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ObjectivesUnderstand the need for a Quality System in molecular diagnostics laboratoriesUnderstand the major components of a QSUnderstand the deliverables of QS in molecular diagnostics

Available Genetic Tests and Laboratories Performing Molecular Genetic Tests

Data source: GeneTests database / www.genetests.org

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Practical Applications of Molecular Diagnostics

Detection, quantitation, genotyping of infectious agents Viruses, bacteria, fungi, and parasites

Detection of defective genes and variations in the genome Molecular genetics: Genetic disorders (neuromuscular, endocrine, cardiovascular, etc., diagnosis of existing disease or predisposition) Molecular oncology: Hematological malignancies, and gene defects, expression profiles, etc., related to cancer Pharmacogenetics: Identification of metabolic gene variants (slow, average, fast metabolizers, non-responders) to optimize drug therapy Genomics: Uses genomic information (gene expression and gene pattern) for disease susceptibility, diagnostic classification, prognosis, and optimal therapy Identification and characterization of individuals Paternity, forensic medicine, pathology, transplantation

Special considerations for molecular diagnostics laboratories

Clinical validity and utility of nucleic acid tests Providing clinical interpretation of test results Staffing and technical expertise Regulatory oversight and best practice considerations

Total Laboratory Testing Process

Establishment of performance specifications

Accuracy Precision Analytic sensitivity Analytic specificity, to include interfering substances Reportable range of test results Reference intervals or normal values (if applicable) For quantitative assays: Linearity Dynamic range Limit or Detection (LOD) Lowest Limit of Quantitation (LLOQ)

For genetic tests: establish clinical usefulness and validity, including clinical sensitivity and specificity, and positive and negative predictive value

If the test is a lab-developed human genetic test

Conduct a review of available scientific studies and pertinent references Define appropriate patient populations for which the test should be performed Select the appropriate test methodology for the disease or condition being evaluated Establish analytic performance specifications and determine quality-control procedures using the appropriate number, type, and variety of samples Ensure that test results can be interpreted for an individual patient or family and that the limitations of the test are well defined and reported

Specimen selection for test validation

Evaluate the adequacy of the specimens for the prevalence of the disease and the mutations or variants Specimen types may include blood, buccal swabs, dried blood spots, fresh or frozen tissue, paraffin-embedded tissue, or prenatal specimens For a multiplex genetic test, all the mutations or variants to be detected should be included in performance establishment For rare genotypes/mutations, alternative samples acceptable Specimen selection for test validation

Documentation of data

Completeness Consistency Accuracy Reconstructability

All data generated during the conduct of a study, except those that are generated by automated data collection systems, shall be recorded directly, promptly, and legibly in ink. All data entries shall be dated on the date of entry and signed or initialed by the person entering the data. Raw data includes the worksheets, calibration information, records and notes of original observations, and activities of a study that are necessary for the reconstruction and evaluation of the study. May include photographic materials, computer printouts, automated and hand recorded datasheets. FDA Good Laboratory Practices

1001,000,000100,00010,000100010123456Defects per millionSigma Scale of measureDomestic airline Fatality rateIRS Tax advice (Phone In)Order write upDoctor prescription writingRestaurant BillsAirline Baggage HandlingLaboratory Errors

Plebani M. The detection and prevention of errors in laboratory medicine.Ann Clin Biochem. 2010 Mar;47(Pt 2):101-10.

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BackgroundGlobal Increase in Molecular Genetic Testing Applications

International Strides for Improving Quality Management in Genetic Testing servicesOECD Guidelines for Quality Assurance in Molecular Genetic Testing. Organisation for Economic Cooperation and Development (OECD); 2007EuroGentest Harmonizing genetic testing across EuropeInternational Organization for Standardization (ISO) 15189 (2012). Medical laboratories requirements for quality and competenceIncreasing adherence to ISO and other national/international quality standards (eg, countries in Europe, Asia, Americas, other continents)

CLSI StandardsA. Quality management systems (QMS) guidelines (eg, GP26A4) Molecular methods guidelines (heritable diseases and oncology, molecular hematopathology, FISH, infectious diseases, new test implementation, etc.)C. Before MM20: No CLSI document specifically addressed QMS implementation and maintenance in molecular genetic testing

