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5. Statistical

Methods

6. Internal quality

Control: Concept and implementation

7. External quality

assessment QA/ Proficiency Testing PT: concept and implementation

8. Laboratory

Accreditation

5. Internal quality Control

It is a set of in-house procedures undertaken by laboratory staff for the continuous monitoring of daily operation

and decide whether the results

of measurement are reliable enough to be released for supporting quality

patient care.

ICQ is an accreditation requirement.

To verify the attainment of the intended quality of results, the

control system provide staff members with clear and easily understood information of

which to base technical and medical decisions (example)

http://www.sciencedirect.com/science/book/9780124078215

http://informahealthcare.com/doi/abs/10.1080/00365518709168460

http://www.pubfacts.com/detail/8546372/The-quality-assurance-system-in-clinical-chemistry.

http://www.pubfacts.com/detail/23924597/Quality-Control-Analytical-Methods:-Selecting-and-Analytical-Method.

Purpose of ICQ

1.

To monitor the accuracy and precision of the entire analytical process

2.

To detect immediate errors that occur because of test-system failures,

adverse environmental conditions and performance of operators

3.

To monitor over time the accuracy and precision of test performance

that may be influenced by changes in system, environmental conditions and

performance of operators

Define

1.

Accuracy

Closeness of the

agreement between the result of a measurement and a true value of the measured

http://hkaml.org/documents/Final_Printing_Version_Sept_2009_A_Practical_Guide_To_IQC_HKAML.pdf

2.

Precision

Closeness of

agreement between quantity values obtained by replicate measurements of a

quantity, under specific condition.

3.

Random Error

The dispersion of

independent test results obtained under specified condition. It expressed

as the maximum allowable coefficient of

variation (CV%) of the test in a

set of replicate measurement.

4.

Systemic error

The difference between the average result obtained by a

procedure under specified conditions and an acceptable reference

value or the deviation of the mean from the target value.

Bias is expressed as the maximum allowable difference (Delta diff ) of an average result in a set of

replicate measurement and its expected reference value.

Control

Material or preparation used to monitor the stability of the

test system within predetermined limits.

·

From

Westgard http://www.westgard.com/glossary.htm#b

·

Bias. A systematic difference or systematic

error between an observed value and some measure of the truth.

Generally used to describe the inaccuracy of a method relative to a

comparative method in a method comparison experiment. It also has a specific

meaning in the statistical t-test, where bias equals the difference between

the mean values of the two methods being compared or the average of all the

differences between the paired sample values.

Analytical Run

Generally defined by CLIA as an 8 hour to 24 hour interval during which

control materials must be analyzed. According to CLSI C24, a run is “an

interval (i.e., a period of time or series of measurements) within which the

accuracy and precision of the measuring system is expected to be stable. In

laboratory operations, control samples are analyzed during each analytical run to

evaluate method performance; therefore the analytical run defines the interval (period of

time or number of

specimens) between evaluations of control results. Between quality

control evaluations, events may occur causing the measurement process to be

susceptible to variations that are important to detect.”

1. Define the quality requirement for the test.

2. Determine method precision and bias.

3. Identify candidate IQC procedures.

4. Predict IQC performance.

5. Set goals for IQC performance.

6. Select an appropriate IQC procedure.

Set up IQC system

1.

Quality Planning

l Define the quality

requirement of the test

Analytic requirement for all assays should be in the form of an allowable total error

The total allowable

difference from the accepted reference value seen in deviation of a single

measurement from the target value.

2.

Determine method precision and bias

1)

Precision check

2)

Analyze samples of the control material (manufacturer of

Third Party) by the analytical method to be controlled on at least 20

different days

3)

Calculate the mean, standard deviation & CV%

for the results for each control material being used

4)

Compare the imprecision with our quality

requirement

“Control charts are set up based on

estimates mean and SD (the standard deviation of the mean) calculated with a

limit number of runs during a preliminary period.

During that period, the assessment

of mean and SD and later the acceptable range is a pivotal step for the set up

of the QC chart. The goal is to differentiate between variability due to chance from

that due to error.”

Determine method Bias

Bias check, run a set of EQAP

sample by the analytical method

Compare the results of EQAP sample

by the analytical method with those of peer groups.

All values exceed =/-2 SD to be unacceptable

3.

