introduction to the design of diagnostic criteria Joop P van de Merwe Dept. of Immunology & Internal Medicine Erasmus MC Rotterdam ESSIC Meeting Baden June 2005

2 * Fries JF et al. Arthritis Rheum 1994;37: Types and purposes of criteria* TypePurpose Classification criteriaTo separate those with a specific disease from those without the disease Subclassification criteriaTo separate diseases or subsets within a disease cluster Prognostic criteriaTo separate subjects with good or potentially favorable outcomes from those with bad outcomes Status indexesTo assess present disease activity or accumulated damage from the disease Activity indexes (implies reversibility) To estimate current disease activity status Damage indexes (implies irreversibility) To estimate accumulated damage from the disease Outcome criteriaTo measure the overall impact of a disease and to serve as dependent variables for clinical studies

3 * Fries JF et al. Arthritis Rheum 1994;37: (modified) CLASSIFICATION CRITERIA* Classification criteria separate patients with the disease from the general population and from patients with potentially confusable conditions Persons with Diseases Persons with Confusable Diseases All Persons Persons with Target Disease

4 overlapping features example: systemic autoimmune diseases the problem

5 systemic autoimmune diseases (1) rheumatoïd arthritis Sjögren's syndrome systemic lupus erythematosus (SLE) antiphospholipid syndrome (APS) mixed connective tissue disease (MCTD) systemic sclerosis (scleroderma, CREST-syndrome) polymyositis / dermatomyositis relapsing polychondritis examples

6 possible features clinical arthritis / arthralgia vasculitis fever Raynaud's phenomenon fatigue various renal diseases laboratory increased ESR, CRP anaemia leukopenia rheumatoid factor ANA trombopenia systemic autoimmune diseases (2) not specific for one single disease not specific for one single disease

7 possible accompaning organspecific autoimmune diseases atrophic gastritis - pernicious anaemia Hashimoto's disease keratoconjunctivitis sicca lymfocytic interstitial pneumonitis myositis pericarditis, pleuritis peripheral neuropathy uveitis (iritis, iridocyclitis) scleritis interstitial cystitis systemic autoimmune diseases (3) no combination is specific for one single disease

8 how do you recognize them ? systemic autoimmune diseases (4)

9 people how do you recognize them ? each person has a face

10 people how do you recognize them ? none of the parts of the face is unique, but the combination is

11 people how do you recognize them ? none of the parts of the code is unique, but the combination is

12 each autoimmune disease has its own "face" how do you recognize them ? systemic autoimmune diseases (4)

13 systemic autoimmune diseases (5) characteristic feature specific way it affects the lacrimal and salivary glands specific way it affects the joints specific way it affects the skin combination of clinical symptoms and anti-RNP specific way it affects the skin combination of symptoms disease Sjögren's syndrome rheumatoid arthritis systemic lupus erythematosus subacute cutaneous lupus erythematosus mixed connective tissue disease (MCTD) systemic sclerosis (scleroderma) CREST syndrome characteristic features

14 characteristic features what are the characteristic features of IC ? what is the consequence of the PBS/IC concept ? ICS definition of PBS/IC PBS: "suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and nighttime frequency in the absence of infection or other pathology" IC: above with "typical cystoscopic and histological features"

15 characteristic features what are the "typical cystoscopic and histological features of IC" ? what has happened to urgency ? ICS definition of IC may be written as: suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and nighttime frequency with typical cystoscopic and histological features in the absence of infection or other pathology what are the characteristic features of IC ?

16 characteristic features what are the "typical cystoscopic and histological features of IC" ?  Cysto features: Hunner's ulcer or low capacity  epithelial denudation, submucosal inflammation, granulation tissue, edema, congestion, haemorrhage; detrusor fibrosis (and myopathy)  increased mast cell number & activation and neuronal staining from: Hanno P, Burks D. Painful bladder syndrome / interstitial cystitis. Course 93 IC, AUA 2005 Annual Meeting, San Antonio, TX, May 21-26,2005

17 characteristic features  Cysto features: Hunner's ulcer or low capacity  epithelial denudation, submucosal inflammation, granulation tissue, edema, congestion, haemorrhage; detrusor fibrosis (and myopathy)  increased mast cell number & activation and neuronal staining from: Hanno P, Burks D. Painful bladder syndrome / interstitial cystitis. Course 93 IC, AUA 2005 Annual Meeting, San Antonio, TX, May 21-26,2005 does this matter as long as the combination is unique ? but these are not unique for IC !

18 PBS / IC concept PBS IC PBS or IC IC has "typical" cystoscopic and histological features of IC in addition to suprapubic pain and frequency

19 gold standard gold standard = diagnosis by experts why ? - the diagnosis by experts is the best standard we have as long as the cause of a disease is unknown advantage - non-experts can diagnose a disease as if they were experts (skill level) - diagnoses are made on the same basis by experts and non-experts (uniformity) - rules are based on information from many experts (acceptance and support)

20 Arthritis Rheum 1990;33: classification methods (1) classification tree the classification tree is constructed by repeated splits of groups into 2 descendant subgroups

21 Arthritis Rheum 1990;33: classification tree pro items may be polychotomous or continuous nonparametric: no reference to a model for the relationship between classification items and disease status high information content - classified groups of subjects in studies may be referred to the exact classifying subgroup of the tree

22 "number of criteria present rule" Ann Rheum Dis 2002;61:554-8

23 Arthritis Rheum 1990;33: classification methods (2) con simple definitions (+/-): - all items are given equal weight - all items must be dichotomous (+/-)  little insight into the characteristics of a classified patient group pro simple definitions (+/-): easy application "number of items present rule"

24 1. collect what information (symptoms and signs*) is used by experts to diagnose IC and differentiate IC from confusable diseases for both men and women suggested approach in a multicentre study * requires definitions and decisions on data format

25 2. collection of data from patients with IC and patients with confusable diseases to define classification criteria for IC (training phase) sensitivity specificity suggested approach in a multicentre study calculate an optimal combination on the basis of how many false negative and false positive diagnoses we accept

26 3.validation with new patient groups suggested approach in a multicentre study the same database can be used to create number of items present rule for clinical diagnoses and a classification tree for scientific studies

27 data may be - continuous avoid entry of cut-off points for continuous data but have the statistical analysis decide - categorical data format

28 tests to be evaluated for their diagnostic value should be done in all patients with IC and confusable diseases 1. antiproliferative factor to be evaluated ….

29 1. decision on broad definition of IC PBS + "typical" cystoscopy and/or histology 2. select diseases with which IC can be confused (confusable diseases, CD) list to be discussed this morning 3. what information is needed to distinguish IC from CD: follows from (2) but needs discussion and decision 4. decision on what percentage of false negative and false positive diagnoses we accept summary & conclusions (1)

30 5. decision on gold standard for the diagnosis IC diagnosis by experts 6. decision on methods of classification classification tree and "number of items present rule" 7.decision to perform a small pilot to test procedures 8.decision on tests to be evaluated APF test summary & conclusions (2)

31 consensus on IC