Programme which has issues an interim statement of the methods it expects to be followed in evaluating diagnostics. http://www.nice.org.uk/media/164/3C/DAPInterimMethodsStatementProgramme.pdf
    20. 20. Simplified Overview of the modelling required The following slides discuss the steps that would be required to generate an estimate of the cost-effectiveness of a diagnostic test (or series of diagnostic tests). The overview is a simplification. More detailed discussion is provided in the previously listed HTA reports (all free to download) and the Diagnostic Methods statement
    21. 21. Estimating Test Accuracy The sensitivity and specificity of a diagnostic test must be estimated. These values would be combined with the estimated prevalence of the condition being tested for, to form an expectation of the number of true positives, true negatives, false positives and false negatives generated by the diagnostic test.
    22. 22. Modelling the patient experience For each of the four groups defined, an estimation of the events that would occur to the patient must be modelled. These may differ due to underlying risks and the chosen medical management. The modelling would include factors such as the risks of mortality, risk of morbidity, length of stay within hospital, costs for initial and subsequent care, treatment-related adverse-events and the quality of life for patients in each potential health state.
    23. 23. Modelling the patient experience Ultimately, an estimation of the life years, quality adjusted life years (QALYs*) and costs can be attributed to each of the four groups. These can be weighted by the proportions in each group to form a total cost and total QALY for patients post diagnosis. The costs of the diagnostic tests performed are then added. * The QALY is a combination of life years and patient utility. A person living for 10 years at a utility of 0.5 would gain 5 QALYs; a person living for 4 years at a utility of 0.75 would gain 3 QALYs
    24. 24. Calculating an ICER* Assume that post diagnosis, an average patient was expected to gain 10 QALYs at a cost of £20,000 under current best practice. These values became 11 QALYs at a cost of £18,000 following a new diagnostic test, which costs £4,000 per patient. In this instance the increase in cost is £2,000 (£18,000 - £20,000 + £4,000) The increase in QALYs is 1. (11 – 10) * An Incremental Cost Effectiveness Ratio.
    25. 25. Calculating an ICER In this example, the ICER would be £2,000 per QALY gained (£2,000 / 1) This would be compared with an estimation of the cost of gaining a QALY in interventions that are likely to be replaced.* Thus if this were the result from a real technology appraisal the diagnostic test would be likely to be recommended for use. * NICE has estimated this to be in the region of £20,000-£30,000
    26. 26. Implications for diagnostic pricing Where a new diagnostic test has a large impact on mortality or on the utility of a patient, then the QALY gained over the current diagnostic will be greater. ICER = Δ Cost / Δ QALY Thus, for a constant ICER, such a test would be able to command a higher price than a test with a smaller QALY gain.
    27. 27. Sequences and subgroups Note that sequences of tests and only incorporating tests on a subgroup of the population are possible. The following slide shows the predicted optimal strategy for diagnosing whether a patient has deep vein thrombosis. The costs of diagnostic tests, the risks of death, morbidity, recurrence, treatment-related adverse-events and the costs of treating future events were all considered in the model.
    28. 28. Example of diagnostic algorithm Taken from Goodacre et al. QJM 2006; 99:377–388
    29. 29. Returning to the example of sepsis Current gold standard is blood culture, but this has poor sensitivity. A new test is available (SeptiFast © ) which has higher accuracy than blood culture tests, but is relatively expensive. The price may preclude use in all patients with suspected sepsis. A decision support system is also available, (Treat © ) which can categorise patients into high, medium and low risk. This may allow SeptiFast © to be used more efficiently.
    30. 30. Estimating the cost-effectiveness of a Treat © and SeptiFast © diagnostic strategy <ul><li>For each Treat © category, the patient experience must be modelled taking into account true positives, false positives, true negatives and false negatives. This will incorporate (amongst others) </li></ul><ul><li>Risks of mortality </li></ul><ul><li>Risks of post-infection sequalae </li></ul><ul><li>Length of stay in hospital </li></ul><ul><li>These variables are expected to be lower where there is appropriate management of a patient with sepsis. </li></ul>
    31. 31. Estimating the cost-effectiveness of a Treat © and SeptiFast © diagnostic strategy Thus there will be a QALY gain (and cost reduction) associated with the new diagnostic tests. It is expected that these will be greatest in those patients denoted high risk. Factoring in the costs of the diagnostic (Treat © for all patients, SeptiFast © for the groups being evalauted) will allow the cost-effectiveness of diagnostic strategies to be evaluated.
    32. 32. Additional complications with evaluating diagnostic tests There are reasons why evaluating diagnostic tests are more difficult than evaluating pharmaceuticals. Due to time restrictions these will be mentioned very briefly under broad headings.
    33. 33. Complicating Issues <ul><li>The need to understand the patient pathway </li></ul><ul><li>Data reporting </li></ul><ul><li>Missing and unobtainable data </li></ul><ul><li>Meta-analyses </li></ul><ul><li>Correlation between tests </li></ul><ul><li>Imperfect gold standards </li></ul><ul><li>Required operator skill </li></ul><ul><li>Spectrum bias </li></ul><ul><li>Incidental findings </li></ul><ul><li>Estimating the costs of diagnostic tests </li></ul>
    34. 34. NICE Decision Support Unit <ul><li>Dr Paul Tappenden </li></ul><ul><li>Senior Research Fellow </li></ul><ul><li>Acting DSU Director </li></ul><ul><li>http://www.nicedsu.org.uk / </li></ul>27/10/11 © The University of Sheffield
    35. 35. Background to DSU <ul><li>Established in 2002. </li></ul><ul><li>Formal collaboration between the Universities of Sheffield (lead), York and Leicester. </li></ul><ul><li>Peripheral members at LSHTM, Brunel and Bristol. </li></ul><ul><li>May also involve highly specialist expertise from elsewhere. </li></ul><ul><li>Expertise covers all key areas of HTA. </li></ul><ul><li>Commissioned by NICE to provide a research and training resource to support the Institute's Technology Appraisal Programme. </li></ul>
    36. 36. Main strands of work <ul><li>Appraisal-specific work </li></ul><ul><ul><li>Rapid evaluation of technical issues/analysis around health economic evaluation/modelling problems within specific technology appraisals </li></ul></ul><ul><ul><li>An independent yet highly qualified voice </li></ul></ul><ul><li>Methods development </li></ul><ul><ul><li>Ongoing role in developing Methods guidance for NICE </li></ul></ul><ul><ul><li>DSU Technical Support Documents </li></ul></ul><ul><ul><li>Training for industry and NICE Appraisal Committee members </li></ul></ul><ul><ul><li>Other methods work </li></ul></ul>
    37. 37. Appraisal-specific work <ul><li>~7 appraisals per year </li></ul><ul><li>Analysis of additional evidence submitted as part of the appraisal process </li></ul><ul><ul><li>Cetuximab for 1 st line metastatic colorectal cancer </li></ul></ul><ul><ul><li>Lapatinib for metastatic breast cancer </li></ul></ul><ul><li>Provision of modelling expertise unavailable elsewhere (software) </li></ul><ul><ul><li>Donepezil for Alzheimer’s Disease </li></ul></ul><ul><li>Evaluating Patient access schemes (PAS) </li></ul><ul><ul><li>Tocilizumab for Rheumatoid Arthritis </li></ul></ul>
    38. 38. The NICE Methods Guide for Technology Appraisal <ul><li>Setting the agenda for, organising and facilitating the NICE methods guide for technology appraisal </li></ul><ul><li>Recent work includes managing the update to the 2008 NICE methods guide – 6 workshops covering issues around evidence synthesis, utilities, uncertainty analysis, subgroups etc. </li></ul><ul><li>Update due in 2011/2012 </li></ul><ul><li>Conduit for leading academic centres in HTA </li></ul>
    39. 39. DSU Technical Support Documents (TSDs) <ul><li>Series of independent, non-prescriptive reports commissioned to support NICE Methods Guide </li></ul><ul><li>14 TSDs completed or near completion </li></ul><ul><li>Main areas: </li></ul><ul><ul><li>Health utilities (x5) </li></ul></ul><ul><ul><li>Evidence synthesis (x7) </li></ul></ul><ul><ul><li>Model development and reviewing evidence for informing model parameters </li></ul></ul><ul><ul><li>Survival modelling using individual patient data </li></ul></ul><ul><ul><li>Use of regression methods in HTA models </li></ul></ul>
    40. 40. Other DSU methods research <ul><li>Report and related publications demonstrating the feasibility of applying Value of Information methods. </li></ul><ul><li>Feasibility projects relating to computerised decision support systems and orphan drugs </li></ul><ul><li>Equity arguments applied to orphan drugs </li></ul><ul><li>Discounting of costs and benefits </li></ul><ul><li>The role of patient valuations of health states </li></ul><ul><li>The incorporation of uncertainty into cost-effectiveness models </li></ul><ul><li>The incorporation of equity weights into cost effectiveness models and decision making </li></ul>
    41. 41. Methods training <ul><li>Bridge between NICE and the pharmaceutical industry in providing methods training </li></ul><ul><li>“ Masterclasses” held: </li></ul><ul><ul><li>Measurement and valuation of health-related quality of life </li></ul></ul><ul><ul><li>Network meta-analysis & indirect comparisons </li></ul></ul><ul><ul><li>NICE Appraisal Process, modelling, what makes a good submission, uncertainty analysis </li></ul></ul>
    42. 42. Future updates <ul><li>Join our mailing list at : http://www.nicedsu.org.uk </li></ul>
    43. 43. Health economic modelling in bowel cancer <ul><li>Dr Paul Tappenden </li></ul><ul><li>Senior Research Fellow </li></ul><ul><li>ScHARR, University of Sheffield </li></ul><ul><li>[email_address] </li></ul>27/10/11 © The University of Sheffield
    44. 44. Health economics and cancer <ul><li>Key area of methodological expertise in ScHARR for >15 years </li></ul><ul><li>Key areas include breast, bowel, cervical, CML, kidney, prostate, lung </li></ul><ul><li>Range of decision-makers/clients including: </li></ul><ul><ul><li>NICE </li></ul></ul><ul><ul><li>NETSCC / NHS R&D Programme </li></ul></ul><ul><ul><li>NHS Cancer Screening Programmes </li></ul></ul><ul><ul><li>Department of Health </li></ul></ul><ul><ul><li>Local decision-makers </li></ul></ul>
    45. 45. Key areas of application <ul><li>Modelling interventions for the early detection / prevention of cancer </li></ul><ul><li>Modelling interventions for the treatment of diagnosed cancer </li></ul><ul><li>Modelling whole disease and treatment pathways (Whole Disease Modelling) </li></ul>
    46. 46. 1. Modelling interventions for the early detection / prevention of cancer <ul><li>Methodological development in modelling natural history disease progression </li></ul><ul><ul><li>Handling competing risks </li></ul></ul><ul><ul><li>Length / lead-time biases </li></ul></ul><ul><ul><li>Consideration of full trade-off between costs and benefits </li></ul></ul><ul><ul><li>Calibration of unobservable parameters (disease progression, presentation behaviours etc) </li></ul></ul><ul><li>Evaluation of screening programmes in breast, bowel, cervical and prostate cancer </li></ul><ul><li>Evaluation of early awareness campaigns </li></ul>
    47. 47. An example – screening for CRC 27/10/11 © The University of Sheffield
