quality assurance in hematological pathology
TRANSCRIPT
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1
Mahboubeh (Mandy) Rahmani, MD, FRCPC
Hematopathologist, QEII, Division of Hematopathology
Assistant Professor, Dalhousie Faculty of Medicine
Quality Assurance in Hematological Pathology
Jan 15th, 2021
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Disclosures
•None
Acknowledgements
•Notes primarily shared by Dr. Ruth Padmore
2
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Objectives
1. Review the Clinical and Laboratory Standards Institute (CLSI)
Quality System Essentials
• Principles of standard operating procedures and document control
• Document and material Retention times
• Recognize safety in the Laboratory
• Describe key features of assessment including internal quality control
and external quality control
2. List laboratory errors (pre analytic, analytic and post analytic) and
have an approach to incident management
3. List critical results –how are they handled
4. Describe test and instrument selection, validation and verification
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Quality Management Hierarchy
• Laboratory quality is conformance to requirements, with the goal of
reporting results acceptable for patient care
• Reliable
• Accurate
• Timely
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Management
• Management with executive responsibility
• Management representative
• Laboratory director
• Management review
• At least twice per year, many hold quarterly
• Key quality indicators will be reviewed
• Documented
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CLSI Quality System Essentials
1. Documents and records
2. Organization
3. Personnel
4. Equipment
5. Purchasing and Inventory
6. Information management
7. Customer service
8. Facilities and safety
9. Process Control
10. Occurrence management
11. Assessment
12. Process improvement
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1. Documents and Records
CLSI-quality system regulation for laboratory developed tests
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Standard Operating Procedures Manuals (SOPs)
• Put together an SOP writing team:
• Team members: operations, training, quality
• Writing:
• Write for your audience, write content to fit the purpose
• Action items; put the verb first:
• Record the expiration date of the vial after opening
• Write the steps in the order they occur
• Modify the steps to prevent potential errors
• Use computers/automation where possible
• Design forms to capture results
• Approval:
• By lab section and lab director or designee
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Record Management
• Collection, confidentiality, maintenance, access, and disposal of records
• Principles for document control include:
• Write and name the document
• Store the documents (written, electronic)
• Keep documents up to date
• Document any changes to the documents
• Use only current documents which have been approved
• All personnel should be knowledgeable re content
• Archive/destroy obsolete documents
• Records retention meets government, accreditation requirements
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Medical Records Retention
• Physicians must ensure medical records are retained for a minimum
of the following time periods
• Adult patients: 10 years from the date of the last entry in the
record.
• Children: 10 years after the day on which the patient reached or
would have reached 18 years of age
College of Physicians and Surgeons of Ontario
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https://www.cap-acp.org/guide_retention-human-biologic-material.php
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Retention of Bone Marrow Specimens and Reports
• Bone marrow slides should be stored at least 20 years or
indefinitely, if possible
• Digital images and electronic reports may be stored indefinitely
• The duration of storage of bone marrow specimens and reports
should comply with (national) regulatory guidelines
ICSH guidelines for the standardization of bone marrow specimens and reports. Int J Lab Hematol 2008;30:349-365
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Retention of Materials in the Hematology Laboratory
• Flow histograms including gating used for reporting: at least 2 years
• CBC tube: 48 hours
• Normal Peripheral blood slides: at least 7 days
• Abnormal Peripheral blood slides:
• In a hospital in Ontario: at least 10 years (or 10 years after 18thbirthday)
• In a community (commercial) lab: 1 years
Ontario Laboratory Accreditation (OLA), version 7.1, item VIII.4.2
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Retention of Materials, Others
• Cytogenetic/molecular reports (neoplastic disorders): 10 years
• Cytogenetic/molecular reports (constitutional/inherited disorders):
20 years
• Test reports: 10 years
• Proficiency testing records: at least 2 years
• Electrophoresis gels and reports should be retained for at least 10
years (or for 10 years after the 18thbirthday, in the case of children)
Ontario Laboratory Accreditation (OLA), version 7.1, item VIII.4.2
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Document Retention - Transfusion Medicine
2020 Canadian Standards Association
Examples of documents with 5 years retention time
Donor suitability assessment
Record of donation (i.e., all donation information other
than that specified above to support lookback/traceback)
Records of inspection of blood components before
release
Quality control testing of blood components, reagents,
equipment, and proficiency testing surveys
Product complaints
Quality assurance reports and records of audits
Temperatures of storage for blood components
Donor apheresis procedure records
Autologous donor collection record
Records of inspection of blood components before
release
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Document Retention - Transfusion Medicine
2020 Canadian Standards Association
Examples of documents with 10 years retention time Examples of documents with 10 years retention time
Determination of temporary donor unsuitability (i.e.,
deferrals) Note: Indefinite deferrals are covered under Item A-7.
