statistics & graphics for the laboratory 54 metrological basis of iqc introduction the error...

Statistics & graphics for the laboratory 1

Metrological basis of IQC


Introduction• The error concept chosen here• The total error concept• Total error – calculations• Instability of the analytical process

Instability and analytical process specifications• Instability – how much can be tolerated?• Analytical process specifications - TEa• IQC and TEa

The error model for IQC• Basic formula• Critical errors• Graphical presentation of critical errors• Calculation of critical errors

Special topic: The TEa problematic

Control rules based on TEa• Automatic selection of rules based on TEa: The Validator• OPSpecs®-Charts• Critical error graphs• Selection of a control rule based on TEa with the Validator: an example• Other selection tools: the TEa/CVa,tot ratio; the IQC decision tool

• Summary and Conclusion



Introduction

FOREWORDCurrently, there is confusion about metrological terms. While the term error is used in the metrological “bible” (VIM [1]), it is deprecated in one of the recent ISO concepts (GUM [2]). This concept, even, recommends to avoid the distinction between random and systematic effects (= uncertainty concept: GUM).Moreover, ISO uses the concept of accuracy [3]:Accuracy = Combined trueness & precisionInaccuracy = Combined ([untrueness]: note: this term is not defined by ISO) and imprecision.Note: Some traditions link accuracy to systematic error.

This book uses the [total] error concept (Adapted from: Stöckl D. Scand J Clin Lab Invest 1996;56:193-7):Total-, systematic-, and random error[In]Accuracy: combined [“un“]trueness and [im]precisionExperimental estimates: Total error, bias, SDNote: all experimental estimates have a statistical uncertainty!

References[1] ISO VIM. Vocabulaire international des terms fondamentaux et généraux de métrologie.[2] ISO GUM. Guide to the expression of uncertainty in measurement.[3] ISO 5725-1. Accuracy (trueness and precision) of measurement methods and results.

Classical metrological error concept:distinction of random and systematic error.

Inaccuracy, “untrueness“ and imprecision:pendents for total-, systematic-, and random error.

Note: All experimental values (bias, s) have a certain statistical level of probability («±uncertainty»).



The total error (TE) concept

The term "total error" (TE) (#) is applied to measurement results that are influenced by random (RE) and systematic (SE) components of error.

Calculation of TE for single measurements:TE = SE + z • RE, or TE = SE + z • s

– (z is usually set to 1.96 or 2.58, encompassing 95% or 99% [two-tailed] of a gaussian distributed population)

Calculation of TE for multiple measurements:TE = SE + tn-1 • [s/n]

– s = the standard deviation, n = number of measurements, tn-1 = student's t-

value for (n-1) degrees of freedom (e.g., at the 95 % confidence level)Note: Random error can be reduced by increasing the number of measurements, systematic error cannot.

Instability of the analytical processes- Due to occurrence of systematic error (1)- Due to increased random error (2)

References#Random, systematic, and total error of measurement [adapted from: Westgard JO, Barry PL. Cost-effective quality control. 4th printing. Washington: AACC Press, 1995]


Instability – how much can be tolerated?The answer is: Poor analytical quality must not invalidate the medical decision!The conclusion is: We have to know the medical requirements for analytical quality («analytical process specifications») Allowable total error (TEa).

Analytical process specifications - TEaConcepts and numerical examples can be found in the literature below (#).Note: Optimally, TEa should be medically justified!

IQC and TEaObservationThe statistically defined "stop-limit" of IQC (TEIQC; e.g., 3 s) may be much lower

than medically relevant (e.g., triacylglycerides).The ideaLet's stop the process at a medically relevant (or otherwise defined) allowable total error: TEa (TEa: also called "quality specification").AdvantagesIf TEa >> TEStable,

"very loose" IQC-rules can be selected.