    48. 48. 2. Modelling interventions for the treatment of diagnosed cancer <ul><li>Curative / palliative treatments for diagnosed cancer </li></ul><ul><li>Numerous appraisals for NICE - main areas covered include bowel and breast </li></ul><ul><li>Key issues around methods for handling </li></ul><ul><ul><li>Extrapolation beyond trial duration </li></ul></ul><ul><ul><li>Handling treatment crossover </li></ul></ul><ul><ul><li>Treatment sequences </li></ul></ul><ul><ul><li>Evidence networks across multiple trials </li></ul></ul>
    49. 49. An example – bevacizumab for MCRC 27/10/11 © The University of Sheffield
    50. 50. 3. Whole Disease Modelling <ul><li>Usefulness of models is in part determined by the scope of the decision it is intended to inform. </li></ul><ul><li>Single isolated point versus whole pathway model. </li></ul><ul><li>“ Modelling the bigger picture” – development of models which can represent whole disease and treatment pathways </li></ul>
    51. 51. A lot of effort so why bother? <ul><li>Consistent basis for economic evaluation across the pathway </li></ul><ul><li>Structurally capable of evaluating any intervention at any point in the pathway </li></ul><ul><li>Capturing upstream and downstream knock-on impacts </li></ul><ul><li>Shift to potentially more useful economic decision rules </li></ul><ul><li>Methodological challenges </li></ul><ul><ul><li>Obtaining agreement regarding pathways </li></ul></ul><ul><ul><li>Handling geographical variability </li></ul></ul><ul><ul><li>Programming / model run time </li></ul></ul><ul><ul><li>Calibration of unobservable parameters </li></ul></ul><ul><li>Non-trivial investment of time at outset but payoff may be considerable </li></ul>
    52. 52. An example – Colorectal Cancer Whole Disease Model
    53. 53. From piecewise CPQ to constrained maximisation 27/10/11 © The University of Sheffield
    54. 54. Colorectal cancer screening : using mathematical modelling to inform policy decisions <ul><li>Dr Sophie Whyte </li></ul><ul><li>Research Fellow </li></ul><ul><li>ScHARR, University of Sheffield </li></ul><ul><li>Email: s.whyte@sheffield.ac.uk </li></ul>27/10/11 © The University of Sheffield
    55. 55. Contents <ul><li>Background </li></ul><ul><li>The current NHS Bowel Cancer Screening Programme </li></ul><ul><li>The flexible sigmoidoscopy screening trial </li></ul><ul><li>Should the screening programme be changed? </li></ul><ul><li>Methods </li></ul><ul><li>Possible screening strategies to consider </li></ul><ul><li>The value of modelling in this context </li></ul><ul><li>Modelling challenges </li></ul><ul><li>Modelling solutions </li></ul><ul><li>Results and conclusions </li></ul><ul><li>Results </li></ul><ul><li>Policy implications </li></ul>27/10/11 © The University of Sheffield
    56. 56. The current NHS Bowel Cancer Screening Programme <ul><li>Roll out commenced in 2006 and now screening covers the whole of England. </li></ul><ul><li>Persons aged 60-69 (being increased to age 74) are offered biennial screening. </li></ul><ul><li>The guaiac faecal occult blood (gFOB) test is used for screening and positives(≈2%) receive follow up with colonoscopy. </li></ul><ul><li>Uptake is 52% </li></ul>27/10/11 © The University of Sheffield
    57. 57. Flexible sigmoidoscopy(FS) screening trial* <ul><li>Trial reported in 2010 </li></ul><ul><li>170,432 persons aged 55-64 were randomised to FS screening or to a control group (no screening). </li></ul><ul><li>40,674 persons underwent FS screening </li></ul><ul><li>After 10 years of follow-up the incidence of CRC was reduced by 33% and mortality was reduced by 43% in the FS group. </li></ul><ul><li>*Atkin et al 2010, Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial, The Lancet </li></ul>27/10/11 © The University of Sheffield
    58. 58. Should the screening programme be changed in light of new evidence? <ul><li>Project for NHS cancer screening “Reappraisal of options for CRC screening” </li></ul><ul><li>Update to “Appraisal of options for CRC screening” completed by Tappenden et al in 2004. </li></ul><ul><li>The reappraisal uses: </li></ul><ul><ul><li>Data from existing screening programme, </li></ul></ul><ul><ul><li>Data from FS trial, </li></ul></ul><ul><ul><li>Data on newer immunochemical FOBTs </li></ul></ul>27/10/11 © The University of Sheffield
    59. 59. Methods: Possible screening scenarios <ul><li>Biennial screening with guaiac or immunochemical FOBT for ages 60-74 </li></ul><ul><li>One-off FS screening (for different ages) </li></ul><ul><li>Combination screening strategies e.g. FS at age 55 then biennial FOBT at ages 60-74 </li></ul>27/10/11 © The University of Sheffield
    60. 60. Methods: Advantages of modelling <ul><li>The number of possible screening strategies is very large </li></ul><ul><li>To demonstrate a significant impact on incidence and mortality rates screening trials require: </li></ul><ul><ul><li>very large numbers of participants </li></ul></ul><ul><ul><li>a long follow-up period </li></ul></ul><ul><li>Hence modelling is very useful for the evaluation of screening strategies </li></ul>27/10/11 © The University of Sheffield
    61. 61. Methods: Modelling challenges <ul><li>Considerable uncertainty surrounding values of some parameters essential for colorectal cancer screening modelling. </li></ul><ul><li>Uncertainty in underlying prevalence of precancerous conditions: </li></ul>27/10/11 © The University of Sheffield
    62. 62. Methods: Modelling challenges <ul><li>Uncertainty in screening test characteristics </li></ul><ul><li>Sensitivity to CRC of the Haemoccult gFOBT : range 0.25-0.96* </li></ul><ul><li>Uncertainty(very little data) on growth rates of colorectal cancer and precancerous conditions as: </li></ul><ul><li>(1) difficult to observe and (2) cancers are removed if found. </li></ul>27/10/11 © The University of Sheffield * Burch JA, Soares-Weiser K, St John DJ, et al. Diagnostic accuracy of faecal occult blood tests used in screening for colorectal cancer: a systematic review. J Med Screen 2007;14(3):132-7.
    63. 63. CRC natural history model structure 27/10/11 © The University of Sheffield
    64. 64. Methods: Modelling solutions 27/10/11 © The University of Sheffield Polyp detection rate at FS screening Polyp prevalence Sensitivity of screening test to polyps
    65. 65. Methods: Modelling solutions 27/10/11 © The University of Sheffield Probability of diagnosis of CRC (due to symptoms or chance detection) State allocation diagram CRC incidence in absence of screening
    66. 66. Methods: Modelling solutions 27/10/11 © The University of Sheffield Parameter values are estimated by using a Bayesian approach in which sets of parameter values for which the model predictions have a good fit to observed data are generated.*
    67. 67. Results and conclusions <ul><li>CRC screening is generally cost-effective: Tappenden et al found FS screening to be cost saving and FOBT screening the have an ICER<£3K. </li></ul><ul><li>“ Reappraisal Project” results will be available by the end of October. </li></ul><ul><li>DOH Press Release 2 nd October 2010 </li></ul><ul><li>“ New Action on Cancer to Save Thousands More Lives Every Year </li></ul><ul><li>Increase detection through a revolutionary new bowel cancer screening technology flexible sigmoidoscopy – a £60 million investment over the next four years to incorporate the latest breakthrough in bowel cancer screening into our existing national programme – saving 3,000 lives a year.” </li></ul>27/10/11 © The University of Sheffield
    68. 68. Potential impact on policy decisions <ul><li>Results of work will allow us to advise NHS cancer screening on various aspects of FS screening implementation. </li></ul><ul><li>At what age will a one-off FS screen provide the greatest health benefits? </li></ul><ul><li>How cost effective are combined screening strategies? </li></ul><ul><li>Would it be cost effective to create a national polyp centre to process all pathology generated through screening? </li></ul><ul><li>What level of FS uptake is required to achieve the same health benefits as the current screening programme? </li></ul>27/10/11 © The University of Sheffield
    69. 69. Calibration method <ul><li>The Metropolis-Hastings algorithm explores the multi-dimensional parameter space to generate multiple sets of parameters for which the model predictions have a good fit to observed data. </li></ul>27/10/11 © The University of Sheffield
    70. 70. <ul><li>Cost utility analysis of interventions to return employees to work following long term sickness absence </li></ul><ul><li>Hazel Squires </li></ul><ul><li>Research Fellow </li></ul><ul><li>ScHARR, University of Sheffield </li></ul><ul><li>Email: h.pilgrim@sheffield.ac.uk </li></ul>27/10/11 © The University of Sheffield
    71. 71. Introduction <ul><li>Background </li></ul><ul><li>Project process </li></ul><ul><li>Modelling methodology </li></ul><ul><li>Results </li></ul><ul><li>Conclusions </li></ul><ul><li>Limitations/ further research </li></ul>
    72. 72. Background <ul><li>People can apply for Incapacity Benefit after they have been on sick leave for >6 months. </li></ul><ul><li>Sickness absence in the UK costs the country around 1% of the annual GDP. </li></ul><ul><li>There is a need to prevent people from going onto Incapacity Benefit. </li></ul>
    73. 73. Process <ul><li>Effectiveness literature review </li></ul><ul><ul><li>Very limited evidence identified – only 3 UK papers </li></ul></ul><ul><li>Cost-effectiveness literature review </li></ul><ul><ul><li>No studies identified which consider the implications of RTW within the UK setting over a sufficient time frame to capture all impacts on costs and benefits of the interventions </li></ul></ul><ul><li>Health economic model </li></ul>
    74. 74. Model scope <ul><li>Population: </li></ul><ul><li>A cohort of employed men & women that have been on between 1 week and 6 months of sick leave due to musculoskeletal disorders. </li></ul><ul><li>Interventions: </li></ul><ul><li>Workplace intervention </li></ul><ul><li>Physical activity and education intervention </li></ul><ul><li>Physical activity, education and workplace visit </li></ul><ul><li>C omparator: </li></ul><ul><li>Usual care for musculoskeletal disorders </li></ul><ul><li>Outcomes: </li></ul><ul><li>Cost per quality-adjusted life year (QALY) gained </li></ul><ul><li>Cost per day on sick leave avoided </li></ul><ul><li>Perspective: </li></ul><ul><li>NHS and PSS </li></ul><ul><li>Societal </li></ul><ul><li>Employer </li></ul>
    75. 75. Modelling methodology (1) <ul><li>Markov model which simulates the experience of a hypothetical cohort of employees who are currently on long term sick leave over a working lifetime. </li></ul>At work On sick leave for 1 week -6 months On sick leave for 6-12 months On sick leave for 12-18 months On sick leave for 18+ months Retirement or death
    76. 76. Modelling methodology (2) <ul><li>Costs and QALYs have been calculated for both cohorts starting at age 41 (average age of sickness absence from evidence) through to retirement at age 66. </li></ul><ul><li>Discount rate of 3.5% for both costs and utilities. </li></ul><ul><li>One-way sensitivity analysis and threshold analysis carried out. </li></ul>
    77. 77. Quality of life <ul><li>Utility scores estimated based on data from the British Household Survey Panel (BHSP) </li></ul><ul><li>Based on whether the individual is at work or on sick leave </li></ul><ul><li>Sf-36 SF-6D </li></ul><ul><ul><ul><li>Transformed using SPSS </li></ul></ul></ul><ul><li>Impact of potential confounding variables assessed using regression </li></ul>Utility at work Utility on sick leave Age<35 0.83 0.66 Age 35-45 0.8 0.59 Age 45-55 0.76 0.61 Age>55 0.76 0.61
    78. 78. Costs State in the model Perspective NHS & PSS Societal Employer At work £0 £0 £0 1 wk to 6 months sick leave Cost of usual care and intervention incurred by NHS NHS & PSS costs + Employer costs - Transfer costs Cost of intervention incurred by employer + Cost of replacing employee + Production loss over friction period + Salary of replacement employee after friction period + Occupational sick pay + Employer’s NI contribution 6-12 months sick leave Cost of usual care Cost of usual care Occupational sick pay + Employer’s NI contribution 12 months+ sick leave Cost of usual care Cost of usual care