Documents generated during the traceback and
lookback processes
Note: Establishment policies could extend the retention
period for reasons outside the scope of this Standard,
(e.g., legal liability).
Post donation information that leads to product recall and/or donor
deferral
Record of transfusion or other final disposition
Blood component preparation Records of washing, pooling, or irradiating of blood
(transformation activities)
Master copies of superseded procedures and manuals (except for the
donor suitability procedures specified in Item A-5)
Record of final disposition of autologous blood
components, including identification of the recipient
Investigations and reports of the following donor and recipient events as
related to the safety of the product:
a) errors and accidents that could lead to serious adverse reactions; or
b) unexpected or serious adverse events, including adverse reactions
Individual personnel qualifications, training, and
Competency (10 years (after end of employment))
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Document Retention - Transfusion Medicine
2020 Canadian Standards Association
Examples of documents with 50 years retention time
Date of donation Record of distribution, including exceptional distribution
and any recalls
Identifying information for the collected blood
components, including the identification of the collecting
facility and the numeric or alphanumeric identification of
the blood component
Record of final disposition of allogeneic blood
components, including identification of the recipient (for
transfused components)
The health care facility’s record of release for transfusion
of allogeneic components
The record of transfusion of allogeneic components
Documents describing the process and criteria for
assessing donor suitability and the dates that the process
and criteria were in effect
Record of release for transfusion, and record of
transfusion
for allogeneic components
Test results from the donor sample for transmissible
disease testing ABO, RhD, and clinically significant
antibody test results
Importation in urgent circumstances
Record of indefinitely deferred donors Record of distribution, including exceptional distribution
and any recalls
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Document Retention - Transfusion Medicine
2020 Canadian Standards Association
Examples of documents with 1 year retention time Examples of documents with 3 years retention time
Date and time a recipient blood sample was drawn and
phlebotomist’s identification
Documentation of maintenance of critical equipment
Packing/shipment documents Documentation of validation of computer systems
Lot number of critical supplies for each process (transformation
activity) and the name of the manufacturer
Lot number of critical supplies for each donation and the name
of the manufacturer
Other Retention time
Documentation of calibration and validation of critical
equipment
Lifetime of the equipment
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2. Organization
• Chart
• Reporting
• Responsibilities
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3. Personnel
• Job qualifications
• Job descriptions
• Training
• Competency assessment
• E.g. direct observation of test performance and instrument
maintenance, recording and reporting results, PT/EQA and/or blind
sample testing, problem solving skills
• Ensure adequate staffing
• Professional development
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4. Equipment
• Policies, process and procedures for operating equipment
• Records of Selection, Acquisition, Installation, Validation,
Calibration, Maintenance, Service and repair
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5. Purchasing and Inventory
• Process, procedure and records of:
• Purchasing equipment, reagents, materials
• Inventory management
• Receipt, and storage of materials
• Listing of labs used, and record of results and samples sent, if using
reference laboratories
• Contracts, requirements, in case of the laboratory service to other
laboratories