Identify candidate IQC procedure

IQC involved the analysis of control materials alongside the routine

test samples. The laboratory must establish the frequency, type and number of QC that monitor the entire

analytical process:

I.

Fixed time intervals,

II.

randomly scheduled within fixed time intervals,

III.

scheduled at random intervals,

IV.

average intervals between QC events was set on 8

hours for all scheduling strategies

Level of QC: number

of analytical runs and specimens analyzed per day

Less than 50 samples

per day: apply at least one level of QC once per day

Between 50-100

samples per day: apply at least two level of QC once a day

More than 100

samples per day: apply at least two level of QCs twice a day.

Six Sigma Principles

Sigma= (Tea-bias)/

precision

4.

Set goals for IQC performance

1.

The goals of IQC is to catch all significant

errors without repeating test unnecessarily

2.

A significant error is defined as a wrong answer

that cause a change in the diagnosis or treatment of a patient, or a

failure in proficiency testing

5.

Select an appropriate IQC procedures

Since Analytes show

varying biological variation and assays show varying accuracy and precision. To

detect significant errors.

To determine the QC

rules for an assay that are specially based on 1) its total allowable Error (TEa) 2) Its specific performance

TEa=allowable error based on CLIA requirements for proficiency testing

or determined from individual and group biological variance

The appropriate IQC procedure is one that has at least a 0.90

probability or 90% chance of detecting

medically important errors (Ped >0.90) and a maximum 0.05 probability or 5% chance of false

rejections (Pfr

QC material

1. General

requirement: Control material needed

to different from calibrator material.

2.

QC material used must cover the analytical concentrations encountered.

Low/normal/ high or normal and abnormal controls as appropriate for the test

3. Controls independent of those produced by the manufacturer of the test

or analyzer should be used.

4.

QC material may be provided by the

instrument manufacturer or by an independent control manufacturer (Third party).

Third Party controls are formulated independently form system manufacturer’s

calibrators and control.

5.

These controls are not limited to use with specific instruments or reagent lots;

consequently they help to provide an unbiased assessment of method or system

performance.

6.

Third party controls are good indictors of the validity of your complete

analytical process, thus better patient care.

Properties of QC material

1.

Matrix of

QC material should be resemble of human

sample

2.

The analytic concentration should

be at medically significant levels

Cover

the clinically important range of analyte’s concentration

3.

Constituent should be stable for a long period of time

4.

Once QC is opened for use,

manufacturer claimed stability should be strictly followed

5.

QC materials may be assyed and

unassyed. Liquid form (ready to use, reconstitution is not required) and lyophilized are available

for use

6. The

control material should be ready to use and require

minimum preparation.

7.

Price should be reasonable

adjusted for different packing

8.

The control should be tested in the same manner as patient

sample

9.

Worldwide report provided for peer

group comparison

http://www.physics.umd.edu/courses/Phys276/Hill/Information/Notes/ErrorAnalysis.html

L6. External Quality

Assurance Program

External Quality Assurance Program EQAP is a

program in which multiple sample are

periodically sent to members of a group of laboratories for analysis and/

or identification; whereby each laboratory’s results are compared with those of other laboratories in the group

and/or with as assigned values, and

reported to the participating laboratories and others” National committee

for clinical laboratory standards

Benefits

of EQAP

1. Accreditation requirement

by Hong Kong Laboratory accreditation scheme

2. Peers comparison on tests

performance

3. Maintain result accuracy

EQAP,

service provider

Bio-rad(

12 sample per year, Lyophilized serum sample)

CAP

(3 batch /yr @5 samples Liquid samples)

RCPA

(48 or 24 per year Lyophilized serum sample)

Chose RCPA?

1. Increase the samples

frequency, these data provide us with more confidence that the result are

reliable and fit for clinical use (medical decision)

2. Chose the EQAP with high

number of participants, increase the peer group size. The laboratory can see

the result they are reporting are consistent with the

results reported by other laboratories using the same methodology.

3. Cost versus benefits

l

Extensive range of programs, extensive method classification system

l

Unique range of reports ( interim, end of cycle, KPI and supervisors)

l

Online data entry, friendly, prompt customer service

l

Target values are set by using international CDC reference

laboratories ( if organizers cannot establish target values, use overall median

as the expected value)

l The acceptable range for

results is determined by allowable limits of

performance

l

Overall QA objectives are listed in Quality

manual

Three

type of reports for reviewing analytical performance:

Performance

summary report, End-of cycle report, Error analysis report

EQAP

1.

