DIAGNOSTIC GUIDELINES A Service for Clinicians and Patients

DIAGNOSTIC GUIDELINESDIAGNOSTIC GUIDELINESA Service for Clinicians and A Service for Clinicians and

PatientsPatients

Mathias M. MüllerMathias M. Müller

LABORATORY MEDICINELABORATORY MEDICINE

OBJECTIVES• Prevention - Risk assessment• Diagnosis of conditions and diseases• Monitoring of therapy - Follow-up of patients

METHODS• Chemical, physical, biochemical,

immunological, molecular biological• Measurement procedures accurate and

precise

CLINICIANS, PATIENTS

Risk assessmentDiagnosis of diseasesMonitoring of treatmentPrognosis assessment

CLINICIANS, PATIENTS

Risk assessmentDiagnosis of diseasesMonitoring of treatmentPrognosis assessment

LABORATORIANS

Analytical proceduresTechnologies, automationStandardisationQuality assurance Quality managementLaboratory organisation

workload, workflowCertification, accreditation

LABORATORIANS

Analytical proceduresTechnologies, automationStandardisationQuality assurance Quality managementLaboratory organisation

workload, workflowCertification, accreditation

INTERESTS and EXPECTATIONSINTERESTS and EXPECTATIONS

No mutual understandingNo confidence in service

When communicating with clinicians, one must think like a clinicianR. H. Christenson 2007

INFANTINFANT

ADULTADULT

ELDERLYELDERLY

wel

lnes

s and

fitne

ss

acut

e an

d

chro

nic

dise

ases

inborn errorsgenetic

disposition

HIERARCHY OF CLINICAL DECISIONSHIERARCHY OF CLINICAL DECISIONS

Decision

Cost effectiveness

Organizational impact

Clinical impactDiagnostic

TherapeuticHealth outcome

Diagnostic performance

Technical performance

C. Price 2000

To use a test ?

GUIDELINESGUIDELINES systematic developed statements to assist practitioner systematic developed statements to assist practitioner

(clinician) and patient decisions about appropriate healthcare (clinician) and patient decisions about appropriate healthcare decisions for specific clinical circumstancesdecisions for specific clinical circumstances

Field and Lohr 1990Field and Lohr 1990

Dissemination of best practice Standardization of medical decisions

• Increased transparency• Better information of patients

Improvement of patient outcome Improve the transperancy and accountability Basis in the training of professionals Improvement in cost-effectiveness

QUESTIONS TO BE ASKEDQUESTIONS TO BE ASKED

CARO QUESTIONS

C: Case What are the patient characteristics, conditions, symptoms, demographics ?

A: Assay Which procedure or strategy is considered ?

R: Reference What is the standard procedure, the comparator ?

O: Outcome What is the interest, the diagnostic validity ? Sensitivity, specificity, predictive values, prognosis ?

R. H. CHRISTENSON 2007

GUIDELINE DEVELOPMENTGUIDELINE DEVELOPMENTTOPIC SELECTION

TARGET GROUP

MULTIDISCIPLINARY DEVELOPMENT TEAM

SCOPE OF GUIDELINE The diagnostic question

SYSTEMATIC REVIEW of LITERATURECritical Appraisal Skill Programme (CASP/NHS)

Appraisal of Guidelines Research and Evaluation (AGREE)

WRITING GUIDLINE RECOMMENDATIONSSynthesis of evidence

Consultation, consensus, peer review

GUIDELINEPresentation, dissemination, monitoring

GUIDELINE RESOURCES

US National Guideline Clearing House: http://www.guideline.gov

Finnish Medical Society:

http.//www.udate-software.com/publications/EBMG/default.html

National Academy of Clinical Biochemistry

http://www.nacb.org Clinical Guidelines from other disciplines

QUALITY of REFERENCESIa Metaanalysis of randomised trials or systematic reviews

based on consistent level Ib studies.

Ib Double blind randomised controlled clinical/diagnostic trial or outcome study of good quality.

II Diagnostic trials or outcome studies of medium quality. Insufficient number of patients, case studies.

III Non-comparative studies. Descriptive studies - case reports.

IV Statements of committees, expert opinions - reviews.

Oosterhuis W. P. et al 2004

STARD (Standards for reporting diagnostic accuracy) - a checklist

Introduction Diagnostic accuracy between tests or across patient groups

Probands Demographic description, inclusion and exclusion criteria, symptoms, data collection criteria.