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Quality Management Workflow optimization:Lean and Sigma 6
• Lean 5-S: Sort, set in order, sweep, standardize, sustain
• Six Sigma: improve quality by decreasing variability
• Lean Six Sigma: combines Lean and Six Sigma to removed 8 kinds
of waste: time, inventory, motion, waiting, overproduction,
overprocessing, defects, skills
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6. Information Management
• Process for receiving and handling patient information to be
• Secure and private
• Accessible
• Accurately transmitted to patient record containing proper info
• All processes must be validated
• In case of computer information system consider
• Storage and data back up
• Hardware/software system maintenance
• Interface and networks
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7. Customer Service
• Provide accurate, timely, and reliable results
• TAT
• Customer surveys
• Critical results
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Critical Results
• Life-threatening results needing immediate notification of the
patient’s health care provider
• Usually reported by telephone
• Read back of results
• Documentation of name of person receiving results
• Document that critical results have been communicated to the appropriate
care giver
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Handling Critical Results
• Inform a hematopathologist of any unusual persistent serial critical values
• If unable to contact the appropriate person in a timely fashion to report the
critical value, document any difficulty
• Establish guidelines for patients with repeated critical results
• If the reported critical value remains critical, a repeat notification will not be
made
• If a patient returns after a period of 14 days and the parameter is critical, it will
be called
• INR & anti-Xa will be called each time the result is critical
• Establish what are these critical results for your laboratory, (related to
medical decision points)
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Critical Results
References: (1) Hematology: McFarlane et al, Int J Lab Hematol 2015
(2) Coag: Pai M et al. Am J Clin Pathol 2011;136:836-841
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8. Facilities and Safety
• Monitor, document, and control laboratory environmental conditions
that can influence quality of results:
• E.g. temperature, humidity, etc
• Safety of laboratory staff
• E.g. hazardous waste, personal protection equipment, etc
• WHMIS
• Workplace Hazardous Materials Information System
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Safety in the Laboratory- WHMIS
• Three Key elements:
• Labels
• Supplier labels, workplace labels
• Safety data sheets
• Worker education
• training yearly
• Employers responsibilities: Label hazardous materials, provided SDS, train employees,
review training program annually
• Workers responsibilities: retrain each year, make sure hazardous materials are labelled,
follow safe procedures including wearing personal protective equipment (PPE), report
deficiencies to the supervisors
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https://www.ccohs.ca/products/posters/pdfs/WHMIS_2015.pdf
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Safety in the Laboratory
• Be aware of pertinent regulation and guidelines
• Identify and control hazards
• Have employee training in lab safety, ensuring knowledge how to use all
equipment and reagents safely
• Have up to date contact with occupational/employee health at your
workplace
• Have an emergency response plan and an accident investigation plan
• Evaluate lab safety program at regular intervals: good record keeping of
training/incidents, written safety policies, feedback from employees,
benchmark (what are your colleagues doing)
• Use risk management tools to improve safety (e.g. FMEA)
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Safety in the Laboratory- Risk Management Tools
• Failure Mode and Effects Analysis (FMEA):
• Prospective analysis of potential safety failures
• Each step in a process evaluated for potential to fail and cause harm.