To monitor the accuracy and precision of our tests

2.

It provide a valuable database for reviewing methods, instruments,

reagents and calibrators.

3.

It showed the number of laboratories using particular systems for selection

of instrument for future development

4.

Sharing of accreditation experience, common nonconformities encountered

in assessments using ISO15189.

Corrective and preventive action Report

l

All EQAP specimens should be treated as patient specimen

l

The EQAP specimen will MIMIC like patient specimens and go through

different stages of analytical cycles, pre-analytical stage, analytical stage

and post analytical stage

l

Prepare standard operating procedures for EQAP

SOP for Pre-analytical stage:

1.

check that instruments have been calibrated and the

performance of the analytical system is under proper control

2.

Follow RCPA recommended procedure to reconstitute the QAP specimen

3.

Reconstitute the EQAP sample with matched diluent

4.

Alkaline phosphatase and Troponin I should be analyzed within 1 hour of

being reconstituted, otherwise sample should be frozen

5.

The constituents are stable for 5 days after reconstitution when stores

at 2-8 C

6.

Create and ID number for RCPA chemical pathology specimen

7.

All chemical pathology EQAP will be registered in the LIS through this

unique ID number

8.

Analysis date: one week before RCPA due day for submission

9.

Responsible person: chem Bench, AMT or medical Technologist

SOP for Analytical stage:

1.

Follow the standard operating procedures of your laboratory instrument

for sample analysis

2.

Responsible person: chem Bench, AMT or medical Technologist

SOP for Post-analytical stage

1. MT will follow the authorization guideline and sign out

procedure to issue report

2. To prevent clerical error, submitted result will be cross-checked by

another AMT or Medical technologist

3. A printed result will be issued for successful entry

4. Responsible people: Chem bench, medical technologist

IF reports have high

or low comments?

1.

Check clerical error

2.

Performance of peer group

3.

QC performance on that particular day

4.

check if there is a change in the lot number of

calibrator or reagent

5.

Check if there is any major maintenance procedure

performed such as replacement of new source lamp, reagent and sample probe

6.

Inform the manufacturer to follow our cause

Consider both

manufacturer and third party contract

Lecture 8 Laboratory accreditation

Accreditation is a voluntary, third party-reviewed process, a formal recognition

given by an authoritative

body to acknowledge that a laboratory is competent to perform specific

examinations.

As part of

accreditation, a laboratory's quality management system is thoroughly evaluated on a regular basis to ensure continued

technical competence and compliance with ISO/IEC 17025.

Laboratory

accreditation can only be granted by an accreditation body.

Example:

The college of American Pathologists USA (CAP) runs CAP 15189 program that provides

accreditation to ISO 15189, an international quality standard for medical

laboratories.

The National Association of testing Authorities, Australia

(NATA):is the authority

responsible for accreditation of laboratories, inspection bodies, calibration

services, producer of certified reference materials and proficiency testing

scheme provider throughout Australia.

What is ISO 15189?

It is an international standard, based on ISO/IEC 17025 and

ISO 9001, that specifies requirements for competency and quality that are

particular to medical laboratories.

ISO 15189 focuses on the continuum of care directly connected with improved patient

safety, risk mitigation and operational efficiency.

Objective of Laboratory

accreditation

1. Confer official recognition to competent

laboratories

2. Upgrade standard of testing

3. Greater private sector role in safety and quality

standard

4. Reduce government expenditure

Accreditation schemes in Hong Kong:

Hong Kong

Accreditation service (HKAS) by government of Hong Kong

Offer

accreditation to laboratories, certification bodies, inspection bodies,

proficiency testing providers and reference material producers.

HKAS is formed

through the expansion of Hong Kong Laboratory accreditation scheme (HOKLAS).

Characteristics of HOKLAS

1. Voluntary

2. Accept application

from public and private organizations

3. Accreditation criteria

based on international standards

4. ISO 15189- for medical

laboratories based on 17025

5. ISO/IEC 17025 for

laboratories

QMS as well technical

competence requirements

Focus on valid test

results

6.

International recognition Independent and impartial

Rights & Obligations

of accredited labs:

1.