Study design Time frame, number and group of probands, time of measurements, treatment of probands

Reference standard

Description of standard and rationale for comparison.

Test method Technical, analytical specifications (linearity, cut-off levels, uncertainty, bias, etc)

Statistical methods

Methods for reporting diagnostic validities, comparisons between groups, test reproducibility

Results Cross tabulaton of results (reference, test), analytical and diagnostic acuracy between groups of probands, ROC-curves, Box-Whiskers plot.

Conclusion Clinical application P. M. Bossuyt et al. 2003

THE DIAGNOSTIC PROCESS

PATIENT CAREPATIENT CARE

PREANALYTICS•Diagnostic strategy•Test selection/request•Patient factors•Sample collection

PREANALYTICS•Diagnostic strategy•Test selection/request•Patient factors•Sample collection

POSTANALYTICS•Laboratory report•Interpretation •Effect on patient•Clinical consultation

POSTANALYTICS•Laboratory report•Interpretation •Effect on patient•Clinical consultation

ANALYTICS•Sample preparation•Measurement•Result verification

ANALYTICS•Sample preparation•Measurement•Result verification

ESSENTIALS IN ESSENTIALS IN DIAGNOSTIC GUIDELINESDIAGNOSTIC GUIDELINES

PREANALYTICSPREANALYTICS• Prevalence of condition• Usefulness of a test

Diagnostic validities

• Diagnostic algorithm• Patient preparation

Timing / frequency of testing

Type / handling of specimen

• Biological variation

Oosterhuis W. P. et al 2004

ANALYTICS• Validated measurement procedure• Analytical characteristics

Detection limits, sensitivity, specificityInterferencesQuality assurance: bias, imprecision

• Laboratory requirementsTurnaround timeQualification, competenceCosts

ESSENTIALS IN ESSENTIALS IN DIAGNOSTIC GUIDELINESDIAGNOSTIC GUIDELINES

POSTANALYTICS• Reference ranges• Medical decision limits• Diagnostic validities

Sensitivity, specificityPredictive valuesLikelihood, ROC analysis

• Interpretation of resultsIntra-individual variationCritical limits

ESSENTIALS IN ESSENTIALS IN DIAGNOSTIC GUIDELINESDIAGNOSTIC GUIDELINES

DATABASE RESOURCES DATABASE RESOURCES for the Development / for the Development /

Appraisal of a GuidelineAppraisal of a Guideline AGREE: Appraisal of guidelines:

http://www.agreecollaboration.org AHRQ: Agency for healthcare research and quality:

http://www.ahrq.gov/ CASP/NHS: Critical appraisal skill programme of the national

health service: http://www.phru.nhs.uk/casp/casp.htm Cochrane: Methods working group on systematic review of

screening and diagnostic tests: www.cochrane.org/cochrane/sadtdoc1.htm

US National Guideline Clearing House: http://www.guideline.gov

IFCC C-EBLM: Committee on evidence based laboratory medicine database: www.ckchmb.nl/ifcc

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RATING of GUIDELINE RECOMMENDATIONS

A Supported by one Ia level systematic review or

at least 2 level Ib studies

B Supported by at least 2 level II studies

C Not supported by sufficient level I or II studies

D Advise of experts

Oosterhuis W. P. et al 2004

MI - Which Test ?MI - Which Test ?

2 4 6 8 12 18 24 32 48 72 144

Hours after Onset

0

100

200

300

400

CK-MB, Troponin T + I

0

500

1000

1500

2000

2500

Myoglobin, CK total

CK total Activity CK-MB Activity CK-MB Mass

Myoglobin Troponin T Troponin I

2 4 6 8 12 18 24 32 48 72 144

Hours after Onset

0

100

200

300

400

CK-MB, Troponin T + I

0

500

1000

1500

2000

2500

Myoglobin, CK total

CK total Activity CK-MB Activity CK-MB Mass

Myoglobin Troponin T Troponin I

I. A. KATZ 1998

Diagnostic ValidtiesDiagnostic Validties6 hours from onset of symptomes6 hours from onset of symptomes