What is theOrganization for Economic Cooperation and Development?(OECD)Governmental Organization - established in 1961.Origin traced to post-WWII Marshal Plan30 member countries + cooperative arrangements with 70+ othersFocus is to promote economic growth and financial stabilityBiotechnology and health care viewed as key sectorsMolecular genetic testing viewed as important and evolvingLack of an international framework

http://www.oecd.org

The Journey to Guideline DevelopmentFocus: Molecular genetic testing for medical (disease-related) conditions

200020052007

Variables associated with higher quality indicesStandard Operating Procedures existStandard operating procedures are reviewed by directorLaboratory test result report is issued (written or electronic)Laboratory test result report is reviewed by director Offering of prenatal / pre-implantation testing Affiliation with a genetics unit Licensing and accreditation Participation in proficiency testing Not primarily in a research setting Maintaining data on turnaround time Lab director has an MD or PhD Lab director is certified Lab director has formal training Lab technicians have a university degree Lab technicians have relevant training

OECD Guidelines for Quality Assurancein Molecular Genetic TestingPromote minimum standardsFacilitate mutual recognition of quality assurance frameworksStrengthen international co-operation to facilitate cross-border flow of patient specimens for medically necessary testingIncrease public confidence in the governance of molecular genetic testing

OECD Guidelines for Quality Assurancein Molecular Genetic TestingComponentsGeneral principles and best practices Quality assurance systems Proficiency testing Quality of result reporting Education and training standardsAnnotationsOrganization:Principles (1,2,3...): Primarily directed to governmentsBest Practices (i, ii, iii): Primarily directed to laboratories and other entities

General principles and best practicesA.2 - Molecular genetic testing should be delivered within the framework of healthcare.A.i - Regulatory/professional bodies should, as appropriate, review whether instruments available to manage a quality assurance framework require adaptation for molecular genetic testingA.3 - All molecular genetic testing services should be provided and practices under a quality assurance frameworkA.iii - Molecular genetic test results should be reported back to the referring health care professional to enable counseling and healthcare decision making

Quality Assurance Systemsin Molecular Genetic TestingB.1 - Governments and regulatory bodies should recognize thataccreditation of medical laboratories is an effective procedurefor assuring quality.B.i. - All laboratories reporting molecular genetic testing results for clinical care purposes should be accredited or hold anequivalent recognition. (additional clarification for roleof research laboratories)B.9 - Governments should encourage international collaboration for the development and validation of molecular genetic tests.B.viii - Laboratories should cooperate (internationally) to collect, develop, verify and make available reference materials

Proficiency Testing:Monitoring the Quality of Laboratory PerformanceC.1 - The performance of laboratories offering clinical molecular genetic tests should be measured.C.iii - Proficiency testing schemes should be structured to assess all phases of the laboratory process, including result reporting.C.4 - Accreditation or equivalent recognition should be the basis for the international recognition of proficiency testing scheme and providers.C.v - Laboratories should participate in a proficiency testing scheme for every test offered, when such schemes exist. When not available, they should participate in alternate methods.

Quality of Result ReportingD.1 - All laboratories should issue molecular genetic testing results in the form of a written and/or electronic report to thereferring health professionalD.i - Reports should communicate information effectively taking into account that the recipient may not be a specialist.D.2 - Where reports are issued directly to patients, it should beencouraged that laboratories recommend consultation with an appropriate health care professional.D.4 - The interpretation of the result should be appropriate to theindividual and clinical situation and based on objective evidence.

Education and TrainingStandards for Laboratory PersonnelE.2 - Standards for laboratory accreditation or other equivalentrecognition should require that all molecular geneticspersonnel have a combination of education, training, skills,and experience that ensures their competence.E.4 - Development of educational and training programmes should be encouraged where they do not exist.E.vi. Comparison of education and training systems between jurisdictions should be facilitated as a means to establish equivalence.E.5 - Relevant government or professional authorities shouldrecognize medical genetics as a discipline comprising both aclinical and a laboratory specialty.