    79. 79. Key model assumptions (1) <ul><li>If an employee has not returned to work within 6 months given the intervention they are subsequently no more likely to RTW than an employee who is given usual care </li></ul><ul><li>The intervention is only given the first time that the person goes onto LTS </li></ul><ul><li>The probability of going onto further episodes of LTS is the same for the intervention cohort and the usual care cohort </li></ul>
    80. 80. Key model assumptions (2) <ul><li>The employee is assumed to receive 15 weeks on full pay and 16.4 weeks on half pay </li></ul><ul><li>Wages and productivity of a replacement worker are assumed to be the same as the employee on LTS </li></ul><ul><li>The probability of dying is assumed to be no different for people on LTS to people who are at work </li></ul>
    81. 81. Results: NHS/ Societal perspective (1) Cost per QALY gained = £2,758
    82. 82. Results: NHS/ Societal perspective (2)
    83. 83. Results: Employer perspective Cost per day on sick leave avoided = £0.34
    84. 84. One way sensitivity analysis <ul><li>If the difference in health utility between being at work and being on LTS is ≤0.02 then cost per QALY >£20,000. </li></ul><ul><li>If the person is aged 55 when going onto LTS then cost per QALY >£8,000. </li></ul><ul><li>All other assumptions tested within the model had a limited impact on model results </li></ul>
    85. 85. Conclusions <ul><li>The model suggests that interventions to return employees to work do not have to be very effective to be considered cost-effective in comparison to other technologies routinely funded by the NHS. </li></ul><ul><li>This can be explained by the high costs of productivity loss and Incapacity Benefit in comparison to the relatively low cost of the intervention. </li></ul>
    86. 86. Model limitations <ul><li>Effectiveness data based on generally poor evidence carried out in non-UK countries </li></ul><ul><li>Costs of interventions are uncertain </li></ul><ul><li>Lack of long term follow up data </li></ul><ul><li>Only able to consider interventions for musculoskeletal disorders due to limited data on interventions for other sickness absence </li></ul><ul><li>Does not take into account different employee/ employer characteristics (although some tested in sensitivity analyses) </li></ul>
    87. 87. Further research <ul><li>Further research is required that: </li></ul><ul><ul><li>Is within the UK setting; </li></ul></ul><ul><ul><li>Provides follow up data beyond 12 months; </li></ul></ul><ul><ul><li>Reports comparable return to work outcomes between studies; </li></ul></ul><ul><ul><li>Reports quality of life data of the employees who are both at work and on sick leave. </li></ul></ul>
    88. 88. Public health modelling: lessons learned from a contraception case study Hazel Squires, Jim Chilcott, Nick Payne, Lindsay Blank, Monica Hernandez, Louise Guillaume ScHARR, University of Sheffield
    89. 89. Introduction <ul><li>Outline methods & results of contraception case study </li></ul><ul><li>Discuss key issues in public health modelling based upon this work </li></ul>
    90. 90. Aim of NICE contraceptive services project <ul><li>To assess the effectiveness and cost-effectiveness of interventions to encourage young people to use contraceptives and contraceptive services </li></ul>27/10/11 © The University of Sheffield
    91. 91. Model scope <ul><li>Population: </li></ul><ul><ul><li>Young people aged between 14 & 16 years within secondary school who have not previously been a parent. </li></ul></ul><ul><li>Interventions: </li></ul><ul><ul><li>School-based dispensing of hormonal contraceptives to 14-16 year olds </li></ul></ul><ul><ul><li>School-based ‘dispensing’ of condoms to 14-16 year olds </li></ul></ul><ul><li>Comparator: School nurse only </li></ul><ul><li>Outcomes: </li></ul><ul><ul><li>Cost per age 14 – 16 Pregnancy Averted </li></ul></ul><ul><ul><li>Cost per Abortion Averted </li></ul></ul><ul><li>Perspective: Public sector perspective (incl. & excl. Benefit payments) </li></ul>27/10/11 © The University of Sheffield
    92. 92. Conceptual model 27/10/11 © The University of Sheffield Education/ employment impacts Impact on ‘unintended’ pregnancies Intervention to encourage contraceptive use Sexually transmitted infection (STI) rate Treatment of STIs Impact upon contraceptive services Abortion Miscarriage/ ectopic Pregnancy/ stilbirth Birth Mistimed Unwanted Low birth weight baby Maternity care Social care Mental health problems (eg. depression) Child health problems Crime Government-funded Benefits
    93. 93. Methods <ul><li>Markov model developed within Excel. </li></ul><ul><li>Cohort of 100,000 14-year olds who have not had a baby followed over lifetime. </li></ul><ul><li>Each year there is a probability of becoming pregnant. </li></ul><ul><li>Following conception, dependent upon age, there is a probability of birth, abortion, miscarriage, ectopic pregnancy or stillbirth. </li></ul><ul><li>Costs are associated with each of these outcomes. </li></ul>27/10/11 © The University of Sheffield
    94. 94. 27/10/11 © The University of Sheffield Outcomes of teenage birth Family, societal and individual characteristics Long term outcomes of child Immediate birth outcomes Long term outcomes of parent(s) Low social class Teenage birth Poor education Poor employment More claims for Means-tested Benefits Teenage pregnancy Crime Low birth weight Foetal death Poorly educated mother Poor behaviour/ education as child Other observable or unobservable characteristics A B C
    95. 95. Literature review: long term outcomes <ul><li>Econometric literature review assessing long term consequences of a teenage birth in the UK </li></ul><ul><ul><li>Controlling for observable & unobservable characteristics (eg. personality) which might predispose a young woman to teenage motherhood </li></ul></ul><ul><ul><li>Eg. Comparing those who’ve had a teenage miscarriage with those that have had a baby as a teenager </li></ul></ul>27/10/11 © The University of Sheffield
    96. 96. Model schematic 27/10/11 © The University of Sheffield t t+1 t+1 t Conception (may be mistimed or unwanted) No conception (may be delayed) Abortion Birth Miscarriage/ ectopic pregnancy/ stillbirth Additional proportion of low birth weight babies Additional Benefit claims of teenage parents Cohort of young people STI No STI t+1 t t t+1
    97. 97. Key model assumptions <ul><li>The negative impacts of a teenage birth include: </li></ul><ul><ul><li>4% more likely to receive Income Support & associated Benefits until age 35 years; </li></ul></ul><ul><ul><li>90% will receive Income Support immediately, hence the earlier the birth, the more years it is received for; </li></ul></ul><ul><ul><li><1% more babies will be low birth weight. </li></ul></ul><ul><li>50% of averted teenage births are mistimed & 50% are unwanted. </li></ul><ul><li>STIs are assumed to be transmitted to 1 person only. </li></ul>27/10/11 © The University of Sheffield
    98. 98. Health outcomes <ul><ul><li>Usually increasing life years is considered to be a good thing. In this case, contraceptives aim to prevent life. </li></ul></ul><ul><ul><li>There is no long term quality of life evidence associated with motherhood by age, adjusted for socioeconomic status </li></ul></ul><ul><ul><li>Similarly, there is no quality of life evidence associated with the child by age of motherhood </li></ul></ul>27/10/11 © The University of Sheffield
    99. 99. Cost-effectiveness decision rules 27/10/11 © The University of Sheffield More expensive Less effective More expensive More effective Less expensive Less effective Less expensive More effective Difference in effectiveness Difference in costs NO YES
    100. 100. Results (excl. Benefits) Cohort of 100,000 14-year olds followed over a lifetime 27/10/11 © The University of Sheffield Expected cost per age 14 – 16 pregnancy averted = £37 (condoms) & £110 (hormonal) compared with no intervention Approx. 50% probability that cost-saving
    101. 101. Results (incl. Benefits) Cohort of 100,000 14-year olds followed over a lifetime 27/10/11 © The University of Sheffield Dominates no intervention
    102. 102. Key issues in public health modelling <ul><li>Model scoping & granularity </li></ul><ul><li>Extrapolating outcomes over the long term </li></ul><ul><li>Valuing outcomes </li></ul><ul><li>Handling uncertainty </li></ul>27/10/11 © The University of Sheffield
    103. 103. Model scoping & granularity (1) <ul><li>Public health interventions & their settings are complex. </li></ul><ul><ul><li>Often need to capture potentially adaptive behaviour (eg. sexual behaviour). </li></ul></ul><ul><ul><li>Often several health areas to be modelled (in this case, pregnancies & STIs). </li></ul></ul><ul><ul><li>Intersectoral impacts (not just health) </li></ul></ul>27/10/11 © The University of Sheffield
    104. 104. Model scoping & granularity (2) <ul><ul><li>Formal OR problem structuring methods such as cognitive mapping could be used: </li></ul></ul><ul><ul><ul><li>To determine the model scope </li></ul></ul></ul><ul><ul><ul><li>To make sure that all important costs & outcomes associated with the intervention are captured </li></ul></ul></ul><ul><ul><li>Further research around the use of these methods applied to public health modelling is required </li></ul></ul>27/10/11 © The University of Sheffield
    105. 105. Extrapolating outcomes over the long term <ul><li>Trials generally collect intermediate outcomes. </li></ul><ul><li>The relationship between these outcomes & final outcomes needs to be understood. </li></ul><ul><li>Long term outcomes (eg. employment) are dependent upon many factors; hence econometric techniques will generally be required to disentangle the impacts of the intervention. </li></ul>27/10/11 © The University of Sheffield
    106. 106. Valuing outcomes <ul><li>Within health economics, benefits are generally measured in terms of QALYs gained </li></ul><ul><li>Within public health economic modelling, the QALY measure may not be sufficiently broad eg. intersectoral costs/ consequences </li></ul><ul><li>There is also generally limited evidence around utilities </li></ul><ul><li>Further research is required around alternative outcome measures </li></ul>27/10/11 © The University of Sheffield
    107. 107. Handling uncertainty <ul><li>Within health economics, uncertainty within model parameters is formally assessed using probabilistic sensitivity analysis (PSA) </li></ul><ul><li>The structure of public health models is also often highly uncertain eg. modelling mistimed pregnancies </li></ul><ul><li>It is important to parameterise structural uncertainties & include these within the PSA as outlined by Bojke et al. (2006). </li></ul>27/10/11 © The University of Sheffield
    108. 108. Conclusions <ul><li>Dispensing contraceptives within schools to 14 – 16 yr olds is likely to be cost-effective </li></ul><ul><li>Key areas for methodological development within public health modelling: </li></ul><ul><ul><li>Model scoping & level of granularity </li></ul></ul><ul><ul><li>Extrapolating outcomes over the long term </li></ul></ul><ul><ul><li>Valuing outcomes </li></ul></ul><ul><ul><li>Handling uncertainty </li></ul></ul>
    109. 109. High dose lipid-lowering therapy Is this strategy cost-effective? <ul><li>Roberta Ara </li></ul><ul><li>Senior Research Fellow </li></ul><ul><li>ScHARR, University of Sheffield </li></ul><ul><li>Email: r.m.ara@sheffield.ac.uk </li></ul>
    110. 110. Background <ul><li>Statin therapy for secondary CVD should “ usually be initiated with a drug with a low acquisition cost (taking into account required daily dose and product price per dose)” ( www.nice.org.uk/TA094, 2006 ) </li></ul><ul><li>Savings: </li></ul><ul><li>£1 billion over 5 years {Moon BMJ, 2006} </li></ul><ul><li>69% PCT switch to generic statins -> </li></ul><ul><li>NHS savings ≥ £85m/year (www.institute.nhs.uk, 2007) </li></ul>
    111. 111. The decision problem To evaluate the cost-effectiveness of high dose statins (atorvastatin 80mg/d, rosuvastatin 40mg/d & simvastatin 80mg/d) versus simvastatin 40mg/d in individuals with acute coronary syndrome.