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Safety Representative Responsibilities
• Provides safety expertise, advice, guidance
• Ensures safety orientation and training of employees is conducted
• Assists with risk management strategies (e.g. FMEA)
• Surveys work sites for safety deficiencies and to recommends
solutions/safety programs
• Posts minutes of safety committee meetings
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Vanderbilt Model to Address Unprofessional Behavior
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9. Process Control
• Verification and documentation of in laboratory, new or changed
processes and procedures
• Standard operating procedures (SOP)
• Validation
• Quality control (schedules, etc)
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10. Occurrence Management
• Processes and procedures for detection, documentation and
investigation of unexpected occurrences
• Lab Errors
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11. Assessment
• To determine if regulations, standards and requirements are being
met
• Accreditation
• Internal assessment (e.g. audits, quality indicators)
• External quality assessment (EQA, proficiency testing)
• where no EQA exists:
• Split samples with other laboratories
• Peer group assessment
• Compare QC results to other labs using that vendor’s device or reagent
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Audits
• Systematic review using explicit criteria
• Compliance audit: determines conformance to a set of rules
• Management audit: determines conformance to a set of rules and
determines the effectiveness of rules in achieving an
organization's goals
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Audits
• Items to include on a audit report form
• Purpose of audit
• Scope of audit
• Standards and reference documents
• Overall summary
• Summary of positive practices
• Summary of nonconformances
• Objective evidence (observations, facts)
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Quality Indicators
• Use quality indicators to monitor and evaluate the laboratory's
standards of performance, contribution to patient care, and quality
improvement of lab services
• QI must have: objectives, methodology, interpretation, limits, action
plans and duration of measurement, documentation
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Quality Indicators: Examples
• Analytic: QC and EQA performance
• Pre-analytic processes (specimen transport time and conditions,
specimen acceptability rates, wrist band identification checks)
• Post-analytic processes (reflexive testing, turn around times [TAT])
• Customer satisfaction (surveys), patient wait times in collection
areas
• Specimen rejection rates, specimen labelling errors
• Monitoring of privacy/confidentiality
• Work related injury monitoring, safety
• Wastage rates (reagents, blood products)
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External quality assessment (EQA)
• EQA samples are to be handled the same way as patient samples
• Results comparison
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12. Process Improvement
• Quality Assurance (QA)
• A system for continuous review and planned systematic actions to ensure the
defined quality objectives were met
• Quality Control (QC)
• Known analytes used to measure, evaluate and monitor errors in patient
samples
• Quality Improvement (QI)
• Understanding of what the problems are and investigation to improve
process/outcome
• Ongoing education and competency following error management
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Quality Improvement (QI)
• PDSA Cycles (Plan-Do-Study/Check-Act)
http://www.hqontario.ca/
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Change Management
• Kotter’s 8-Step Process for Leading Change
• Create a sense of urgency
• Build a guiding coalition
• Form a strategic vision and initiatives
• Enlist a volunteer army
• Enable action by removing barriers
• Generate short term wins
• Sustain acceleration
• Institute/anchor change
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Lab Errors
• An adverse medical event is an injury related to the patient’s
medical care and not due to their medical condition
• The just culture:
• Most errors are honest human errors, which require system fixes
• Focusing on system fixes avoids “name, shame and blame”
culture
• Accountability
• Confront situations where employees are misfit to their job
duties
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Types of Errors
1. Unintended human errors
Cognitive errors = mistakes, errors involving thought or judgment,
may be due to lack of knowledge (remedy: more
training/supervision
Non-cognitive errors = slips: lapses in concentration while
performing repetitive tasks (remedy: process improvement:
checklists, automation, removal of distractions)
2. At-risk behaviors (remedy: better adherence to existing plans)
3. Reckless behaviors: (remedy: better adherence to existing plans)
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QUALITY ASSURANCE
POST-ANALYTICALANALYTICALPRE-ANALYTICAL
• Record keeping
• Reporting Accurate
results
• TAT
• Validation
• Day controls/QC material
• Proficiency testing
• Direct observation reviews
• Patient identification
• Sample collection
• Test ordering
• Personnel competency test
• Evaluation
• Sample transport
• Sample receipt/accessioning
Reporting results
acceptable for patient care
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Lab Errors
• Most lab errors occur at the pre-analytical phase
• Specimen collection
• Ordering the wrong lab test
• Errors on requisition, unlabeled specimen
• Mislabeled specimen (wrong blood in tube –WBIT)
• Incorrect tube
• Incorrect order of draw (1 blood culture, 2 citrate (3.2% Na
citrate for INR), 3 serum, 4 heparin, 5 EDTA, 6 fluoride/glucose)
• NSQ: underfilled Na citrate or high Hct: prolonged PTT, INR
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Lab Errors - Pre-analytical
• Specimen Transport:
• Delayed transport
• Specimen lost
• Temperature too high: degradation of Factors V and VIII.