Offer full cooperation during on site assessments

2.

HOKLAS endorsed reports meet requirements

3.

Inform HKAL any significant change

4.

Participate in Proficiency testing

5.

Inform HKAS complaints unresolved within 60days

6.

Comply with relevant HKSA & HOKLAS regulations and criteria

7.

Only claim accreditation in respect of service accredited

8.

Pay Fees (HKLAS 0006)

9.

Reports and HOKLAS accreditation not used in misleading manner

10. Same standard of

service to all clients

6 disciplines:

anatomical pathology, chemical pathology, clinical microbiology and infection,

hematology, immunology and medical genetics

HOKLAS

accreditation procedure

1.

Organization submits and

application with its quality manual and other documents. HKAS executive reviews

the organization’s documents to determine if an appropriate quality system has

been established.

2.

HKAS executive pays an

advisory/ pre-assessment visit if necessary

l answer any questions relating to technical criteria and regulations

l Advise on any obvious improvements to existing practice as

necessary.

l Advise on probable calibration requirements for the tests for which

accreditation is being sought.

l Comment on acceptability of organization’s quality manual.

3.

Preparation for assessment:

The organization submits the final copies of it quality manual and

test procedures. HKAS executive seeks any further information required from the

organization and arrangement of a on-site assessment.

4.

Rigorous on-site assessment

conducted by a HKAS assessment team and assessment findings reported to the

organization.

l All key organization personnel shall be available for interview

during the on-site assessment

l The organization may be asked to undertake typical tests as part of

the assessment process.

l Assessment report: recommendation for granting of accreditation for

all or part of the scope sought by the applicant organization

l List of any action which may be necessary before accreditation for

all or part of the scope that can be further consider, details of follow-up

action.

5.

If the outcome is satisfactory,

accreditation granted.

l For reassessment and assessment for extension of accreditation

within a test category/ certification system/inspection field for which the

organization is already accredited. Report reviewed by HKAS executive

l For initial assessment: assessment report reviewed by HKAS executive

and accreditation advisory board

6.

Remedial actions if required

The applicant organization submit the documents of remedial actions

have been taken. HKAS will take follow up action and on-site assessment if

required.

Assuming the remedial actions are found acceptable, a recommendation

for accreditation will normally follow. A formal notification letter and

certificate of accreditation will be issued.

7.

After accreditation

l After accreditation has been granted, accredited organization are

reassessed the following year and thereafter at intervals normally not exceeding two year.

l Socope of accreditation extended or reduced or they may seek changes

to their approved personnel: require on site assessment

l Required to time to time to participate in proficiency testing

programmes organized or specified by HKAS

l Under HKAS regulations to advise the HKAS executive in writing any

changes in the organization’s circumstance which may affect the continued

conformity with HKAS requirements.

Change in ownership and name of the accredited organization

Its organization structure and managerial staff, approved

signatories, organizational policies, its registered address or any place where

the accredited activities are to be carried out, working procedures and

resources( personnel, equipment, facilities), nature of work performed by an

accredited organiszation

ISO 15189:2012 : the

transition period for the implementation will conclude on 1 Mar 2016. NEW

edition of HKLAS 015 5th edition

Westgard

rule summary

Westgard Rules are multirule QC rules to help analyze whether or

not an analytical run is in-control or out-of-control. It uses a combination of

decision criteria, usually 5 different control rules to judge the

acceptability of an analytical run.

By comparison, a

single-rule QC procedure uses a single criterion or single set of control

limits, such as a Levey-Jennings chart with control limits set as either the mean plus or minus 2 standard

deviations (2s) or the mean plus or minus 3s.

"Westgard

rules" are generally used with 2 or 4 control measurements per run, which means they are appropriate when two

different control materials are measured 1 or 2 times per material, which is

the case in many chemistry applications. Some alternative control rules are

more suitable when three control materials are analyzed, which is common for

applications in hematology, coagulation, and immunoassays.

Warning

rules

12s

One control

measurement exceeding 2 standard deviations of control limits either above or

below the mean.

This rule is used

a warning rule to trigger careful inspection of the control data.

41s

This rule rejects

a run with the 4th consecutive control measurement exceeding 1 standard deviation

on the same side of the mean.

10x

This rule rejects

a control run when there are 10 consecutive controls on the same side of the mean.