    112. 112. Markov health states
    113. 113. Clinical Data Literature review: 28 RCTs > 12 week duration Benefit: LDL-c Synthesis: MTC Relationship: LDL-c & CV events
    114. 114. Mean Relative Risks (95% CI)   Atorvastatin 80mg/d Rosuvastatin 40mg/d Simvastatin 40mg/d Simvastatin 80mg/d Non-fatal MI 0.425 (0.302 - 0.544) 0.378 (0.241 - 0.51) 0.588 (0.500 - 0.675) 0.510 (0.404 - 0.613) Non fatal stroke 0.623 (0.508 - 0.737) 0.593 (0.465 - 0.717) 0.730 (0.647 - 0.813) 0.679 (0.580 - 0.777) Stroke death 0.809 (0.429 - 1.242) 0.794 (0.384 - 1.261) 0.863 (0.593 - 1.173) 0.837 (0.516 - 1.206) CHD death 0.580 (0.445 - 0.715) 0.545 (0.397 - 0.692) 0.699 (0.601 - 0.796) 0.642 (0.527 - 0.758)
    115. 115. Adherence to therapies   Scenario A Scenario B   Yr 1 Yr 5 Yr 1 Yr 5 S40 ITT ITT ITT ITT A80 ITT ITT 95% 85% R40 ITT ITT 95% 85% S80 ITT ITT 95% 85%
    116. 116. Treatment costs   Annual cost Sensitivity analyses Atorvastatin 80mg/d £368 £92 Rosuvastatin 40mg/d £387 Simvastatin 40mg/d £17 Simvastatin 80mg/d £34         Monitoring cost £76    
    117. 117. Results <ul><li>C omparing with simvastatin 40mg/d: </li></ul>  Atorvastatin 80mg/d Rosuvastatin 40mg/d Simvastatin 80mg/d Scenario A   £17,469 £12,484 £5,319 Scenario B £17,217 £12,277 £5,226  
    118. 118. Results – reduced cost for Atorvastatin simvastatin 40mg/d simvastatin 80mg/d atorvastatin 80mg/d rosuvastatin 40mg/d 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 £0 £5,000 £10,000 £15,000 £20,000 £25,000 £30,000 Threshold ratio Probability cost effective
    119. 119. Summary & Conclusion <ul><li>Rosuvastatin 40mg/d is currently the most cost-effective alternative </li></ul><ul><li>Atorvastatin 80mg/d is the most cost-effective (@ 25% of current price) </li></ul><ul><li>Simvastatin 80mg/d is not recommended </li></ul><ul><li>Current PCT policies intended to minimise primary care drug acquisition costs result in sub-optimal treatment for patients with ACS </li></ul>
    120. 120. A cost-effectiveness model of prostate cancer screening Matthew Mildred, Jim Chilcott, Silvia Hummel ScHARR, University of Sheffield
    121. 121. Contents <ul><li>Introduction to the project and topic </li></ul><ul><li>Disease natural history model </li></ul><ul><li>Data and model calibration </li></ul><ul><li>Validation </li></ul><ul><li>Results </li></ul><ul><li>Conclusions </li></ul>05/04/2011 © The University of Sheffield
    122. 122. The project <ul><li>Client: </li></ul><ul><li>UK National Screening Committee </li></ul><ul><li>Purpose: </li></ul><ul><li>Help determine IF a national prostate cancer screening programme should occur AND which screening strategy is best. </li></ul><ul><li>Objectives: </li></ul><ul><li>Estimate costs, benefits and resource implications of alternative screening options. </li></ul>05/04/2011 © The University of Sheffield
    123. 123. Introduction to prostate cancer <ul><li>The prostate is a small gland in men behind the bladder. </li></ul><ul><li>The most common cancer in men in UK </li></ul><ul><li>(excluding non-melanoma skin cancer) </li></ul><ul><li>In 2008: </li></ul><ul><li>Over 37,000 men diagnosed </li></ul><ul><li>Over 10,000 men died from prostate cancer </li></ul>05/04/2011 © The University of Sheffield
    124. 124. Aim of screening: <ul><li>Reduce cancer mortality, morbidity and treatment costs through early diagnosis and intervention. </li></ul>05/04/2011 © The University of Sheffield Current evidence: <ul><li>In 2009 two large RCTs reported apparently inconsistent results in terms of the death rate ratio: </li></ul><ul><li>ERSPC – significant reduction in PCa death rate </li></ul><ul><li>PLCO – no statistically significant reduction </li></ul>
    125. 125. Challenges: <ul><li>Effectiveness of different screening programmes unknown. </li></ul><ul><li>Scarce data around disease process due to its unobservable nature. </li></ul><ul><li>Multiple unknown parameters in cancer screening model. </li></ul>05/04/2011 © The University of Sheffield
    126. 126. Solution: <ul><li>Develop loosely parameterised cancer screening simulation model. </li></ul><ul><li>Calibrate unobservable model parameters to observed data. </li></ul><ul><li>Estimate impact of prostate cancer screening using calibrated model. </li></ul>05/04/2011 © The University of Sheffield
    127. 127. About the model: <ul><li>Disease natural history model (Simul8) </li></ul><ul><li>Calibration module (Excel, Visual Basic) </li></ul><ul><li>Simulation model of prostate cancer screening (Simul8) </li></ul><ul><li>Resource impact model (Excel) </li></ul>05/04/2011 © The University of Sheffield
    128. 128. Screening strategies investigated 05/04/2011 © The University of Sheffield No. Screens Screening Age (years) Screening Interval (years) Single 50 N/A 55 60 65 70 Repeat 50-70 2, 4 50-74 1, 2, 4 55-70 2, 4 55-74 2, 4
    129. 129. Outputs: <ul><li>Age-specific incidence </li></ul><ul><li>Age-specific mortality </li></ul><ul><li>Prostate cancer stage distributions </li></ul><ul><li>Over-detection rate </li></ul><ul><li>Lead time </li></ul><ul><li>Life years gained, QALYs gained </li></ul><ul><li>Probability of developing prostate cancer </li></ul><ul><li>Etc... </li></ul>05/04/2011 © The University of Sheffield
    130. 130. Definitions & terms used 05/04/2011 © The University of Sheffield PCa Onset Screen Detection PCa Mortality Clinical Diagnosis Other Cause Mortality PCa Onset Screen Detection PCa Mortality Clinical Diagnosis Other Cause Mortality Lead-time Lead-time Over-detection: Relevant:
    131. 131. Disease natural history model 05/04/2011 © The University of Sheffield
    132. 132. Data 05/04/2011 © The University of Sheffield Data Source Age specific cancer incidence Office of National Statistics Cancer stage distributions ProtecT RCT UK Cancer Registry (ERIC) Gleason score distributions ProtecT RCT UK Cancer Registry (ERIC) PSA/biopsy test characteristics ERSPC RCT (Rotterdam section) Progression Free Survival ERSPC RCT (Rotterdam section) Overall Survival ERSPC RCT (Rotterdam section)
    133. 133. Calibration process 05/04/2011 © The University of Sheffield
    134. 134. Total SSE during calibration 05/04/2011 © The University of Sheffield
    135. 135. Validation: Incidence 05/04/2011 © The University of Sheffield
    136. 136. Validation: PCa mortality 05/04/2011 © The University of Sheffield
    137. 137. Validation: BAUS 05/04/2011 © The University of Sheffield
    138. 138. Results: Incidence 05/04/2011 © The University of Sheffield
    139. 139. Results: Mortality 05/04/2011 © The University of Sheffield
    140. 140. Over-detection & Lead time: 05/04/2011 © The University of Sheffield Once at 50 50-74 every 4 years 50-74 every 2 years 50-74 every year Over-detection rate 18% 44% 45% 46% Lead time (for over-detected cases) 15.2 yrs 11.6 yrs 12.5 yrs 13.0 yrs
    141. 141. Conclusions: <ul><li>A minimal life gain is offset by the high levels of disease management and over-diagnosis: </li></ul><ul><li>One off screening: life gain of 0.004 years (1.2 days) with 36 years of additional disease management </li></ul><ul><li>Repeat screening: life gain of 0.03 years (10-11 days) with 67-84 years of additional disease management </li></ul>05/04/2011 © The University of Sheffield
    142. 142. Have you heard our findings? 05/04/2011 © The University of Sheffield BBC News 06/12/2010 http://www.bbc.co.uk/news/health-11930979
    143. 143. Acknowledgements: <ul><li>Dr Anne Mackie and Prof Julietta Patnick at the UK National Screening Committee </li></ul><ul><li>The South West Public Health Observatory </li></ul><ul><li>The British Association of Urological Surgeons </li></ul><ul><li>The ProtecT team </li></ul>05/04/2011 © The University of Sheffield
    144. 144. Healthcare costs alone do not describe the total costs directly attributable to Ankylosing Spondylitis <ul><li>R. Ara 1 , R. Rafia 1 , J. C. Packham 2,3 , K L Haywood 4 , E.L. Healey 2,4 </li></ul><ul><li>1 University of Sheffield, 2 Staffordshire Rheum Centre, 3 University of Warwick, 4 Arthritis Research Campaign, Keele. </li></ul>27/10/11 © The University of Sheffield
    145. 145. Introduction <ul><li>Ankylosing Spondylitis (AS) is a chronic, progressive disease and prognosis is often poor. In addition to direct health care costs, AS is associated with substantial indirect costs due to privately funded health care, absenteeism from work and early retirement. </li></ul>27/10/11 © The University of Sheffield
    146. 146. Objectives <ul><li>To explore the total costs directly attributable to AS patients attending rheumatological centres in the UK. </li></ul><ul><li>To explore the relationship between total costs and disease severity (classified using the Bath AS Disease Activity Index (BASDAI) and the Bath AS Functional Index (BASFI) variables) </li></ul>27/10/11 © The University of Sheffield
    147. 147. Methods <ul><li>Health care costs included: medications, inpatient, GP/ outpatient, physiotherapy, hydrotherapy </li></ul><ul><li>Non medical indirect costs included: productivity losses (unemployment, early retirement, absenteeism, presenteeism) </li></ul><ul><li>Productivity losses were assessed using human capital approach </li></ul><ul><li>Absenteeism = number of days off sick (average 5 working days per week) </li></ul><ul><li>Presenteeism = relative to age/gender adjusted gross pay & WLQ-16 </li></ul><ul><li>Two-step model used to explore relationship between disease severity and costs using data collected at baseline </li></ul><ul><li>1: logistic regression for probability incurring cost </li></ul><ul><li>2: generalised linear model conditional on incurring any cost </li></ul><ul><li>Performance of the estimated model tested on data collected at 6 months </li></ul>
    148. 148. Results (1) <ul><li>Healthcare Utilisation: </li></ul><ul><li>41% reported no health care resources </li></ul><ul><li>45% reported no NHS funded healthcare resources </li></ul><ul><li>26% reported ≥ 1 medication </li></ul><ul><li>71/162 received anti-TNF treatment </li></ul><ul><li>10 hospitalisations due to AS (mean duration 11 days) </li></ul><ul><li>215 reported ≥ 1 GP consultation </li></ul><ul><li>Number consultations > for greater disease activity (1.7 vs 2.6) </li></ul><ul><li>Number consultations > for non workers (2.8 vs 1.9) </li></ul><ul><li>19% ≥ 1 physiotherapy session (33% of these self funded) </li></ul><ul><li>11% ≥ 1 hydrotherapy session (46% of these self-funded) </li></ul><ul><li>Number sessions > non workers (7.1 vs 13.1) </li></ul><ul><li>Number sessions > for greater disease activity (7.0 vs 12.3) </li></ul>27/10/11 © The University of Sheffield
    149. 149. Results (2) <ul><li>Total Costs: </li></ul><ul><li>The distribution of costs is heavily skewed with small number incurring high costs and substantial proportion incurring none. </li></ul><ul><li>Average 3 month direct health care costs = £420 ± £988 (median = £27) </li></ul><ul><li>Average 3 month total costs = £2,837 ± £3,358 (median = £1,228) </li></ul>Mean 3 month total costs sub-grouped by disease severity bands
    150. 150. Results (3) <ul><li>Absenteeism/ presenteeism </li></ul><ul><li>25% of working age reported not working or early retirement due to AS </li></ul><ul><li>25% (85/339) of workers reported time off sick </li></ul><ul><li>93% (315/339) of workers reported a reduction in productivity while at work </li></ul><ul><li>Mean number of days off sick due to AS = 5.7 (range 1 – 62) </li></ul><ul><li>Mean reduction in productivity at work = 20% (range = 1 – 90%) </li></ul>27/10/11 © The University of Sheffield
    151. 151. Results (4) <ul><li>Using BASDAI & BASFI to predict AS disease costs </li></ul><ul><li>Model 1 : </li></ul><ul><li>Probability of incurring costs = 3.26106 +0.13308*BASFI + 0.27695*BASDAI – 0.01323*BASFI*BASDAI + 0.30472*male – 0.04869*age – 0.01171*disease duration </li></ul><ul><li>Model 2 : </li></ul><ul><li>3 month total costs, conditional on costs incurred = 6.89107 + 0.26335*BASFI + 0.12048*BASDAI - 0.01411*BASFI*BASDAI + 0.46456*male – 0.01679*age + 0.00364*disease duration </li></ul>Actual and predicted total 3 month costs
