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A friendly clinician has asked you to go about setting up a test for a genetic disorder previously characterised by a research laboratory. Discuss how.

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Presentation on theme: "A friendly clinician has asked you to go about setting up a test for a genetic disorder previously characterised by a research laboratory. Discuss how."— Presentation transcript:

1 A friendly clinician has asked you to go about setting up a test for a genetic disorder previously characterised by a research laboratory. Discuss how you would go about designing a robust diagnostic assay that could be offered as a service to other laboratories. Concentrate on factors that you would need to take into account when setting up a service. FRCPath Part 1 9 th November 2009

2 assess clinical utility of setting up a genetic test clinical utility refers to the likelihood that the test will lead to an improved outcome takes into account the impact and usefulness of the test results to the individual, the family and society clinical benefit diagnosis, treatment, prognosis, management and family planning family benefit carrier, predictive, pre-natal alternative diagnostic test available biochemical, histological, clinical genetic test may remove need for expensive/invasive test ethical, legal and social implications (ELSi) insurance, employment, stigmatisation cost effective

3 severity and prevalence adequate demand – regional and/or national regional clinical management sufficient clinical expertise adequate clinical staff

4 research disorder clinical symptoms mode of inheritance penetrance gene(s) involved – size of gene(s), pseudogenes, SNPs mutations – type, hot spots - ethnic differences communicate with research lab and/or diagnostic lab current testing strategy detection rate positive controls for validation – informed consent

5 establish testing strategy dependent on expected referral numbers estimate level of service to provide diagnostic, carrier, predictive, pre-natal, screening range testing levels – common mutations, whole gene screen, other genes clinical acceptance criteria technique(s) utilised pre-screen – SNPs, GC content, referral size sequence – certain exons, all exons MLPA – commercial kit, in-house other techniques – e.g. ARMS, primer extension assay, FRET probes may be dependent on equipment available

6 amenable to automation available capacity meet TAT batching referrals adequate staffing estimate set up time workload of established service funding – fixed term, permanent – scientist/GT

7 test validation design primers/probes SNP check BLAST search order reagents/kits optimise reactions test negative and positive control (with known mutations) samples large number 100% concordance robust and reproducible assay reproducible results within and between runs – same controls used robust – low failure rate saves time and money

8 measure test performance analytical validity defines the ability of a genetic test to measure accurately and reliably the genotype of interest analytical sensitivity probability of positive result in presence of mutation analytical specificity probability of negative result in absence of mutation ideal sensitivity and specificity 100%

9 clinical validity defines the ability of a genetic test to detect or predict the presence or absence of the phenotype, clinical disease or predisposition to disease clinical sensitivity probability of positive test result when disease is known to be present clinical specificity probability of negative test result when disease is known to be absent positive predictive value probability of developing disease given a positive result negative predictive value probability of not developing disease given a negative result dependent on prevalence penetrance genetic heterogeneity allelic heterogeneity UCVs

10 gather SNP data screen anonymised controls test specific UCVs large numbers required expensive time consuming ethnic diversity write validation document SOP

11 establish service offer service at regional level test patients with unknown genotype IQC – include appropriate positive and negative controls establish reporting templates – state limitations of test consider issuing reports for retrospective testing initial mutation identified by research lab – ethical considerations continual monitoring of assay ensure maintenance of robust and reproducible test EQA scheme regular literature search new mutations identified SNPs mutations in different ethnic groups continual technique search new kit available

12 offer service nationally review service after period of time establish cost advertise service conferences – CMGS, BSHG, ESHG lab website UKGTN – submit gene dossier

13 setting up a genetic test summary establish clinical utility improved outcome, ELSi, cost research disorder establish testing strategy expected referrals, level of service, techniques, TAT, staffing test validation robust, reliable analytical validity – sensitivity, specificity clinical validity – sensitivity, specificity, PPV, NPV regional service IQC, monitor assay, EQA national service establish cost, UKGTN gene dossier

14 Grosse and Khoury (2006) Genetics in Medicine 8: Kroese et al. (2007) European Journal of Human Genetics 15: Kroese et al. (2007) OECD workshop, PHG Foundation Melzer et al. (2008) British Medical Journal 336: Prence (1999) Genetic Testing 3: Zimmern and Kroese (2007) Journal of Public Health 29: UKGTN


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