The warning rule is broken when one control

measurement exceeds the +-2 SD guideline.

The other rules must now be tested by examining other

control values in run (Within run) and in previous (across runs) before making

a decision on the acceptability of the patient result.

If any of the remaining rules are violated, the

laboratory professional must thoroughly examine the test’s analytical

procedure, troubleshoot steps in procedure, and or perform instrument

maintenance, etc before making any decision about releasing the results or

re-running the test.

Rejection Rules

13s

This rule is

commonly used with a Levey-Jennings chart when the control limits are set as

the mean +3 standard deviations of control limits. A run is rejected

when a single control measurement

exceeds the mean +3 control limits.

The within-run

only rule: detect random error for a control but may also point to systematic

error. The run is considered out of control when one control value exceeds

the +-3SD limits.

But

random errors may occur with no warning and for unknown reason.

Repeating

a control when it is out of range often remedies the situation.

Note that the errors for

patient specimen are not detected as this refers only to control.

22s

The control run is

rejected with 2 consecutive control

measurements 2 standard deviations of control limits on the same side of mean

with this rule.

Two-consecutive

control rule: is designed to detect systematic error and can be applied within and across

runs. It is violated when two consecutive control values exceed the same +-

2SD limit.

R4s

This rule rejects

a run if two control measurements in a group exceed the mean with a 4 standard

deviation difference between the 2 controls

The range rule is applied within the same

run only to detect random error.

It is violated when the SD difference between

two consecutive contraol values exceeds 4SD. The 4SD spread may occur across

the mean value and include a positive and a negative value from the mean.

If a systematic change occurred between two runs,

perhaps due to a calibration problem, the R4s rule would respond to this

systematic change as well as any change in random error. Because we want to use

these rules to give us some indication of the type of error occurring (which

would help us in trouble-shooting the method), we prefer to use the R4s rule only within a run and detect between-run systematic changes with other rules such as the

22s or 41s. Not everyone

agrees with this and some analysts choose to apply the R4s rule across runs,

so be sure to look carefully at how the R4srule is being applied in your

own laboratory.

https://www.westgard.com/lesson74.htm#1

How do you perform

multirule QC?

You collect your control

measurements in the same way as you would for a regular Levey-Jennings control

chart. You establish the means and standard deviations of the control materials

in the same way. All that's changed are the control limits and the

interpretation of the data, so multirule QC is really not that hard to do! For

manual application, draw lines on the Levey-Jennings chart at the mean

plus/minus 3s, plus/minus 2s, and plus/minus 1s. See QC - The Levey Jennings chart for

more information about preparing control charts.

In manual applications, a 12s rule

should be used as a warning to trigger application of the other rules, thus

anytime a single measurement exceeds a 2s control limit, you respond by

inspecting the control data using the other rules. It's like a yield or warning

sign at the intersection of two roads. It doesn't mean stop, it means look

carefully before proceeding.

How do you "look

carefully"? Use the other control rules to inspect the control points.

Stop if a single point exceeds a 3s limit. Stop if two points in a row exceed

the same 2s limit. Stop if one point in the group exceeds a plus 2s limit and

another exceeds a minus 2s limit. Because N must be at least 2 to satisfy US

CLIA QC requirements, all these rules can be applied within a run. Often the 41s and

10x must

be used across runs in order to get the number of control measurements needed

to apply the rules. A 41s violation

occurs whenever 4 consecutive points exceed the same 1s limit. These 4 may be

from one control material or they may also be the last 2 points from a high

level control material and the last 2 points from a normal level control

material, thus the rule may also be applied across materials. The 10xrule

usually has to be applied across runs and often across materials.

Computer applications don't

need to use the 12swarning

rule. You should be able to select the individual rejection rules on a

test-by-test basis to optimize the performance of the QC procedure on the basis

of the precision and accuracy observed for each analytical method and the

quality required by the test.

What is N?

When N is 2, that can mean 2

measurements on one control material or 1 measurement on each of two different

control materials. When N is 3, the application would generally involved 1

measurement on each of three different control materials. When N is 4, that

could mean 2 measurements on each of two different control materials, or 4

measurements on one material, or 1 measurement on each of four materials.

In general, N represents the

total number of control measurements that are available at the time a decision

on control status is to be made.

https://www.westgard.com/mltirule.htm

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