    152. 152. Conclusion <ul><li>This study shows that direct healthcare costs alone do not describe the total costs associated with AS and that productivity losses associated with AS are considerable. Additional research examining interventions and measures that improve both presenteeism and absenteeism will have the largest affect on the cost to society. </li></ul>27/10/11 © The University of Sheffield
    153. 153. The direct healthcare resource costs associated with Ankylosing Spondylitis patients attending a UK secondary care rheumatology unit <ul><li>RM Ara 1 , JC Packham 2 , KL Haywood 3 </li></ul><ul><li>1 University of Sheffield; 2 Staffordshire Rheumatology Centre, Stoke on Trent; 3 Royal College of Nursing Institute, Oxford, UK </li></ul>27/10/11 © The University of Sheffield
    154. 154. Introduction <ul><li>Anti-TNF inhibitors such as etanercept (ETN), are now licensed for treating patients with severe Ankylosing Spondylitis (AS). </li></ul><ul><li>These treatments have larger cost implications than previously available therapies and comprehensive economic evaluations of these novel treatments in individual disease areas are increasingly requested by policy decision makers to inform reimbursement decisions.  </li></ul>27/10/11 © The University of Sheffield
    155. 155. Objectives <ul><li>To explore the direct healthcare resources utilised by AS patients attending a UK secondary care rheumatology unit to inform an economic evaluation of ETN in AS patients. </li></ul><ul><li>To establish if resources, and thus health care costs, vary by disease severity (as classified using the Bath AS Disease Activity Index (BASDAI) and the Bath AS Functional Index (BASFI) variables). </li></ul>
    156. 156. Methods <ul><li>Costs: </li></ul><ul><li>Costs were assessed using a micro-costing approach starting with a detailed inventory and measurement of resources consumed by the patient. </li></ul><ul><li>Unit cost multipliers were applied to the quantity of each type of resource consumed. </li></ul><ul><li>The mean cost per patient is estimated using the total cost divided by the total number of patients included. </li></ul><ul><li>Resources included : </li></ul><ul><li>NHS physiotherapy, outpatient appointments; inpatient days, laboratory based tests (FBR, ESR, LFT, U&E), X-rays, scans, prescribed medications. </li></ul>27/10/11 © The University of Sheffield
    157. 157. Results (1) <ul><li>Mean Annual Disease Costs </li></ul><ul><li>The mean total annual costs is estimated to be £1,837 (s.d. = £2,764; median = £772). </li></ul><ul><li>The total annual costs range from £101 to £18,012 with an asymmetric distribution (just 11/147 patients have annual costs concentrated beyond £7,000). </li></ul><ul><li>The mean annual cost per patient is correlated with both measures of disease activity (BASDAI) and functional disability (BASFI) </li></ul>The mean annual costs by levels of disease activity and functional disability Mean (proportion) annual costs by resource type and disease severity BASDAI < 60 BASDAI > 60 BASFI < 60 BASFI > 60 Physiotherapy £281; 22% £1,575;45% £123; 13% £1,547; 43% Hospitalisation £303; 23% £785; 23% £243; 26% £779; 22% Medication £315; 24% £479; 14% £225; 24% £615; 17% Outpatient/tests £397; 31% £668; 19% £351; 37% £688; 19%
    158. 158. Results (2) <ul><li>Using BASDAI & BASFI to predict AS disease costs </li></ul><ul><li>Both the BASDAI and BASFI measurements were moderately correlated with the log transformed annual costs (Pearson correlation = 0.40 and 0.48 respectively; p < 0.001). </li></ul><ul><li>The model # with the best predictive ability was </li></ul><ul><li>Annual direct costs = exp(0.006*BASDAI + 0.016*BASFI + 5.862) </li></ul><ul><li># Adj R 2 =0.24 hence BASDAI and BASFI only partially account for the variability in costs. </li></ul><ul><li>A 10 unit increase in both BASDAI and BASFI measurements incurs an increment of approximately £130 for scores of 40 and below; and an increment of approximately £480 for scores of 70 and above. </li></ul>
    159. 159. Discussion/Future Research <ul><li>The results of this costing study give an indication of the range of direct healthcare costs associated with patients who have AS and are eligible for anti-TNF treatments in the UK. </li></ul><ul><li>Due to time constraints only readily accessible data such as clinical visits; inpatient care, technical procedures including radiographic examinations, prescribed medications, and physiotherapy appointments were included. </li></ul><ul><li>The study would benefit from inclusion of additional information such as the number of GP visits. </li></ul><ul><li>Further research into the most (cost)-effective provision of physiotherapy to patients with AS would be constructive. </li></ul><ul><li>As AS is a progressive debilitating disease, it may be appropriate to include non-medical resources such as aids and appliances or formal household care and paid productivity losses such as absence from paid work. </li></ul>
    160. 160. A treatment option for patients with severe active Ankylosing Spondylitis: the costs and benefits associated with etanercept <ul><li>RM Ara 1 , A Reynolds 2 , P Conway 2 </li></ul><ul><li>1 University of Sheffield; 2 Wyeth Pharmaceuticals, UK </li></ul>27/10/11 © The University of Sheffield
    161. 161. Introduction <ul><li>Ankylosing Spondylitis (AS) is a progressive inflammatory disease that can cause irreversible skeletal damage. Typically presenting in young males, the long term prognosis is poor. High levels of pain and severe loss of physical function can have a large effect on health related quality of life (HRQoL). </li></ul><ul><li>The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) are validated and established measures in AS patients. </li></ul>
    162. 162. Objective <ul><li>To explore the costs and benefits associated with etanercept (ETN) in patients with severe AS in the UK under the BSR criteria. </li></ul>27/10/11 © The University of Sheffield
    163. 163. Methods <ul><li>The model (written in Excel 2003) estimates the costs and benefits associated with ETN (2x 25mg/week) plus NSAIDS compared with NSAIDs alone. </li></ul><ul><li>Effectiveness of ETN is based on patient level data obtained from two RCTs </li></ul><ul><li>Placebo data are used to inform the comparator (88% of patients received NSAIDS) </li></ul><ul><li>Effectiveness of treatment are measured by changes in BASDAI and BASFI at weeks 12 and 24 </li></ul><ul><li>Initial response is supported by three year open label data [6,7] </li></ul><ul><li>Direct healthcare costs associated with AS are obtained from a UK costing study and are estimated using the relationship [8] </li></ul><ul><li>Annual direct costs = exp(0.006*BASDAI + 0.016*BASFI + 5.862) </li></ul><ul><li>QoL data (EQ-5D) collected during the RCT are used to estimate quality adjusted life years (QALYS) using the relationship </li></ul><ul><li>Utility = 0.923 – 0.004*BASFI – 0.004*BASDAI </li></ul><ul><li>A 25 year time horizon is used to reflect the chronic progressive nature of AS and results are also presented for shorter horizons </li></ul><ul><li>Univariate sensitivity analyses are used to explore the impact of varying individual key parameters </li></ul><ul><li>Costs and benefits are discounted at 3.5% per annum </li></ul>
    164. 164. Assumptions <ul><li>Natural disease progression: BASFI increases at 0.7 units per annum </li></ul><ul><li>For responders to ETN: BASDAI & BASFI measurements remain constant at values observed in RCTS </li></ul><ul><li>BASDAI & BASFI measurements revert to baseline values and follow natural disease progression after withdrawal from ETN </li></ul><ul><li>10% annual withdrawal from ETN due to lack of efficacy/ adverse effects </li></ul><ul><li>Age and sex related life expectancy is adjusted using ratio of 1.5 and assumed equal in both arms </li></ul>27/10/11 © The University of Sheffield
    165. 165. Base case results 27/10/11 © The University of Sheffield
    166. 166. Univariate sensitivity analyses <ul><li>The tornado diagram shows that the three variables that have the largest impact of the 25 year results are: </li></ul><ul><li>the values used to represent HRQoL </li></ul><ul><li>the annual withdrawal rates </li></ul><ul><li>the health care costs directly attributable to AS </li></ul>27/10/11 © The University of Sheffield Tornado diagram showing the parameters which have the largest impact on the results
    167. 167. Monte Carlo results <ul><li>Using a 25 year horizon and a £30k per QALY threshold, ETN would be considered a cost-effective treatment when compared to NSAIDs in individuals with severe AS. The corresponding cost effectiveness acceptability curve shows that ETN is 93% likely to be cost effective when using a £25k per QALY threshold. </li></ul>27/10/11 © The University of Sheffield Cost effectiveness plane ETN plus NSAIDs compared with NSAIDs
    168. 168. Areas for future research <ul><li>Potential impact of radiological progression on long term disability </li></ul><ul><li>Efficacy of ETN in individuals with BASDAI < 40 </li></ul><ul><li>Strengthen relationship between BASDAI/BASFI and both costs and utilities </li></ul><ul><li>BASDAI & BASFI further explore the relationship to disease costs </li></ul><ul><li>Effect of ETN on early retirement </li></ul><ul><li>Develop prognostic algorithms to identify patients who would benefit the most from ETN </li></ul><ul><li>Quantify natural disease progression and disease progression for individuals responding to ETN </li></ul>
    169. 169. An economic evaluation of etanercept in the treatment of patients with psoriatic arthritis <ul><li>RM Ara and R Rafia </li></ul><ul><li>ScHARR, University of Sheffield </li></ul>27/10/11 © The University of Sheffield
    170. 170. Introduction <ul><li>Psoriatic Arthritis (PsA) is a chronic, progressive disease and prognosis is often poor. </li></ul><ul><li>Anti_TNF agents such as etanercept are effective alternatives for patients whose current treatment is symptomatic. </li></ul>
    171. 171. Objective <ul><li>To explore the costs and benefits associated with etanercept in the treatment for patients with psoriatic arthritis to inform a NICE submission. </li></ul>
    172. 172. Methods <ul><li>The model compares ciclosporin to anti-TNF agents (etanercept, adalimumab, infliximab) and it is assumed that patients have failed methotrexate and sulphasalazine prior entering the model. </li></ul><ul><li>Relationship between HAQ and costs associated with PsA and HAQ and health related quality of life are then used to estimate the long term costs and benefits accrued. </li></ul><ul><li>Treatment effectiveness was derived from a Mixed Treatment Comparison published in a previous STA. </li></ul><ul><li>Treatment discontinuation was modelled using PsARC response rate at 12 and/or 24 weeks using results from the MTC. Long term withdrawal rate was derived from data from a recent observational study conducted by the BSRBR. </li></ul><ul><li>A set of 27 univariate sensitivity analysis was performed to test the robustness of the model to main assumptions. </li></ul><ul><li>The overall uncertainty was examined using a Monte Carlo approach. </li></ul><ul><li>Costs and quality of life benefits were discounted at 3.5% per annum as per NICE recommandations for economic evaluation </li></ul><ul><li>The model was extended beyond the trial duration to a 50 years time horizon </li></ul>
    173. 173. Relationship between HAQ and HrQoL <ul><li>Relationship estimated from PRESTA trial for the base case: </li></ul><ul><li>Utility (EQ-5D) = 0.8996 – 0.4559 * HAQ – 0.0010 * Age + 0.0201 * male + 0.0031 *Age * HAQ – 0.0388 * male * HAQ </li></ul>