Prerequisite for IQCTEstable < TEa

There must be some room left for the IQC-procedureNote: IQC cannot transform an intrinsically poor method into a good method

#References• Strategies to set global analytical quality specifications in laboratory medicine. Consensus Statement, Stockholm 1999. Scand J Clin Lab Invest 1999;59:585• Stöckl D, Baadenhuijsen H, Fraser CG, Libeer J-C, Hyltoft Petersen P, Ricós C. Desirable routine analytical goals for quantities assayed in serum. Eur J Clin Chem Clin Biochem 1995;33:157-69. • www.westgard.com


Instability and analytical process specifications

How much instability?TEIQC, max < TEa work within

specificationsTEIQC,max: Maximum total error

guaranteed by the IQC-procedure (95% of results should be within ±TEa)



The error model for IQC

Basic formula (#)TE = Bias + [SEcont • smeas] + z • [REcont • smeas]

• Bias: method bias, usually assumed to be zero• SEcont: change in systematic error that can be detected by the quality control

procedure• smeas: measured, intrinsic standard deviation of the test

• REcont: change in random error that can be detected by the quality control

procedure• z: statistical multiplier related to the portion of a distribution exceeding a quality requirement ("defect rate")Note: mostly, a z-value of 1.65 is selected to obtain a 5% defect rate (one-tailed). When pure random error is addressed, a z-value of 1.96 is selected to obtain a 5% defect rate (two-tailed).

Critical random and systematic error definition:• The amount of error that places 5% of results outside TEa.• The role of IQC is to detect process deterioration before >5% of the results exceed TEa.

Graphical presentation of critical errors

References # Westgard JO, Barry PL. Cost-effective quality control. 4th printing. Washington: AACC Press, 1995]

Introduction of an SE that places 5% of results outside TEa: SEcrit = 2

Increase of an RE that places 5% of results outside TEa: REcrit = 2(REi = intrinsic or stable imprecision)



Calculation of critical errors

Assumption of imprecision and biasCritical random error (REc) and critical systematic error (SEc) can be calculated that cause measurements to exceed TEa in 5% of the cases (= defect rate) due to either increased imprecision or increased systematic error.

Formulae for a 5% defect rate:• Case with SEc = 0

REc = (TEa - bias)/1.96 • smeas;

• Case with REc = 1SEc = [(TEa - bias)/smeas] - 1.65

Assumption of zero biasFor the purpose of IQC, the bias of the method often is assumed to be zero.This is justified if a laboratory establishes its own IQC target values or if it can verify the system-specific target values of commercial IQC materials.

Formulae for REc and SEc with bias = 0• REc = TEa/1.96 • smeas;

• SEc = (TEa/smeas) - 1.65

Note: For simplification, the QC-Validator® program applies the default factor 2 (for RE and SE) for the stable process (elder versions: 1.65!). The factor may be changed by the user.

Checklist – Metrology and rule selection

Metrology, knowledge of• The total error concept (TE, SE, RE)• Concept of maximum allowable total error (TEa) (process specifications)• Critical error

Rule selection• Statistical basis: A rule is chosen based on Pfr and Ped. SD-limits are taken from

stable performance.• TEa basis: From a specification for TEa, critical error values can be calculated. From the critical error values, adequate IQC rules can be selected, naturally, on statistical basis.• Selection tools: power functions, OPSpecs, the TEa/CVa,tot ratio; the IQC

decision tool


Special topic: the TEa problematic


Introduction

Specifications for TEa, the concepts Clinical Biological

– Notes on IQC rules based on biological TEa– IQC rules from biological TEa and reality

Expert• Summary

Checklist – TEa values



Introduction

BEWAREThere are a lot of misunderstandings when selecting a TEa for IQC purposes. We look into TEa in more detail!

Questions• What is a responsible choice for TEa?• Is there a consensus about TEa?

Investigate current concepts for establishing values for TEa.

Specifications for TEa

Current concepts for TEaThe Table below lists, in hierarchical order, current concepts for establishing values for TEa.

Sources (in hierarchical order#)• Clinical concepts (few analytes)• Concepts based on biological variation• Expert opinion• Regulations• "State-of-the-art" #Consensus Statement (Stockholm 1999). Scand J Clin Lab Invest 1999;59:585. See also: ISO 15196



Specifications for TEa

Inspection of proposed numbers for TEa EXAMPLE: Serum-sodium

When we compare the currently proposed numbers, we can conclude that:• There is no consensus about TEa!• Additionally: TEa may depend on concentration/disease

Source TE (%)

Biological variation 0,9%(Ricos data, “Westgard page”)

¼ of the 2,2%reference-interval

American EQA (CLIA) 2,9%(mean of ref. int.)