• Temperature too cold: loss of Factor VIII and vWF
• Pneumatic tube transport (validate pneumatic tube system)
• Specimen Processing
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Lab Errors - Pre-analytical Examples
• Patient is on DOAC but this is not documented: e.g. factitiously
overestimate Protein C and Protein S using clot based assays
• Reference lab: aliquot received for Factor V testing (not in original
tube), but sample was collected in EDTA not citrate (coag samples
collected in EDTA show increased INR, increased PTT, low factor V
and VIII levels with non-parallelism, high K+ and absent Ca2+)
• Measurement of unfractionated heparin using PTT: centrifuge within
1 hour and test plasma within 4 hours because of potential for
heparin neutralization by platelet factor 4
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Lab Errors - Pre-analytical - WBIT and Delta Checks
• Delta check to identify WBIT errors
• Compares the present value with the previously reported value
• Delta check failure:
• The difference between the current value and the previous value
exceeds the threshold set by the lab
• E.g. 30% Hgb, 7% MCV, 50% platelets
• Lab result either not reported, or reported with a flag
• To improve PPV of delta checks:
• Velocity of change, relative change, maximum look-back time, multi-
analyte delta check (machine based learning)
Rosenbaum et al. Am J Clin Pathol 2018;150:555-566
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Lab Errors – Analytical and Post-analytical
• Analytical errors
• Safe guards include IQC, EQA, specimen tracking, automation
• Post-analytical errors:
• Results delayed
• Results not reported
• Results reported to wrong provider
• Incorrect post-analytical data entry error
• Incorrect test results interpretation/Results not understood by
clinicians (brain to brain)
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Quality Control (QC)
• Internal assessment of analytical quality
• Used to increase the probability that each result reported by the lab is
valid
• Monitors precision and accuracy of analytical method on a daily
basis
• Accuracy: Degree of closeness of determined value to the true value
• Precision/ imprecision: dispersion of repeated measurements about the
mean
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Quality Control
• Selection of control material:
• 3 levels, low, normal, high, clinically relevant levels/medical decision points
• Commercial QC from same manufacturer as instrument
• Patient control
• Frequency of running QC
• At least once a day, after calibration
• Patient controls: after reagent changes, following lot changes, maintenance,
throughout analytical run
• Interinstrument quality control comparison
• Patients samples
• At least weekly
Reference: Johnston A et al. Guidance for quality control practices and precision goals for CBCs based on IQMH
patterns-of-practice survey. Int J Lab Hematol 2019;41:15-22
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Monitoring QC
• Use QC rules which detect clinically important errors while
minimizing false rejections
• Have at least one rule for random error and one rule for systematic
error
• Track QC with standardized control chart (Levey-Jennings chart,
radar plot), QC software: readily available for review by all staff
Reference: Johnston A et al. Guidance for quality control practices and precision goals for CBCs based on IQMH
patterns-of-practice survey. Int J Lab Hematol 2019;41:15-22
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QC Target Limits
• Establish target mean and SD for each separate instrument, using
20 QC points over 10 runs
• Run current lot number concurrent with old lot number
• Use patient sample to rule out matrix effect (use normal and
abnormal patient)
Reference: Johnston A et al. Guidance for quality control practices and precision goals for CBCs based on IQMH
patterns-of-practice survey. Int J Lab Hematol 2019;41:15-22
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QC with patient samples: Xb
• Bull’s moving average, X-bar-B
• Consecutive patient results compared with the running mean
• Only results within the normal range are averaged
• Indices tracked: MCV = Hct/RBC, MCH = Hgb/RBC, MCHC = Hgb/Hct
• When to investigate:
• Bull's mean of one batch is outside 3% OR
• Average of three consecutive Bull's means is outside 2% limits
• Advantages: savings on QC reagent costs, detects in-run analytical
error, helps troubleshoot cause of errors
-
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Monitoring Quality Control
Wikipedia.org
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Lab Errors
• Random errors:
• Affect precision
• Do not affect entire batch
• Systematic errors (bias):
• Affect accuracy
• Affects all samples in batch equally
• Detected by testing controls
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Westgard Rules
• 10x 10 # of points falling on same side of mean
• Used to detect very small systematic changes
• R4s Shift in consecutive data >4SD
• Used to detect random error
• 13s 1 point falling outside 3 of SD
• Cannot differentiate between random and systematic error
• 22s and 41s Multiple consecutive points falling outside # of SD
• Used to detect systematic error
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Management of QC Out of Control
• Discontinue testing
• Notify clinicians of any erroneous results released
• Determine root cause
• Implement corrective action
• Document all actions
• Repeat test patient samples from last acceptable quality control
• Follow-up with risk management: review QC failures and their
causes and look for solutions
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Investigation of Lab Errors: Root Cause Analysis Example
• The freezer alarm sounds (the problem)
• Why?-The freezer temperature is too warm (first why)
• Why?-The freezer is not functioning properly (second why)
• Why?–There has been dust/dirt build-up on the back of the freezer.