    174. 174. Relationship between HAQ and Direct health care Costs <ul><li>Health care costs include both primary and secondary care resources. </li></ul><ul><li>The relationship between HAQ and costs was examined using a Generalised Linear Model assuming a poison distribution and a log link: </li></ul><ul><li>Cost = 3.5367 + 2.0484 * HAQ + 0.0260 * Age – 0.0119 * Age * HAQ </li></ul>Actual and predicted annual cost by HAQ
    175. 175. Base case results
    176. 176. Uncertainty in results <ul><li>The model results were sensitive to both the magnitude of the rebound of HAQ after withdrawal from treatment, and annual HAQ progression rates, relationship between HAQ and QoL and discount rates. </li></ul><ul><li>Results from the PSA, demonstrate one is 65% confident that etanercept is a cost-effective strategy when using a threshold of £20,000 per QALY. </li></ul>27/10/11 © The University of Sheffield Cost-Effectiveness- Acceptability Curve
    177. 177. Conclusion <ul><li>While this evaluation provides evidence on the potential cost-effectiveness of etanercept compared to other anti-TNF agents or ciclosporin for adults with PsA, there are limitations with the evidence based used to populate the model. </li></ul>27/10/11 © The University of Sheffield
    178. 178. Evidence Review and Synthesis 27/10/11 © The University of Sheffield
    179. 179. Extensive experience of systematic review and evidence synthesis work for <ul><ul><li>National Institute for Health and Clinical Excellence (NICE), </li></ul></ul><ul><ul><li>NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) </li></ul></ul><ul><ul><li>NICE Public Health Collaborating Centre (PHCC) </li></ul></ul><ul><ul><li>Multiple clients in industry. </li></ul></ul>27/10/11 © The University of Sheffield
    180. 180. Systematic review of clinical evidence <ul><li>High quality systematic reviews for submissions to key reimbursement bodies or for publication </li></ul><ul><ul><ul><li>Clinical reviews </li></ul></ul></ul><ul><ul><ul><li>Critical appraisal of reviews </li></ul></ul></ul><ul><ul><ul><li>Review updates </li></ul></ul></ul><ul><ul><ul><li>Other review methods </li></ul></ul></ul><ul><ul><ul><li>Mapping reviews </li></ul></ul></ul><ul><ul><ul><li>Reviews of model parameters </li></ul></ul></ul><ul><ul><ul><li>Rapid reviews </li></ul></ul></ul><ul><ul><ul><li>Research reports </li></ul></ul></ul>27/10/11 © The University of Sheffield
    181. 181. Generalised evidence synthesis <ul><li>Classical and Bayesian meta analysis, including network meta analysis </li></ul><ul><ul><li>RCTs </li></ul></ul><ul><ul><li>Observational studies </li></ul></ul><ul><ul><li>Diagnostic studies </li></ul></ul><ul><ul><li>Qualitative studies (meta synthesis) </li></ul></ul><ul><ul><li>Mixed methods </li></ul></ul>
    182. 182. Examples of Systematic reviews conducted in HEDS 27/10/11 © The University of Sheffield
    183. 183. PET and MRI for the assessment of axillary lymph node metastases in early stage breast cancer <ul><li>A Systematic review </li></ul><ul><li>Susan Harnan </li></ul><ul><li>Research Associate </li></ul><ul><li>ScHARR, University of Sheffield </li></ul><ul><li>Email: s.harnan@sheffield.ac.uk </li></ul>27/10/11 © The University of Sheffield
    184. 184. Background <ul><li>Axillary staging is important for breast cancer staging and treatment planning </li></ul><ul><li>Current techniques include </li></ul><ul><ul><li>Axillary lymph node dissection (ALND) </li></ul></ul><ul><ul><li>Sentinel lymph node biopsy (SLNB) </li></ul></ul><ul><ul><li>Sampling techniques such as four node sampling (4-NS) </li></ul></ul><ul><li>All these procedures (ALND, SLNB and 4-NS) have short and long term adverse effects such as lymphoedema </li></ul>27/10/11 © The University of Sheffield
    185. 185. Diagnostic pathway <ul><li>NICE diagnostic pathway </li></ul><ul><li>*Either fine needle aspiration cytology (FNAC) or core biopsy. </li></ul><ul><li>Positron emission tomography (PET) and magnetic resonance imaging (MRI) may offer alternatives with fewer adverse events </li></ul><ul><ul><ul><ul><ul><li>Could replace SLNB/4-NS </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Or be added to the pathway </li></ul></ul></ul></ul></ul>27/10/11 © The University of Sheffield
    186. 186. HTA report <ul><li>National Institute for Health Research Health Technology Assessment (HTA) programme commissioned research to evaluate PET and MRI: </li></ul><ul><ul><li>Diagnostic accuracy </li></ul></ul><ul><ul><li>Cost-effectiveness </li></ul></ul><ul><ul><li>Patient outcomes </li></ul></ul><ul><li>Work carried out by ScHARR: Katy Cooper, Yang Meng, Sue Harnan, Sue Ward, Patrick Fitzgerald, Diana Papaioannou </li></ul><ul><li>With clinical advisers: Lynda Wyld, Christine Ingram, Iain Wilkinson, Eleanor Lorenz </li></ul>27/10/11 © The University of Sheffield
    187. 187. Methods <ul><li>Searched eleven databases </li></ul><ul><li>Inclusion criteria: </li></ul><ul><ul><li>Assessed diagnostic accuracy of PET or MRI for assessment of axillary metastases in patients newly diagnosed with early-stage invasive primary breast cancer </li></ul></ul><ul><ul><li>PET studies only included if ≥ 20 patients </li></ul></ul><ul><ul><li>Studies with > 20% non-early stage, non-newly diagnosed or DCIS were excluded. </li></ul></ul><ul><li>Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist used. </li></ul>27/10/11 © The University of Sheffield
    188. 188. Diagnostic accuracy studies <ul><li>Patients are classified against a reference standard (eg ALND or SLNB) as true positive, true negative, false positive or false negative </li></ul><ul><li>Sensitivity is % of positive patients correctly identified </li></ul><ul><li>Specificity is % of negative patients correctly identified </li></ul><ul><li>Studies only included if TP, TN, FP and FN were reported or could be calculated. </li></ul><ul><li>Bivariate random effects model used to meta-analyse data as sensitivity and specificity are linked. </li></ul>
    189. 189. Results 27/10/11 © The University of Sheffield
    190. 190. PET results <ul><li>Quality generally acceptable, though some problems with patient spectrum, blinding, availability of relevant clinical information and reporting of uninterpretable results. </li></ul><ul><li>26 studies of PET or PET/CT </li></ul>27/10/11 © The University of Sheffield
    191. 191. PET results – forest plots
    192. 192. PET sensitivity analyses
    193. 193. MRI results <ul><li>Quality generally good. Some problems with patient spectrum, availability of relevant clinical information and uninterpretable results. </li></ul><ul><li>Small numbers, different methods </li></ul><ul><li>Nine studies of MRI, meta-analysed using highest reported sensitivity and specificity from each study </li></ul>
    194. 194. MRI results – forest plot 27/10/11 © The University of Sheffield
    195. 195. MRI results <ul><li>Criteria for positivity varied across studies, including variables of size, morphology and uptake. Uptake pattern appeared to give better combined sensitivity and specificity. </li></ul><ul><li>Sensitivity analyses </li></ul><ul><li>Sensitivity analyses for size and nodal status not possible as these were not reported </li></ul><ul><li>Lower specificity and a trend towards higher sensitivity was seen for studies with only early-stage, newly-diagnosed non-DCIS patients, but wide range. </li></ul><ul><li>Study quality did not affect estimates (note small sample, little variation in scores) </li></ul>27/10/11 © The University of Sheffield
    196. 196. Adverse effects <ul><li>No adverse effects were reported for PET </li></ul><ul><li>Mild to moderate adverse effects reported for MRI include mild rash following USPIO administration, claustrophobia and back pain. </li></ul><ul><li>Cautions and contraindications exist for both including pregnancy (PET), allergy to contrast agents, renal and liver dysfunction, pacemakers, metallic implants (MRI). </li></ul>27/10/11 © The University of Sheffield
    197. 197. Discussion <ul><li>PET, PET-CT and MRI have lower sensitivity and specificity than ALND, SLNB and 4-NS </li></ul><ul><li>PET and PET-CT are similar to ultrasound in terms of sensitivity and specificity, MRI is slightly higher. </li></ul><ul><li>MRI has higher sensitivity than PET or PET-CT, but similar specificity. </li></ul><ul><li>USPIO-enhanced MRI gave highest estimates of sensitivity and specificity, but these are based on a small number of studies </li></ul><ul><li>All results vary widely between studies and caution should be taken when interpreting results </li></ul>27/10/11 © The University of Sheffield
    198. 198. Discussion (2) <ul><li>Based on these estimates, if PET or MRI are used to replace SLNB/4-NS in the diagnostic pathway, more women will be at greater risk of recurrence or metastatic spread (false negatives) and more women will undergo ALND unnecessarily (false positives) </li></ul><ul><li>However PET and MRI have few adverse effects and much fewer women would undergo SLNB/4-NS and be at risk of the long term problems associated with them. </li></ul><ul><li>Decision modeling is needed for overall evaluation of benefits and harms. </li></ul><ul><li>Decision modeling will help evaluate the effects if PET or MRI are used in addition to SLNB/4-NS in the diagnostic pathway. </li></ul>27/10/11 © The University of Sheffield
    199. 199. PET results – ROC plot 27/10/11 © The University of Sheffield All PET studies, showing ROC curve (solid line), mean sensitivity/specificity (black spot) and 95% confidence region (dashed ellipse)
    200. 200. MRI results – ROC plot 27/10/11 © The University of Sheffield All MRI studies, showing ROC curve (solid line), mean sensitivity/specificity (black spot) and 95% confidence region (dashed ellipse)
    201. 201. Systematic reviews of relevant data Myfanwy Lloyd Jones Senior Research Fellow ScHARR, University of Sheffield Email: m.lloydjones@sheffield.ac.uk
    202. 202. More specifically <ul><li>Drawing on the experience of the pilot diagnostics project, how do systematic reviews of diagnostic interventions differ from systematic reviews of therapeutic interventions, when both are undertaken to inform NICE decision-making? </li></ul><ul><ul><li>Review question </li></ul></ul><ul><ul><li>PICO(S) components </li></ul></ul><ul><ul><li>Meta-analysis </li></ul></ul>27/10/11 © The University of Sheffield
    203. 203. The review question <ul><li>Is there a bigger difference between the overall project question and the question that forms the focus of the systematic review of clinical effectiveness in an assessment of a diagnostic intervention than in an assessment of a therapeutic intervention? </li></ul><ul><ul><li>Therapeutic intervention: strontium ranelate TAR (2005) </li></ul></ul>27/10/11 © The University of Sheffield
    204. 204. Therapeutic intervention <ul><li>Research question defined in the protocol: </li></ul><ul><li>To establish the clinical and cost effectiveness of strontium ranelate for the prevention of osteoporotic fractures in postmenopausal women with osteoporosis </li></ul><ul><li>Systematic review of clinical effectiveness: </li></ul><ul><li>What is the clinical effectiveness of strontium ranelate for the prevention of osteoporotic fractures in postmenopausal women with osteoporosis, with or without prior fracture? </li></ul>27/10/11 © The University of Sheffield
    205. 205. In PICOS terms <ul><li>Population: postmenopausal women with osteoporosis, with or without prior fracture </li></ul><ul><li>Intervention: strontium ranelate </li></ul><ul><li>Comparator: placebo/no treatment; specified active treatments if evidence available </li></ul><ul><li>Outcomes: </li></ul><ul><ul><li>Principal: incident fractures (vertebral & nonvert) </li></ul></ul><ul><ul><li>Secondary: adverse effects, health-related quality of life etc </li></ul></ul><ul><li>Study design: RCTs </li></ul>27/10/11 © The University of Sheffield