German EQA 5,0%



TE from biology

BUT: Some are too stringent for current technologyBiology gives extreme low values for some analytes: TEa sodium: Ricos: 0.9% (http://www.westgard.com/biodatabase1.htm; but note: CVg on that site = CVb)

Apply a bottom-line##Stöckl D. Desirable Performance criteria … based on biological analyte variation - hindrances to reaching some and reasons to surpass some. Clin Chem 1993;39:913-4.

Bottom-line (for stable process!)CV: 1%Bias: 1,5%TE: 3,2%

Consider to surpass someThink about using more stringent goals than derived from biology the goals are a compromise; account for IQC; some goals are surpassed, by far, by current technique.

• Stöckl D. Desirable Performance criteria … based on biological analyte variation - hindrances to reaching some and reasons to surpass some. Clin Chem 1993;39:913-4.• Tonks: 10% upper limit for TE

Mon DiagSE=0 RE=0 Ricos"0,5" "0,25" "1,65"

Analyte CVw CVb CVg REmax SEmax TEmaxSodium 0.7 1.0 1.2 0.4 0.3 0.9Chloride 1.2 1.5 1.9 0.6 0.5 1.5Calcium 1.9 2.8 3.4 1.0 0.8 2.4Protein 2.7 4.0 4.8 1.4 1.2 3.4Albumin 3.1 4.2 5.2 1.6 1.3 3.9

Mon DiagSE=0 RE=0 Ricos"0,5" "0,25" "1,65"

Analyte CVw CVb CVg REmax SEmax TEmaxUrea 12.3 18.3 22.0 6.2 5.5 15.7Triglycerides 20.9 37.2 42.7 10.5 10.7 27.9CK 22.8 40.0 46.0 11.4 11.5 30.3ALT 24.3 41.6 48.2 12.2 12.0 32.1Bilirubin 25.6 30.5 39.8 12.8 10.0 31.1Iron, total 26.5 23.2 35.2 13.3 8.8 30.7

http://www.westgard.com/biodatabase1.htm



Proposed numbers – How realistic are they?

The numbers proposed by clinical and biological concepts, usually, are desirable numbers (= goals), which would allow medical decisions to be made without compromise of analytical quality. However, the laboratory has to work with “real numbers” = “state-of-the-art” quality.

Comparison of reality with “goals” from biologyThe Figure below compares “ state-of-the-art” quality with desired quality: 1/4 of the reference interval.

[1] TEa = ¼ of the reference interval[2] State-of-the-art total CVa.*Rules calculated with the above TEa and CV values by the Validator(90% assurance; 2 materials; bias: Na 0.5%, Trigl 2%, others: 1%).

ObservationSome state-of-the-art CVs are too big to allow calculation of IQC-rules from biology-derived TEa values, for example, for sodium.

Expert TEa values

Sodium: other numbersKoch, Westgard et al. Clin Chem 1990;36:230-3.We have seen that sodium was a problem for IQC with TEa values derived from biology. For others, however, sodium seems to be very easy for IQC (see below). They propose a 3.5 s rule.Note: TEa was chosen by experts and was the US EQA-limit (2.9%). Additional, their “state-of-the-art” CV (0.5%) seems to be quite optimistic!

CONCLUSIONDon’t cheat yourself by selecting the most liberal TEa values and by underestimating your actual CV.

None1.01.6Sodium

None2.06.5Protein

None2.810Glucose

3.0 s2.715Creatinine

2.5 s2.614Cholesterol

3.5 s2.530Triglycerides

IQC-rule*CV [2]TEa (%) [1]Analyte

None1.01.6Sodium

None2.06.5Protein

None2.810Glucose

3.0 s2.715Creatinine

2.5 s2.614Cholesterol

3.5 s2.530Triglycerides

IQC-rule*CV [2]TEa (%) [1]Analyte

3.5 s0.52.9 (CLIA)Sodium

IQC-rule*CV (%)TEa (%)Analyte

3.5 s0.52.9 (CLIA)Sodium

IQC-rule*CV (%)TEa (%)Analyte


More on expert TEa values

Below, are shown more examples of IQC rule setting by use of expert TEa values (upper example) and by general expert opinion (lower example).