Purposes of MM20Provide guidance for implementing and maintaining QMS in molecular genetic testing.Address specific QMS challenges in technical processes and laboratory/user interphases of molecular genetic laboratory services.Provide a resource to facilitate harmonized approaches to accreditation to international laboratory standards.

Whats Special in MM20?Extends international QMS standards/guidelines (eg, ISO 15189, CLSI document GP26) into molecular genetic testing servicesIncorporates recognized best practices for molecular genetic testing worldwideFollows new/extended path of workflowApplies quality system essentials (QSEs) to quality management and technical processes of molecular genetic testingFeatures many tools, job aids, resources

ScopeGuidance for Implementing and Maintaining QMS for Nucleic AcidBased Human Molecular Genetic Testing

Intended for heritable (including pharmacogenetic testing) and acquired conditions (eg, molecular oncology testing)

Not intended to address molecular infectious disease testing, biochemical genetic testing, cytogenetic testing, specific technical processes of molecular cytogenetic testing, molecular testing for nonclinical purposes, or directtoconsumer laboratory services

Concordant with Use of ISO QMS Standards and Other CLSI Guidelines (eg, GP26, MM01, MM12, MM17, MM19)

Quality ManagementChallenges

Need for Specific QualityManagement SystemGuidanceQuality Laboratory ServicesMost appropriate examination proceduresBest suited sample(s)Accurate and timely results with proper interpretationAccurate and timely communications

Quality Management Challenges for Molecular Genetic TestingDiverse spectrum of testing servicesExpanding applications impacting all medical disciplinesNew users and clients continuously faced by laboratoriesLaboratorys continuing need to Consider new examination methods/procedures. Update existing examination procedures. Ensure effective communications with users and clients.

Prerequisites for Providing Testing ServicesPlanning and preparation activities to ensure QMS/readiness for introducing or providing molecular genetic testing servicesValidation/verification of new or updated examination procedures before receiving test requests/testing patient samples

Path of workflow

Quality SystemEssentials for MolecularGenetic TestingDiscuss implementation of 12 QSEs in molecular genetic testing services (Section 6 in MM20).

6.1 Organization6.2 Personnel6.3 Documents and Records6.4 Advisory Services6.5 Assessment6.6 Management of Nonconforming Events6.7 Information Management6.8 Continual Improvement6.9 Use of Referral Laboratories6.10 Evaluation of Vendor Qualification6.11 Laboratory Equipment6.12 Facilities, Environment, and Safety

Describe policies and procedures to specifically address QMS needs in providing molecular genetic testing services.

Example: Quality SystemEssential AssessmentQuality Indicators (QIs) providing examples in the laboratorys path of workflow

Internal Audits Horizontal for general processes in the path of workflow (eg, acceptance of sequencing reactions) Vertical for a specific laboratory process (eg,following a sample from sample receipt to result reporting)

External AssessmentVoluntary and mandatoryAccreditation vs (thirdparty) certification

Management Review

Example: Quality SystemEssential InformationManagementLaboratory Information Systems (LIS) ConsiderationsDirect interface/compatibility with electronic medical records (for test ordering and reporting)Patient information (eg, race/ethnicity, indication for testing, family history) collected and directly entered with test requestsAccommodating all fields/elements of molecular genetic test reportsMonitoring examination procedures, quality control (QC) tracking, followup on TAT

Accessibility and Retrievability

Confidentiality and Security

Data ManagementMaintaining databases of sequence variants (eg, sequence variants identified in the laboratory and literature, reference sequences, diseasespecific mutation databases)Monitoring/updating as variants are reclassifiedEnsuring consistency of result interpretation

Path of Workflow Technical ProcessesPlanning and Preparation

Validation/Verification of Test Performance

Processes for providing examination services to laboratory usersPreexamination activitiesExamination activitiesPostexamination activities

Planning and PreparationFundamental Management Considerations for Providing Molecular Genetic Test Services

Ensuring all QSEs are in place and adequate for new tests/test services

Determining preparedness for all applicable requirements

Determining needs and demands, benefits and costs

Identifying personnel competencies, training needs, and responsibilities

Identifying special issues

Informed consentGenetic counselingIntellectual property/licensing concernsEthical issues (testing of minors, use of tested samples, confidentiality)