    206. 206. Diagnostic intervention <ul><li>Decision problem defined in the protocol: </li></ul><ul><li>Will using non-invasive liver assessment tools in patients with suspected alcohol-related liver fibrosis who might otherwise be candidates for biopsy or referral to specialist care reduce the number of referrals or biopsies and improve the health outcomes and quality of life of those patients? </li></ul><ul><li>Systematic review of clinical effectiveness: </li></ul><ul><li>The subject of some debate </li></ul>27/10/11 © The University of Sheffield
    207. 207. In PICOS terms: population & intervention <ul><li>Population: patients suspected of having liver fibrosis related to alcohol consumption </li></ul><ul><li>Intervention: the scope and protocol specified 4 non-invasive liver assessment tools (NILTs) </li></ul><ul><ul><li>? A fifth – how binding is the protocol? </li></ul></ul>27/10/11 © The University of Sheffield
    208. 208. In PICOS terms: the comparator <ul><li>The current UK decision-making process? </li></ul><ul><ul><li>What the NICE team wanted: </li></ul></ul><ul><ul><ul><li>A relevant comparator for the model </li></ul></ul></ul><ul><ul><ul><li>Problematic given the lack of consensus among clinicians about the potential role of NILTs </li></ul></ul></ul><ul><ul><ul><li>A problematic comparator for the systematic review because no study is likely to have been set up with that comparator </li></ul></ul></ul><ul><li>A specific diagnostic test (reference standard)? </li></ul><ul><ul><li>Feasible in terms of the evidence base </li></ul></ul><ul><ul><li>What many clinicians are likely to want to know is how a NILT compares with the reference standard (at least if the reference standard is what they generally use) </li></ul></ul>27/10/11 © The University of Sheffield
    209. 209. In PICOS terms: outcomes <ul><li>Test accuracy compared with the reference standard </li></ul><ul><li>Number of test failures or other withdrawals </li></ul><ul><li>Adverse events </li></ul><ul><li>Number of referrals to specialist care </li></ul><ul><li>Number of biopsies needed (presumably because of test failures or borderline results) </li></ul><ul><li>Longer-term health outcomes </li></ul><ul><li>Quality of life </li></ul><ul><li>Which of these should be the primary outcome? </li></ul>27/10/11 © The University of Sheffield
    210. 210. In PICOS terms: study design <ul><li>Protocol: “The best available level of evidence will be included, with priority given to controlled studies if available” </li></ul>27/10/11 © The University of Sheffield
    211. 211. Population (1) <ul><li>Therapeutic intervention: </li></ul><ul><ul><li>reasonable match between review question and study populations (main exclusions related to conditions which could interfere with bone metabolism, and recent treatment with antiosteoporotic agents; 1 study excluded women aged >78) </li></ul></ul><ul><li>Diagnostic intervention: </li></ul><ul><ul><li>mismatch introducing spectrum bias </li></ul></ul>27/10/11 © The University of Sheffield
    212. 212. Population (2) <ul><li>In diagnostic studies, if the reference standard is invasive (eg liver biopsy) or particularly expensive, then for ethical or cost reasons the study populations are likely not to be representative of the full range of people eligible for the index test </li></ul><ul><ul><li>Either the whole study population is unrepresentative because of disease severity (eg already scheduled for liver biopsy because of suspected severe fibrosis) </li></ul></ul><ul><ul><li>Or the whole population is more representative, but liver biopsy is only performed in the subset whose index test results suggest more severe disease </li></ul></ul>
    213. 213. Intervention <ul><li>Therapeutic intervention: </li></ul><ul><li>Description and other useful data from EMEA and BNF </li></ul><ul><li>Diagnostic intervention: </li></ul><ul><li>No structured descriptions of the technology – not even sponsor submissions: </li></ul><ul><ul><li>Data pulled together from assorted articles and manufacturers’ websites </li></ul></ul>27/10/11 © The University of Sheffield
    214. 214. Comparator: what is it? <ul><li>Therapeutic intervention: </li></ul><ul><li>No active intervention (placebo or no treatment) </li></ul><ul><li>Active intervention likely to have a direct effect on relevant clinical outcomes </li></ul><ul><li>Diagnostic intervention: </li></ul><ul><li>Subject of debate: test or care pathway? </li></ul><ul><ul><li>Primary comparator: liver biopsy </li></ul></ul><ul><ul><li>Secondary comparators: tests used to identify conditions associated with liver fibrosis </li></ul></ul>
    215. 215. Comparator: issues <ul><ul><li>Studies of diagnostic test accuracy assume that the reference standard has 100% sensitivity and specificity, which is clearly unlikely </li></ul></ul><ul><ul><ul><li>Some reference standards (eg liver biopsy) are known to be imperfect </li></ul></ul></ul><ul><ul><li>Discordance between the results of the index test and reference standard may result from error in either test </li></ul></ul><ul><ul><li>Some studies may try to determine, for each individual discordant result, whether the reference standard or the new test is more likely to be correct, but will never identify cases where the results are concordant but both wrong </li></ul></ul>27/10/11 © The University of Sheffield
    216. 216. Outcomes: therapeutic intervention <ul><li>Primary outcome: fracture </li></ul><ul><ul><li>Clinical relevance clear </li></ul></ul>27/10/11 © The University of Sheffield
    217. 217. Outcomes: diagnostic intervention <ul><li>Primary outcome: subject of debate </li></ul><ul><ul><li>Test accuracy? </li></ul></ul><ul><ul><ul><li>Fundamental: if the new test is inaccurate, no point in going further </li></ul></ul></ul><ul><ul><ul><li>Problematic, and often poorly reported </li></ul></ul></ul><ul><ul><li>Patient outcomes? </li></ul></ul><ul><ul><ul><li>Clinical outcomes: obviously relevant, but may depend heavily on clinician or patient choices subsequent to the test result (eg, for NILTs, would a positive test result make the patient more or less likely to stop drinking?) </li></ul></ul></ul><ul><ul><ul><li>Safety/ patient acceptability relative to current practice </li></ul></ul></ul>27/10/11 © The University of Sheffield
    218. 218. Reporting of outcomes: therapeutic intervention (1) <ul><li>The Consort statement says that “for each outcome, study results should be reported as a summary of the outcome in each group (for example, the number of participants with or without the event and the denominators, or the mean and standard deviation of measurements), together with the contrast between the groups, known as the effect size” </li></ul><ul><li>For binary outcomes, the effect size could be the relative risk, odds ratio, or risk difference </li></ul>27/10/11 © The University of Sheffield
    219. 219. Reporting of outcomes: therapeutic intervention (2) <ul><li>1 </li></ul>27/10/11 © The University of Sheffield Number (%) Relative risk (95% CI) Endpoint Strontium ranelate (n=719) Placebo (n=723) Nonvertebral fracture 112 (15.6) 122 (16.9) 0.90 (0.69 to 1.17)
    220. 220. Reporting of outcomes: therapeutic intervention (3) <ul><li>Vertebral fracture: </li></ul><ul><ul><li>SOTI trial reported %ages plus RR; numbers of participants in each treatment group with fracture obtained from investigator </li></ul></ul><ul><ul><li>The STRATOS trial and, at the time of our review, the TROPOS trial only reported %ages plus RR </li></ul></ul><ul><li>Nonvertebral fracture: </li></ul><ul><ul><li>SOTI and TROPOS reported numbers of participants in each treatment group with fracture, with RR (and %ages for TROPOS) </li></ul></ul><ul><ul><li>STRATOS just reported %ages, as adverse events </li></ul></ul>27/10/11 © The University of Sheffield
    221. 221. Reporting of outcomes: diagnostic intervention (1) <ul><li>The STARD (Standards for Reporting of Diagnostic Accuracy) guidelines require “a cross tabulation of the results of the index tests (including indeterminate and missing results) by the results of the reference standard; for continuous results, the distribution of the test results by the results of the reference standard ” </li></ul>27/10/11 © The University of Sheffield
    222. 222. Reporting of outcomes: diagnostic intervention (2) 27/10/11 © The University of Sheffield Reference standard positive Reference standard negative Index test positive True positive (TP) False positive (FP) Index test uninterpretable Uninterpretable (U 1 ) Uninterpretable (U 2 ) Index test negative False negative (FN) True negative (TN) Sensitivity = (TP/(TP+U 1 +FN))x100 Specificity = (TN/(TN+U 2 +FP))x100
    223. 223. Reporting of outcomes: diagnostic intervention (3) 27/10/11 © The University of Sheffield
    224. 224. Reporting of outcomes: diagnostic intervention (4) <ul><li>NILTs produce results on a continuous scale, but liver biopsy results are expressed in terms of ordinal scoring systems, so when NILTs are compared with liver biopsy the results are also generally presented as ordinal data (fibrosis stages) </li></ul><ul><ul><li>Most of the studies in the pilot project identified the threshold values for those stages from the ROC curve, rather than validating prospectively identified values </li></ul></ul><ul><li>Only 1/11 studies in the pilot project which compared a NILT with liver biopsy published a reasonably clear tabulation of test accuracy </li></ul>27/10/11 © The University of Sheffield
    225. 225. Study design <ul><li>Therapeutic intervention: </li></ul><ul><li>Only RCTs included </li></ul><ul><li>Diagnostic intervention: </li></ul><ul><li>No relevant RCTs identified: </li></ul><ul><ul><li>Where RCTs of diagnostic test accuracy exist, they are generally underpowered to detect a difference between 2 tests </li></ul></ul><ul><li>15 cross-sectional studies, 2 of which were extended to form cohort studies looking at longer-term outcomes </li></ul><ul><li>Non-RCTs carry the risk of double-counting: often not clear whether different publications by the same research group include some of the same patients </li></ul>27/10/11 © The University of Sheffield
    226. 226. Meta-analysis (1) <ul><li>Therapeutic intervention: </li></ul><ul><li>Generally straightforward using Review Manager </li></ul><ul><li>In the strontium ranelate example, not possible because the relevant data for all 3 included studies were not published and could not be obtained from the original investigators </li></ul><ul><li>Diagnostic intervention: </li></ul><ul><li>Complex, only partially possible in Rev Man </li></ul><ul><li>Data often not published in suitable format </li></ul>27/10/11 © The University of Sheffield
    227. 227. Meta-analysis (2) <ul><li>Not appropriate if studies have heterogeneous populations, and in diagnostic studies that heterogeneity includes different prevalences of the condition of interest </li></ul><ul><ul><li>How similar do populations need to be before the data can be combined? </li></ul></ul><ul><li>Requires special techniques if studies use different diagnostic thresholds to define a positive result </li></ul><ul><li>Is it generally better to use the results of the best quality study which has the greatest clinical relevance to the study question? </li></ul>27/10/11 © The University of Sheffield
    228. 228. Systematic reviews of relevant data Myfanwy Lloyd Jones Senior Research Fellow ScHARR, University of Sheffield Email: m.lloydjones@sheffield.ac.uk