CK ActivityMyoglobin

TnT TnI

CK-MB ActivityCK-MB Mass

0

20

40

60

80

100

120Sensitivity - %

CK ActivityMyoglobin

TnT TnI

CK-MB ActivityCK-MB Mass

0

20

40

60

80

100

120Sensitivity - %

CK ActivityMyoglobin

TnT TnI

CK-MB ActivityCK-MB Mass

0

20

40

60

80

100

120Specificity - %

CK ActivityMyoglobin

TnT TnI

CK-MB ActivityCK-MB Mass

0

20

40

60

80

100

120Specificity - %

J. ZIMMERMAN et al. CC 1999

MyoglobinCK Activity

TnT TnI

CK-MB ActivityCK-MB Mass

0

20

40

60

80

100

120

140Sensitivity - %

MyoglobinCK Activity

TnT TnI

CK-MB ActivityCK-MB Mass

0

20

40

60

80

100

120

140Sensitivity - %

MyoglobinCK Activity

TnT TnI

CK-MB ActivityCK-MB Mass

0

20

40

60

80

100

120Specificity - %

MyoglobinCK Activity

TnT TnI

CK-MB ActivityCK-MB Mass

0

20

40

60

80

100

120Specificity - %

Diagnostic ValidtiesDiagnostic Validties18 hours from onset of symptomes18 hours from onset of symptomes

J. ZIMMERMAN et al. CC 1999

Troponin I - Assay PerformanceTroponin I - Assay Performance

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F. S. APPLE et al. AmHJ 2002

ESC - ACC - MI DIAGNOSTIC ESC - ACC - MI DIAGNOSTIC GUIDELINE (Redefinition)GUIDELINE (Redefinition)

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Ventricular DysfunctionVentricular Dysfunction Natriuretic Peptides Natriuretic Peptides

proANP proANP 1-126 proBNP proBNP 1-108

-ANP -ANP 99-12699-126active t/2 2.5 min

NTproANP NTproANP 1-98

1-30 31-67 79-98

NTproBNP NTproBNP 1-76t/2 60-120 min

BNP BNP 77-108active t/2 20 min

Volume overloadVolume overloadMyocardial wall tensionMyocardial wall tension

Natriuresis - DiuresisNatriuresis - DiuresisVasodilatation Vasodilatation

Hammerer-Lercher et al. 2001 CCA

LVEF < 55% LVEF < 40 %

Natriuretic PeptidesNatriuretic PeptidesLeft Ventricular DysfunctionLeft Ventricular Dysfunction

NATRIURETIC PEPTIDESNATRIURETIC PEPTIDESin heart function assessmentin heart function assessment

• Assessment of cardiac conditions• Screening of NYHAN I patients• Diagnosis of left ventricular dysfunction• Diagnosis of heart failure• Diagnosis of ventricular hypertrophy• Prognosis of myocardial infarction• Diagnosis of essential hypertension

C. J. BURDBURY et al HSQ Scotland 2005S. K. JAMES et al. Circulaton 2003

ÖGLMKC: DIAGNOSTIC GUIDELINE ÖGLMKC: DIAGNOSTIC GUIDELINE OF THYREOD FUNCTIONOF THYREOD FUNCTION

Investigation ofo Newborn (screening)o Asymptomatic adults > 50 a

family history of thyreoidea dysfunctionpatients in hospitalsbefore exposure to Jodide

o Symptomatic adults Hypothyreosis ?Hyperthyreosis ?Autoimmun disease ?InfertilityPost PartumDepression, demenzia Abnormal lipids

1st Diagnostic test: TSH> TSH within reference range - euthyreosis> TSH > 3.0 mU/L - hypothyreosis> TSH < 3.0 mU/L - hyperthyreosis

C. BIEGLMAYER et al. 2007

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1

Clinical Diagnosis

2 Control after 3 months

Control after2 months

Clinical Diagnosis

3

1 - medication 2 - T3/T4 medication 3 - Initial phase of thyreostatic therapy 4 - sec. Hyperthyreosis, hormone resistance

Thyroid function tests: Reference ranges for adults

Elecsys/ Modular (Roche)

Advia Centaur (Bayer)

Immulite 2000

(DPC) Architect (Abbott)

Axsym (Abbott)

IMX (Abbott)

Dimension (Dade

Behring)

Erwachsene von bis von bis von bis von bis von bis von bis von bis MW von MW bis CV von CV bis

TSH mU/L 0,27 4,20 0,35 4,50 0,40 4,00 0,35 4,94 0,47 4,64 0,47 5,01 0,34 4,82 0,38 ± 0,07 4,59 ± 0,38 19% 8%

TT3 nmol/L 1,27 3,07 0,92 2,79 1,26 2,76 0,89 2,45 1,22 2,29 0,79 2,54 1,34 2,57 1,10 ± 0,22 2,64 ± 0,26 20% 10%

