1. Chronic eye disease: Role and Overview of Screening Richard Wormald London School of Hygiene and Tropical Medicine

2. acknowledgements Richard Wormald is funded in the UK by financial support from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this presentation are those of the author and not necessarily those of the Department of Health.” No commercial conflicts of interest or financial gain exist to the presenter in the context and contents of this talk

3. In this talk What is screening? What is its relevance to chronic eye disease? Children ROP, Amblyopia, refractive error etc Older people vision impairment Prevention of blindness Diabetic retinopathy Glaucoma Open angle glaucoma Angle closure Evidence for effectiveness Lead time bias Length bias Overdiagnosis and disease mongering

4. Confusion due to loose use of poorly defined terms Screening Active identification and enumeration, invitation and testing an entire and defined population at risk Case finding Any method for finding people who may be affected by disease before they present to health services Indiscriminate testing of participants at health fairs and exhibitions etc, is often more about marketing a product than a public health intervention Opportunistic surveillance Testing people in a clinical setting when they attend for other concerns – such as testing for glaucoma in a person needing reading glasses Screening tests may be used in all of the above as well as in population sample surveys and trials

5. screening Is a specific public health intervention intended to reduce the burden (morbidity/mortality/disability, economic impact) of a specific disease or condition in a defined population (at risk) It is a totally different model of health care delivery to the traditional one where the patient actively seeks help In screening, we impose a health intervention on a population so evidence of safety and effectiveness is even more important Implicit is that early detection in a presymptomatic phase of the condition has a strong beneficial influence on outcome Only relevant for chronic conditons – hence wet ARMD not suitable Screening is harmful: false negatives, false positives and wastage of scarce resources Ultimately, the only way to determine effectiveness of screening is the impact on the burden of disease in the population

6. Measuring the impact of screening with reliable outcomes What is the intended effect? For Breast Cancer reduced mortality from the disease For glaucoma, diabetic retinopathy Prevention of blindness Squint and amblyopia? Number of cases detected is a process measure not an outcome Measuring the effect can only be achieved by.. Randomised controlled trials of screening Economic modelling

7. UK National screening committee criteria Based on 10 commandments of Wilson and Jungner WHO 1968 http://www.screening.nhs.uk/criteria#fileid9287 The condition – 1..4 The test – 5…9 The treatment – 10….12 The programme – 13….22

8. The condition 1. The condition should be an important health problem 2. The epidemiology and natural history of the condition, including development from latent to declared disease, should be adequately understood and there should be a detectable risk factor, disease marker, latent period or early symptomatic stage. 3. All the cost-effective primary prevention interventions should have been implemented as far as practicable. 4. If the carriers of a mutation are identified as a result of screening the natural history of people with this status should be understood, including the psychological implications.

9. The test 5. There should be a simple, safe, precise and validated screening test. 6. The distribution of test values in the target population should be known and a suitable cut-off level defined and agreed. 7. The test should be acceptable to the population. 8. There should be an agreed policy on the further diagnostic investigation of individuals with a positive test result and on the choices available to those individuals. 9. If the test is for mutations the criteria used to select the subset of mutations to be covered by screening, if all possible mutations are not being tested, should be clearly set out.

10. The treatment 10. There should be an effective treatment or intervention for patients identified through early detection, with evidence of early treatment leading to better outcomes than late treatment. 11. There should be agreed evidence based policies covering which individuals should be offered treatment and the appropriate treatment to be offered. 12. Clinical management of the condition and patient outcomes should be optimised in all health care providers prior to participation in a screening programme.