(third why)
• Why?–Facilities maintenance has not vacuumed/cleaned the back of the
freezer according to policy (fourth why)
• Why?-Facilities maintenance did not think that vacuuming the back of
the freezer was needed/important (fifth why, a root cause)
• Why? –No communication from lab staff that this was important and no
form/record to document when task was completed
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Investigation of Lab Errors - Root Cause AnalysisFishbone Ishikawa diagram
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Instrument Selection
• Gather information about the methods in question
• From vendor
• From literature
• From other laboratories that run the method
• Conditions to be considered:
• Dimensions of the device and space in the lab
• System characteristics:
• Throughput of the instrument, sample/h, peds, ease of use
• Technical skill required
• Maintenance/ calibration frequency
• Reagent required/preparation, QC material
• Financial considerations: cost of device, cost per test, etc
• Level of dependability (manual intervention)
• Safety (biohazards)
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Principles for Test Set Up
• Define appropriate specimens, collection methods, transport and storage
conditions
• Write QC, calibration and new lot number verification procedures
• Set up validation rules
• Check interphases with lab information systems
• Write test procedure, write procedure for LIS down time
• Obtain lab license for the test
• Enroll in proficiency testing program for the new test
• Train staff and assess staff for competency
• Establish critical values
• Establish interpretative comments
• Define clinical indications for test and educate caregivers re indications and
interpretation
• Specify suppliers and ordering procedures
• Define instrument maintenance
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Validation
• Confirmation, through the provision of objective evidence, that the
requirements for a specific intended use or application have been
fulfilled• According to CLSI guidelines:
• Validation should in principle be performed by the manufacturer for
the intended scope
• Verification by the clinical laboratory of the manufacturers claim is
sufficient
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Method Validation
• Precision (reproducibility)
• Accuracy (method comparison)
• Analytical sensitivity (limit of detection)
• Analytical specificity (including interfering substances)
• Analyte stability
• Patient correlation studies
• Linearity
• Carryover
• Analytical measuring range, reportable range
• Reference intervals, normal range
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Inclusion and Exclusion Criteria
Example: automated hematology analyzers
• Inclusion criteria
• EDTA specimens collected in the tubes normally used by the site
• K2EDTA preferred if options available
• Test samples within 8 hours of phlebotomy
• To minimize aging effects on CBC mneasurands
• Exclusion criteria
• Visibly hemolyzed specimens
• Visibly clotted specimens
• Insufficient blood collected
• >8h old
• Unless an aging study is part of the experiment
• Analyte stability
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Precision (Reproducibility)
• Within Run Precision:
• Assay each level of control material 20 times in a single batch
• Between Run Precision:
• Assay each level of control once per day for 10-20 days
• Calculate the mean, standard deviation, coefficient of variation for
each control material
• Compare with manufacturer’s published performance specification
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Accuracy (Method Comparison)
• Analyze samples (e.g. 100 samples for PLT concentration, or 400-
cell WBC differential)
• Samples on both new and old/reference methods (run within 2 hours
of each other)
• r value of 1 is perfect! (aim for r2 >0.95)
Vis JY, Huisman A. Verification and quality control of routine hematology analyzers. International journal of laboratory hematology.