TT4 nmol/L 59 154 58 148 67 161 63 151 58 154 58 154 60 171 60 ± 3 156 ± 8 6% 5%

FT3 pmol/L 3,95 6,80 3,08 6,47 2,77 6,47 2,63 5,71 2,23 5,36 2,59 5,45 2,88 ± 0,59 6,04 ± 0,61 21% 10%

FT4 pmol/L 12,0 22,0 10,3 21,9 10,3 24,5 9,0 19,0 9,1 23,8 9,1 23,8 7,6 15,1 9,6 ± 1,4 21,4 ± 3,3 14% 16%

Alter TSH mU/L

FT4 pmol/L

Frühgeborene - – 4. T ag

0,8 – 6,9

5,15 - 36

Neugebo rene 3. Tag

1,3 - 16

25,74 – 51,48

Kinder 1 – 12 Monate

0,9 – 7.7

11,58 – 33,46

Kinder prä pube rtär

0,6 – 5,5

10,3 – 28,31

Kinder Pubert är

0,5 – 4,8

10,3 – 29,6

Age

Thyroid function tests: Reference ranges for children

ÖGLMKC: WG: Laboratorians, Clinicians (endocrinology,

internal medicine, nuclear medicine, practitionare).

1. Clinical practice guidelines, laboratory diagnosis and monitoring of hypothyroidism in adults. http://www.anaes.fr

2. Clinical practice guidelines, laborartory diagnosis and monitoring of hyperthyroidism in adults. htttp://www.sante.fr

3. Guidelines for in vivo and in vitro procedures for thyroid disease – version 2. 4. Laboratory medicine practice guidelines, laboratory support for the diagnosis and

monitoring of thyroid disease. http://www.nacb.org 5. American association of c linical endocrinologists, medical guidelines for clinical

practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. http://www.aace.com/pub/guidelines/

6. Medical/surgical guidelines for clinical practice: management of thyroid carcinoma. http://www.aace.com/pub/guidelines/

7. National guidelines clearinghouse, guidelines for detect ion of thyroid dysfunction. http://www,guidelines.gov/summary/summary.aspx?doc_id=2362

8. Leitlinien zur Schilddrüsendiagnostik. http://www.nuklearmedizin.de/publikationen/leitlinien/schild_diagn.php

9. Protocol for the use of thyroid function tests in the diagnosis and monitoring of patients with thyroid disease. http://www.hlth.gov.bc.ca/msp/protoguides/gps/thyroid.html

10. Laboratiory testing guidelines for investigation of thyroid dysfunction (adults). http://www.albertdoctors.org

11. Prodigy guidance – hyperthyroidism. http://www.prodigy.nhs.uk/guidance.asp? 12. Key recommendations and overview for the management of thyroid cancer

(differentiated and medullary). http://www.rcplondon.ac.uk/pubs/wp_thyroidcancer_summarysummary.htm

Databases:

References: 1. - 35 - 1990 - 2004

Thyroid function tests in serious diseasesThyroid function tests in serious diseases

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DISEASED RECOVERY

DEMERS AND SPENCER NACB 2002

Thyroid function tests during medicationThyroid function tests during medication

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CLINICSThyreostatics

Intermediatephase

Intermediatephase

NormalTSH/FT4

Equilibrium

Diagnostic Test

Referencerange

Months

DEMERS AND SPENCER NACB 2002

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SCREENING forSCREENING forDIAGNOSIS of DIAGNOSIS of DYSLIPIDAEMIADYSLIPIDAEMIACardiovascular Risk Cardiovascular Risk PopulationPopulation(Family History CVD, smoker, (Family History CVD, smoker, hypertension, diabetes, hypertension, diabetes, obese obese

FLP: Fasting lipids(TG, Chol, HDL-Chol)

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SCREENING forSCREENING forDIAGNOSIS of DIAGNOSIS of DYSLIPIDAEMIADYSLIPIDAEMIANot Cardiovascular Risk Not Cardiovascular Risk PopulationPopulation

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WHAT IS A GOOD GUIDELINE ?WHAT IS A GOOD GUIDELINE ?

A good guideline is one that leads to improved outcomes in patients.

Needs to be based on evidence

Needs to be used(implemented)

Needs to be regularly assessed,and updated

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A lot of work !A lot of work !