Technical Aspects to Consider

Specific intended use (and examination method to be used), different planning issues:

Diagnostic testingCarrier testingPresymptomatic testingPrenatal diagnosis

Documenting clinical validity and utility:

IndicationsContraindications

Planning for validation/verification of test performance

Validation/Verification ofTest PerformanceDevelop validation/verification proceduresThe intended use of the test (eg, carrier testing, fetal testing, diagnostic testing)Target genes, sequences, mutationsExpected patient populationTest methods to be compared or the method of choice to be usedType(s) of samples to be usedAnalytical performance characteristics to be determinedSources of reference materialsHow performance specifications will be analyzedHow test limitations should be defined (eg, rate of allele dropout, interfering mutations, polymorphisms)Corrective actions when problems occur

Identify samples/materials for analytical validation/verification

Adequate number, type, and variety of samples for establishing test performance specifications and defining limitationsControl materials, calibration materials, other reference materials

Determine analytical performance characteristics; define performance specifications and limitations.

Document results/findings.

Prepare operational procedures for examination of patient samples.

Perform ongoing validation.

Pre-examination ActivitiesBegin with the laboratory informing users about:The molecular genetic tests it performsTest selectionPatient preparation (if needed)Sample collection, handling, transport, submission with test requisitions (eg, sample collection/submission manual)

Information provided by laboratory aids health care providers and other users in:Considering indications for testing/recognizing the need for a genetic testSelecting indicated test(s)Shared decision making between a health care provider and the patient/pretest genetic counseling leading to informed consent as indicatedSending test request with patient sample(s) to laboratory

Advisory services regarding consideration/selection of genetic tests

Test referring process in case of sample referral

Examination ActivitiesExamination ActivitiesSelection of test procedures according to user needs/expectationsSample preparation/processing (eg, nucleic acid extraction/purification)Examination proceduresQC proceduresDocumentation of test results and findings

QC Plan/ProgramDescribe how all steps of analytical examination procedures are monitored.Essential elements:Types of controls/control materialsFrequency and placement of controlsAnalysis and recording of QC resultsPass/fail criteriaCorrective and preventive actionsAlternative control procedures when control materials are not available

Postexamination ActivitiesPostexamination ActivitiesReviewing examination resultsProviding laboratory interpretationGenerating examination reportsTransmitting test reports to the test requestor or other clinical usersProviding laboratory consultation regarding test results, result interpretation, followup examinations or servicesArchiving of examination records, reports, and tested patient samples

Recommended Contents of Molecular Genetic Test Reports

Procedures for Releasing/Reporting Test ResultsWho may release test results and to whomMaintaining confidentiality of patient/family informationMonitoring accidental disclosure and documenting corrective actions

Procedures for Corrected, Revised, Amended Reports

Ensuring Quality ofPatient TestingProficiency Testing/External Quality Assessment (PT/EQA)Existing programs for commonly performed molecular genetic tests (eg, CAP, CF [European] Network, EMQN, EuroGentest, UK NEQAS)Differences between PT/EQA samples and actual patient samples: greater benefits from challenging more steps of the testing processSection 7.3.3 in MM20 and CLSI documents GP27, MM01, MM14, and MM19

Alternative Performance AssessmentInterlaboratory comparison and intralaboratory evaluation when sample exchange is not AvailableAs frequent as would be required by participation in formal PT/EQARigorous in review and interpretation of results

Management of Performance Assessment ResultsImportant part of the laboratorys quality assurance planDocumentation of assessment, results, and corrective actionsWritten policies on review and retention of performance assessment results

Personnel Qualifications,Responsibilities, Competency

Personnel CompetencyAssessmentMethods for Competency Assessment for Laboratory ManagementAppropriate levels of continuing education unitsPeerreviewed journal articles studiedMembership/participation in professional organizationsCredentials and maintenance of certification activitiesProficiency slides or samples examinedInterlaboratory sample exchanges with interpretationAssessment at annual review or other time, documented with appropriate form

Personnel competency assessment for testing personnelDetermining when competency assessment is neededKey elements of competency assessment program for testing personnel

Example of a LaboratoryQuality Manual

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