2016 May;38:100-9.
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Interfering Substances
• Analyte Specificity
• Ability to unequivocally assess the analyte in a standard specimen in
the presence of other components (interferences)
• Should be recognized and procedures for dealing with them
required; examples:
• Icteric/Lipid plasma – saline replacement procedure
• Cryoglobulins/Cold agglutinins – warm sample
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Detection of Interferences
Interference (examples) Measurands Potentially Affected
Leukocytosis Hb, Plt, RBC, MCV
RBC rouleaux or agglutinates RBC, MCV
Plt aggregates Plt, WBC, differential
RBC microcytosis Plt
Lysis-resistant RBC (Hb-S, Hb-C) Hb, WBC, differential, NRBC
Microclots MCV, Plt, MPV
Thrombocytosis, macrothrombocytes EBC, RBC, Hb, Plt, MPV
Lipemia, chylomicronemia Hb, WBC, differential, Plt, eosinophils
Parasites (e.g. malaria, filaria) Eosinophils, monocytes
Hyperbilirubinemia Hb
CLSI H26-A2: 2010 Validation, Verification, and Quality Assurance of Automated Hematology Analyzers, 2nd edition
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Specifications Overview
For hematology:
• Limit of blank
• Background noise
• Lower limit of detection (LLoD)
• Average of the background results plus a constant multiplied by the SD of the
background results
• Lower Limit of quantification (LLoQ)
• The lowest WBC and Plt concentrations used, %CV measured to identify which
concentration
https://validationmanager.com/
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Carry Over
• Expressed as a percent effect of one sample on the
succeeding sample
• “High target value” (HTV) concentrations are
processed in triplicate, followed by three “low target
value” (LTV) specimens (e.g. WBC, RBC, Hb, and Plt)
• Calculation:
• %Carryover=(𝑳𝑻𝑽𝟏−𝑳𝑻𝑽𝟑)
(𝑯𝑻𝑽𝟑−𝑳𝑻𝑽𝟑)x 100
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Linearity (Analytical Measuring Interval)
• To provide results proportional to the concentration of the analyte
within a given range
• Duplicate dilution series
• Plot average values against % dilution; Line of best fit
• Acceptance criteria based on the statistical correlation coefficient of
linear regression
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Analytical Reportable Range
• Analytical measurement range (AMR)
• The interval between the upper and lower analyte concentrations for which the
analytical method has demonstrated a suitable level of precision, accuracy, and
linearity without pretreatment (dilutions)
• Reportable range (RR)
• Range of analyte concentrations in which the analytical method demonstrates
suitable level of precision, accuracy, and linearity with pretreatment (dilutions
or concentrations)
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Reference Range
• Collect samples from a healthy population
• Should not be hospitalized or clinic patients unless necessary (pediatric,
geriatric)
• Questionnaire can be used for exclusion criteria
• Written consent form required
• 120 (ICSH recommendations) for each age/gender reference interval run over
10 –20 day
• Reference range is mean +/- 2SD, if results follow gaussian distribution
• Should be verified when established; e.g.