11. The screening programme 13. There should be evidence from high quality Randomised Controlled Trials that the screening programme is effective in reducing mortality or morbidity. Where screening is aimed solely at providing information to allow the person being screened to make an “informed choice” (eg. Down’s syndrome, cystic fibrosis carrier screening), there must be evidence from high quality trials that the test accurately measures risk. The information that is provided about the test and its outcome must be of value and readily understood by the individual being screened. 14. There should be evidence that the complete screening programme (test, diagnostic procedures, treatment/ intervention) is clinically, socially and ethically acceptable to health professionals and the public. 15. The benefit from the screening programme should outweigh the physical and psychological harm (caused by the test, diagnostic procedures and treatment). 16. The opportunity cost of the screening programme (including testing, diagnosis and treatment, administration, training and quality assurance) should be economically balanced in relation to expenditure on medical care as a whole (ie. value for money). Assessment against this criteria should have regard to evidence from cost benefit and/or cost effectiveness analyses and have regard to the effective use of available resource.

12. The screening programme 17. All other options for managing the condition should have been considered (eg. improving treatment, providing other services), to ensure that no more cost effective intervention could be introduced or current interventions increased within the resources available. 18. There should be a plan for managing and monitoring the screening programme and an agreed set of quality assurance standards. 19. Adequate staffing and facilities for testing, diagnosis, treatment and programme management should be available prior to the commencement of the screening programme. 20. Evidence-based information, explaining the consequences of testing, investigation and treatment, should be made available to potential participants to assist them in making an informed choice. 21. Public pressure for widening the eligibility criteria for reducing the screening interval, and for increasing the sensitivity of the testing process, should be anticipated. Decisions about these parameters should be scientifically justifiable to the public. 22. If screening is for a mutation the programme should be acceptable to people identified as carriers and to other family members.

13. Screening for vision impairment in the elderly

15. Systematic review and economic analysis Exhaustive review of the literature on prevalence, accuracy of screening tests and economic modeling of glaucoma screening Large team of reviewers, clinicians and economists working over 18 months Less than £200k

16. Results – bottom line only Most screening tests had an estimated specificity of 85% or higher None were clearly superior and good quality evidence was scarce Prevalence would have to be 3-4% in 40 year olds with a screening interval of 10 years to approach cost effectiveness Selective screening of higher risk groups with a higher risk might be worthwhile although this would cover only 6% of the population Screening using a test with initial automated classification followed by assessment by specialised optometrist for test positives was more cost-effective than initial assessment by optometrists

18. More bottom line The cost-effectiveness of the screening programme was highly sensitive to the perspective on costs (NHS or societal). In the base-case model, the NHS costs of visual impairment were estimated as £669. If annual societal costs were £8800, then screening might be considered cost-effective for a 40-year-old cohort with 1% OAG prevalence assuming a willingness to pay of £30,000 per quality-adjusted life-year. Of lesser importance were changes to estimates of attendance for sight tests, incidence of OAG, rate of progression and utility values for each stage of OAG severity.

19. More bottom line Cost-effectiveness was not particularly sensitive to the accuracy of screening tests within the ranges observed. However, a highly specific test is required to reduce large numbers of false-positive referrals. The findings that population screening is unlikely to be cost-effective are based on an economic model whose parameter estimates have considerable uncertainty. In particular, if rate of progression and/or costs of visual impairment are higher than estimated then screening could be cost-effective.

20. Screening tests Vs diagnostic tests What’s the difference? Hierarchy of tests “gold” or reference standard, Maybe composite – requiring more than one test or outcome Maybe longitudinal – does early detection lead to better later outcome? Diagnostic test Maybe one component of the reference standard Screening test Positive result increases the probability of a diagnosis justifying further investigation – colon cancer, prostate cancer, negative result rules it out (almost)

21. Validity of diagnostic tests SeNsitivity and sPecificity N for false negatives, P for false positives 1- N, Sensitivity = proportion of true positives of all positive cases 1 – P, = proportion of true negatives out of all negative cases +PPV – predictive value of a positive test, probability of a positive test being a true positive -PPV – predictive value of a negative test, probability of negative test being a true negative

22. disease (or truth) always on top Disease positiveDisease negative Test positiveTrue positiveFalse positive+PPV Test negativeFalse negativeTrue negative-PPV sensitivityspecificityPrevalence