    229. 229. The aim of the assessment <ul><li>To answer the research question: Will using the specified non-invasive liver assessment tools in patients with suspected alcohol-related liver fibrosis who might otherwise be candidates for biopsy or referral to specialist care reduce the number of referrals or biopsies and improve the health outcomes and quality of life of those patients? </li></ul>
    230. 230. The specified tests <ul><li>Three patented blood tests: </li></ul><ul><ul><li>The Enhanced Liver Fibrosis (ELF) test </li></ul></ul><ul><ul><li>FibroTest </li></ul></ul><ul><ul><li>FibroMAX </li></ul></ul><ul><li>Transient elastography </li></ul><ul><ul><ul><li>FibroScan </li></ul></ul></ul><ul><li>Test results are affected by alcohol consumption </li></ul>
    231. 231. Outcomes of interest: <ul><li>Diagnostic test accuracy (including numbers of test failures) </li></ul><ul><li>Number of patients tested in primary care requiring referral to secondary care for further investigation or treatment </li></ul><ul><li>Number of patients requiring liver biopsy </li></ul><ul><li>Number of patients giving up alcohol, or significantly reducing alcohol consumption, because of test result </li></ul><ul><li>Long-term patient outcomes (disease progression, complications related to liver disease, need for liver transplantation, mortality) </li></ul><ul><li>Adverse effects of testing </li></ul><ul><li>Health-related quality of life </li></ul><ul><li>Cost-effectiveness </li></ul>
    232. 232. Reference standard tests <ul><li>Liver biopsy </li></ul><ul><li>Also used in some studies </li></ul><ul><ul><li>Hepatic venous pressure gradient (HVPG) measurement to identify portal hypertension </li></ul></ul><ul><ul><li>Upper intestinal endoscopy to identify oesophageal varices </li></ul></ul>
    233. 233. Systematic review of clinical effectiveness <ul><li>Population: patients with suspected alcohol-related liver fibrosis </li></ul><ul><li>Intervention: any of the 4 specified tests </li></ul><ul><li>Comparators: </li></ul><ul><ul><li>Primary: liver biopsy </li></ul></ul><ul><ul><li>Secondary: HVPG measurement; upper endoscopy </li></ul></ul><ul><li>Outcomes: previously listed </li></ul><ul><li>Study design: cohort or cross-sectional studies (prospective or retrospective) </li></ul>
    234. 234. Included studies: ELF test <ul><li>Rosenberg 2004: patients with chronic liver disease (subgroup with ALD); test accuracy vs liver biopsy </li></ul><ul><ul><li>Parkes in press: follows cohort of English patients from Rosenberg study; survival (median follow-up 6.86 years) </li></ul></ul>
    235. 235. Included studies: FibroTest (1) <ul><ul><li>2 studies specifically in patients with known or suspected alcohol-related liver disease, both of test accuracy vs liver biopsy: </li></ul></ul><ul><ul><ul><li>Naveau 2005 </li></ul></ul></ul><ul><ul><ul><li>Nguyen-Khac 2008 </li></ul></ul></ul><ul><ul><ul><li>Naveau 2009: 5 and 10 year survival of patients included in Naveau 2005 </li></ul></ul></ul>
    236. 236. Included studies: FibroTest (2) <ul><li>3 studies in mixed aetiology liver disease: </li></ul><ul><ul><li>1 study in patients with chronic liver disease: </li></ul></ul><ul><ul><ul><li>- Thabut 2003: test accuracy vs endoscopy </li></ul></ul></ul><ul><ul><li>1 study in patients undergoing transjugular liver biopsy for clinical reasons: </li></ul></ul><ul><ul><ul><li>- Thabut 2007a: test accuracy vs HPVG </li></ul></ul></ul><ul><ul><li>1 study in patients with severe cirrhosis: </li></ul></ul><ul><ul><ul><li>- Thabut 2007b: survival at 2 and 6 months </li></ul></ul></ul>
    237. 237. Included studies: FibroMAX <ul><li>No relevant studies identified </li></ul>
    238. 238. Included studies: FibroScan (1) <ul><li>6 studies specifically in patients with known or suspected alcohol–related liver disease, all looking at test accuracy vs liver biopsy: </li></ul><ul><li>4 biopsied all patients </li></ul><ul><ul><li>Kim 2009, Mueller 2010, Nahon 2008, Nguyen-Khac 2008 </li></ul></ul><ul><li>2 biopsied subset only: </li></ul><ul><ul><li>Janssens 2010: biopsy only in those with FS score > 9.6, indicating severe fibrosis ( > F3) (this study also looked at test accuracy vs HPVG) </li></ul></ul><ul><ul><li>Melin 2005: biopsy only in patients with FS score >13 kPa (chosen as threshold for cirrhosis in patients with hepatitis C) </li></ul></ul>
    239. 239. Included studies: FibroScan (2) <ul><li>3 studies in mixed aetiology liver disease: </li></ul><ul><ul><li>1 study in patients undergoing transjugular liver biopsy for clinical reasons: </li></ul></ul><ul><ul><ul><li>Bureau 2008: test accuracy vs HVPG </li></ul></ul></ul><ul><ul><li>2 studies in patients with cirrhosis: </li></ul></ul><ul><ul><ul><li>Lemoine 2008: test accuracy vs HVPG </li></ul></ul></ul><ul><ul><ul><li>Nguyen-Khac 2009: test accuracy vs endoscopy </li></ul></ul></ul>
    240. 240. AUROCs from key studies: test vs liver biopsy Test Degree of fibrosis Study AUROC (95% CI) ELF ‘ Moderate/severe’ Rosenberg 0.94 (0.84-1.00) FibroTest F2-F4 Naveau 0.83 (0.81-0.87) Nguyen-Khac 0.79 (0.69-0.90) Cirrhosis (F4) Naveau 0.95 (0.94-0.96) Nguyen-Khac 0.84 (0.72-0.97) FibroScan Severe fibrosis (F3-F4) Kim 0.98 (0.94-1.02) Mueller 0.91 + 0.03 Nahon 0.94 (90-0.97) Nguyen-Khac 0.90 (0.82-0.97) Cirrhosis Kim 0.97 (0.93-1.01) Mueller 0.92 (0.87-0.97) Nahon 0.87 (0.81-0.93) Nguyen-Khac 0.94 (0.87-0.98)
    241. 241. Sensitivity and specificity: ELF Test (subgroup with ALD) Degree of fibrosis Study Threshold score Sensitivity Specificity ‘ Moderate/severe’ Rosenberg 0.087 100% 16.7% 0.431 93.3% 100%
    242. 242. Sensitivity and specificity: FibroTest (all patients ALD) Degree of fibrosis Study Threshold score Sensitivity Specificity Moderate-severe (F2-F4) Naveau 0.30 84% 66% 0.70 55% 93% Cirrhosis (F4) Naveau 0.30 100% 50% 0.70 91% 87%
    243. 243. Sensitivity and specificity: FibroScan (all patients ALD, all biopsied) Degree of fibrosis Study Threshold score Sensitivity Specificity Moderate-severe (F2-F4) Nguyen-Khac 7.8 kPa 80% 90.5% Severe (F3-F4) Mueller 8.0 kPa 91% 75% Nguyen-Khac 11 kPa 86.7% 80.5% Nahon 11.6 kPa 87% 89% Cirrhosis (F4) Mueller 11.5 kPa 100% 77% 12.5 kPa 96% 80% Nguyen-Khac 12.8 kPa 100% 75.4% 19.5 kPa 85.7% 84.2% Nahon 22.7 kPa 84% 83% Kim 28.5 kPa 90% 87%
    244. 244. Sensitivity and specificity: FibroScan (all patients ALD, only subset biopsied) Degree of fibrosis Study Threshold score Sensitivity Specificity Severe (F3-F4) Janssens 13.9 kPa 81% 59% 15.8 kPa 75% 70% 16.5 kPa 72% 70% 17.0 kPa 72% 76.5% 17.3 kPa 69% 76.5% Cirrhosis (F4) Janssens 19.6 kPa 80% 76% 21.1 kPa 75% 80% 23.5 kPa 65% 83%
    245. 245. FibroScan: exclusion of patients with laboratory signs of ASH Degree of fibrosis No of patients AUROC Threshold score Sensitivity Specificity F4 101 0.921 11.5 100% 77% 12.5 96% 80% F4 without GOT >100 U/L 86 0.944 11.5 100% 84% 12.5 95% 90% F3-F4 101 0.914 8.0 91% 75% F3-F4 without GOT >100 U/L 80 0.922 8.0 87% 87%
    246. 246. Evidence re outcomes of interest (1) <ul><li>Diagnostic test accuracy: NILTs appear to have reasonable accuracy, but the evidence is not drawn from full spectrum of patients </li></ul><ul><li>Number of patients tested in primary care requiring referral to secondary care: no data </li></ul><ul><li>Number of patients requiring liver biopsy following NILT: no evidence of what this would be in clinical practice rather than study setting </li></ul>
    247. 247. Evidence re outcomes of interest (2) <ul><li>Numbers of patients giving up or significantly reducing alcohol consumption following test result: only reported in one study, and not subdivided by test results. </li></ul><ul><li>Long-term patient outcomes: ELF test and FibroTest may have some prognostic value </li></ul><ul><li>Adverse effects of NILTs: no specific AEs, but tests which use a blood sample have AEs associated with venepuncture </li></ul>
    248. 248. Liver biopsy: an imperfect reference standard <ul><li>Diagnostic studies assume that the reference standard has 100% sensitivity and specificity </li></ul><ul><li>Not true of liver biopsy: </li></ul><ul><ul><li>Sampling error (may affect >30% of samples) </li></ul></ul><ul><ul><li>‘ Significant’ inter- and intra-observer variation in interpretation of samples </li></ul></ul><ul><li>Some studies try to determine whether, in discordant cases, the index test or the biopsy is more likely to be correct </li></ul><ul><li>What if the index test and the biopsy are concordant but both wrong? </li></ul>
    249. 249. Liver biopsy: ethical aspects affect study design <ul><li>Adverse events: </li></ul><ul><ul><li>Minor adverse events: 9.39% </li></ul></ul><ul><ul><li>Severe adverse events (including death): 0.86% </li></ul></ul><ul><ul><li>Death: 0.08% </li></ul></ul><ul><li>Consequently, study populations not representative of full range of people with suspected ALD: </li></ul><ul><ul><li>Either whole study population is unrepresentative because of disease severity (eg already scheduled for biopsy) </li></ul></ul><ul><ul><li>Or whole population is more representative, but biopsy is only performed in subset with NILT result suggesting more severe disease </li></ul></ul>
    250. 250. How much homogeneity is required for meta-analysis? <ul><li>The studies of FibroTest and FibroScan included in this review are heterogeneous in terms of: </li></ul><ul><ul><li>Prevalence of the condition of interest </li></ul></ul><ul><ul><li>Diagnostic threshold for identifying that condition </li></ul></ul><ul><li>Because of this heterogeneity, it seems inappropriate to combine their results using meta-analysis </li></ul>
    251. 251. Health Economics and Outcomes Research 27/10/11 © The University of Sheffield
    252. 252. Areas of Particular Strength <ul><li>Quality of life and outcomes measurement, wellbeing and equity </li></ul><ul><li>Primary economic evaluation in clinical studies, costing studies and service evaluation </li></ul><ul><li>Statistical methods in health economics </li></ul>
    253. 253. Research centre <ul><li>Centre for Well-being in Public Policy (CWiPP) </li></ul><ul><li>The goals of the centre are to consider as to how people’s health and wellbeing can be defined, measured and improved in ways that help policy-makers determine the best use of scarce resources, and to investigate the determinants of well-being insofar as these are relevant to policy formulation </li></ul>27/10/11 © The University of Sheffield
    254. 254. For example: <ul><li>HEDS in collaboration of the Department of Economics, University of Sheffield run a number of joint research projects in the area of health and well-being, including the Independent Review of the Effects of Alcohol Pricing and Promotion project funded by the Department of Health </li></ul>27/10/11 © The University of Sheffield
    255. 255. Examples of health outcome studies conducted in ScHARR 27/10/11 © The University of Sheffield
    256. 256. Developing and testing condition-specific preference-based measures: Lessons learnt and policy implications John Brazier, Donna Rowen, Ifigeneia Mavranezouli, Aki Tsuchiya , Tracey Young, Yaling Yang, Michael Barkham
    257. 257. Acknowledgements <ul><li>COSMeQ team: John Brazier 1 , Aki Tsuchiya 1 , Ifigeneia Mavrazenouli 1,2 , Tracey Young 1 , Yaling Yang 3 , Rachel Ibbotson 4 , Michael Barkham 1 </li></ul><ul><ul><li>1 University of Sheffield </li></ul></ul><ul><ul><li>2 University College London </li></ul></ul><ul><ul><li>3 Brunel University </li></ul></ul><ul><ul><li>4 Sheffield Hallam University </li></ul></ul><ul><li>COSMeQ project, MRC-NIHR Methodology Research Programme project number 06/97/04 </li></ul>
    258. 258. Economic evaluation <ul><li>Economic evaluation using cost utility analysis (CUA) increasingly used to inform resource allocation decisions </li></ul><ul><li>CUA measures health outcomes using the Quality Adjusted Life Year (QALY) </li></ul><ul><
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