• 20 for each age/gender reference interval run over 3 –4 days
• ≤10% outside range of 95% confidence interval acceptable
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Calibration
• Adjusting the analyzer using a traceable calibrator
• Set-point
• For automated hematology analyzers, whole blood cross-reference
check is performed
• Calibrator characteristics
• Assigned values
• Stability
• Labeling
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Constant and Proportional Bias
• Difference between the test results and the true value
• zero bias calibration factor = 1.00
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Calibration Verification (Verification of Set-Point)
• Recommended after changes of reagent lots, major maintenance,
significant change in QC data, or when recommended by the
manufacture
• Materials for calibration may include, but are not limited to
• Calibrators used to calibrate the analytical measurement system
• Materials provided by the vendor for this purpose
• Previously tested unaltered patient specimens that are still “fresh”
• Primary or secondary standards or reference materials with matrix
characteristics and target values appropriate for the method
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Statistics
• Mean Average value of a group of test results
• SD = 𝑿−𝒎𝒆𝒂𝒏𝟐
𝒏−𝟏
• Coefficient of Variation (%CV): 𝑺𝑫
𝒎𝒆𝒂𝒏x100
• Expressed as a percentage
• Sensitivity 𝑨 (𝑻𝑷)
𝑨 𝑻𝑷 +𝑪(𝑭𝑵)
• Specificity 𝑫 (𝑻𝑵)
𝑩 𝑭𝑷 +𝑫(𝑻𝑵)
• Positive predictive value 𝑨 (𝑻𝑷)
𝑨 (𝑻𝑷)+𝑩(𝑭𝑷)
• Negative predictive value 𝑫 (𝑻𝑵)
𝑪 𝑭𝑵 +𝑫(𝑻𝑵)
Positive Negative Total
Positive A B A+B
Negative C D C+D
Total A+C B+D
Reference method
New
meth
od
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ROC Curves
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Point of Care Test Set Up
• Which instrument to choose, who will pay for it, verify billing
• What test(s) will be performed, what is the specimen type
• Where will testing be performed by who (qualifications of the
personnel)
• Set up IT connectivity, set up QC and PT/EQA including review of
these results
• Appoint a POC coordinator: oversees training and competency
assessment, writing SOP, etc.
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Point of Care Device (POCD)
Bland-Altman Plot Linear regression
Louw S, Mayne AL, Wan YO, Mayne E. Validation of the Mission Point-of-care device for haemoglobin measurement. International
Journal of Laboratory Hematology. 2020 Oct 3.
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Useful Websites
• Lab Management: TM committee:
http://transfusionontario.org/en/documents/?cat=transfusion
• CMA code of Ethics and Professionalism, updated 2018 link:
• https://www.cma.ca/cma-code-ethics-and-professionalism
• www.WHMIS.org
• www.Westgard.com
• www.islh.org education –webinars: Hematology Test Validation. Dr.
Kandice Marchant
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References
• CLSI-quality system regulation for laboratory developed tests
• Johnston A, Bourner G, Martin T, McFarlane A, Good D, Padmore R, Raby A, Aslan B. Guidance for quality control
practices and precision goals for CBCs based on IQMH patterns-of-practice survey. International journal of laboratory
hematology. 2018 Aug 23;41(1):15-22.
• Rosenbaum MW, Baron JM. Using machine learning-based multianalyte delta checks to detect wrong blood in tube
errors. American Journal of Clinical Pathology. 2018 Oct 24;150(6):555-66.
• Louw S, Mayne AL, Wan YO, Mayne E. Validation of the Mission Point-of-care device for haemoglobin measurement.
International Journal of Laboratory Hematology. 2020 Oct 3.
• Hickson GB, Pichert JW, Webb LE, Gabbe SG. A complementary approach to promoting professionalism: identifying,
measuring, and addressing unprofessional behaviors. Academic Medicine. 2007 Nov 1;82(11):1040-8.
• Vis JY, Huisman A. Verification and quality control of routine hematology analyzers. International journal of laboratory
hematology. 2016 May;38:100-9.
• Hoo ZH, Candlish J, Teare D. What is an ROC curve?.
• CLSI H26-A2:2010 Validation, Verification, and Quality Assurance of Automated Hematology Analyzers, 2nd Edition
• 2020 Canadian Standards Association
• Hematology: McFarlane et al, Int J Lab Hematol 2015
• Pai M et al. Am J Clin Pathol 2011;136:836-841