23. Worked example - POAG Disease positiveDisease negative Test positive1898116 (18.4%) Test negative2882884 (0.2%) 20 (90%)980 (90%)1000 (2%)

24. Other important process measures Coverage The proportion of the target population tested in one screening round A screening test with 100% sensitivity will be much less sensitive in reality if coverage is only 50% especially when responders are the worried well and non-responders, the careless sick

25. yield How many tested to reveal one true positive 1000/18 = 56 Economics Cost per case detected (Cost per test x 1000) / 56 Cost of false positive evaluation Against cost of not detecting or preventing morbidity/mortality Opportunity cost

26. Other statistics ROC (receiver operating characteristic) curve Plot sensitivity by 1 – specificity for different test cut-off values, calculate the area under the curve Likelihood ratio statistics Diagnostic odds ratio Bayesian methods

27. ROC curves

28. Positive predictive value and prevalence Disease positive Disease negative total Test positive Test negative total

29. Positive predictive value and prevalence Disease positive Disease negative total Test positive Test negative total201000

30. Positive predictive value and prevalence Disease positive Disease negative total Test positive 18 Test negative 2 total201000

31. Positive predictive value and prevalence Disease positive Disease negative total Test positive 18 Test negative 2 total209801000

32. Positive predictive value and prevalence Disease positive Disease negative total Test positive 1898116 Test negative 2882884 total209801000

33. Positive predictive value and prevalence 90/90/2 PPV = 18/116 = 15.5% Between one in six or seven people who screen positive have the disease

34. Positive predictive value and prevalence – 99% sensitivity Disease positive Disease negative total Test positive 1989801160 Test negative 288208840 total200980010,000

35. Positive predictive value and prevalence 99/90/2 PPV = 198/1160 = 0.17 Between one in five or six people who screen positive have the disease

36. Positive predictive value and prevalence – 99% specificity Disease positive Disease negative total Test positive 18098278 Test negative 2097029722 total200980010000

37. Positive predictive value and prevalence 90/99/2 PPV = 180/278 = 0.65% One in every one or two people with positive test have the disease

38. Positive predictive value and prevalence – 20% prevalence Disease positive Disease negative total Test positive 18080260 Test negative 20720740 total2008001000

39. Positive predictive value and prevalence 90/90/20 PPV = 180/260 = 0.69% One in every one or less than two people who test positive have the disease

40. Where and when used The validity of a screening test can only be evaluated in the setting in which it is to be used on a sample of the population to be screened. The ability of the test to discriminate between disease and non-disease states will depend on the prevalence of the disease in the sample population and the case mix Discriminating between known obvious cases and known obvious normals will not reflect its performance in the real world.

41. Angle closure Glaucoma Definable at risk population by a simple noninvasive test? Single quick safe and effective intervention? Potential long term benefit But also harms? Is lens extraction better than PI? We await ZAP and EAGLE

42. Lead time and length bias Lead time bias Detecting a disease earlier in it course may create the illusion of longer survival where in fact all that has occurred is a prolonged awareness (and anxiety) due to the illness Length bias Disease with slow natural history and more benign cause more likely to be detected by interval screening than rapidly progressive aggressive disease

43. Lead time bias AFMC Primer on population health

44. Length bias AFMC Primer on Population Health

45. Pros and Cons Prevention better than cure Early diagnosis is key to good outcome Health awareness and surveillance Overdiagnosis and overtreatment Disease mongering The worried well – half the population are sick

47. Preventing overdiagnosis Clear case definition setting the threshold for disease status where 1: the diagnosis is not in doubt 2: intervention has a clear margin of benefit over harm 3: and is cost-effective (including opportunity cost)

48. IN ANCIENT CHINA, THE DOCTOR WAS PAID ONLY WHEN THE PATIENT WAS WELL? Is it true?