Koch, Westgard, et al. Clin Chem 1990;36:230-33 (see also : Westgard & Stein. Clin Chem 1997;43:400-3).Based on “expert” TEa values, following rules were proposed:13.5s (n = 2) for: Sodium (TEa = 2.9%, CV = 0.5%), potassium, urea nitrogen,

creatinine, phosphate, uric acid, cholesterol, total protein, total bilirubin, GGT, ALP, AST, and LD.12.5s (n = 2) for: Chloride, total CO2.

Calcium was a problem: Compared to TEa, precision was considered as too poor.

Mugan, Carlson, Westgard. J Clin Immunoassay 1994;17:216-22.12.5s (n = 3) for: Prolactin, ß-hCG, CEA, FSH, LH, TSH, ß2-microglobulin.

Experts tend to simple rules; choice is not directly related to medical requirements

Rules selected by general opinionSteindel SJ, Tetrault G. Arch Pathol Lab Med 1998;122:401-8.2.5 – 2.7s rule: generallyTetrault GA. CAP Today 1995 (April):60-1.3.5 s rule: generally Experts tend to simple rules; choice is often more related to considerations about Pfr than to medical requirements. Sometimes, experts change their minds.

Observations Experts tend to simple rules; choice is not directly related to medical requirements Choice is often more related to considerations about P fr than to medical

requirements. Sometimes, experts change their minds.




TEa and IQC

Summary

• Different models give different TEa values• Additionally: TEa may depend on concentration/disease• Many proposals do not account for the needs of IQC• Some values that are recommended are beyond the state-of-the-art of routine methods, or give IQC rules with high Pfr

• Experts tend to simple rules; choice is often more related to considerations about Pfr than to medical requirements. Sometimes, experts change their minds.

• Don’t choose the most convenient TEa.• The most useful general purpose TEa numbers result from the concept of biological variation.

– But, apply bottom-line values

Checklist – TEa values

Apply TEa values from the following hierarchy• 1. Clinical models (e.g., cholesterol; glucose)• 2. Biological variation (obtain the database)• Bottom-line values• No numbers from 1-2: 3. Expert models• No numbers from 1-3: 4. Regulation• No numbers from 1-4: 5. Better state-of-the-art

Note: Critically review the proposed numbers.


Control rules based on TEa


• Automatic selection of rules based on TEa: The Validator• OPSpecs®-Charts• Critical error graphs• Selection of a control rule based on TEa with the Validator: an example• Other selection tools: the IQC decision tool; the TEa/CVa,tot ratio;

• Summary and Conclusion



Selection of control rules based on TEa

Tools for IQC rule decision based on TEa• The Westgard software tools (OPSpecs® chart)• The STT IQC decision tool• The ratio of TEa/total-CVa: should be >4

Automatic selection of rules based on TEa: The Validator®Based on the TEa concept and the calculation of critical errors, the Validator software allows an automatic selection of the most appropriate control rule.

OPSpecs-chartsThe Validator makes use of so-called OPSpecs-charts (“Charts of Operational Process Specifications”) to relate TEa and stable method performance (bias and imprecision) with IQC-rule selection.

Based on a preselected TEa, these charts allow to select IQC rules for different combinations of bias/imprecision (see Figure).• The charts are specific for a specific total error requirement, for example, a chart for a TEa of 5% will differ from one requiring 2%.• A selection between QC procedures for systematic error or random error has to be made and the probability level for error detection has to be specified, for example, 90% (80% for RE), 50%, etc (OPSpecs®-Charts for RE not in EZ rules!). • Imprecision is plotted on the x-axis and bias is plotted on the y-axis. Stable imprecision and bias are plotted as operating point (Figure: 2%/0%).• A selection of IQC-rules is presented.



Critical error graphs

The Validator®

Additionally, it shows the power functions of the rules with indication of the critical error (= critical error graphs).

• Critical error graphs are made for systematic and random error, separately.• They show the power functions for the IQC rules that the Validator proposes.• Additionally, a box is presented that indicates P fr and Ped of the respective rules.

• The critical error is indicated by a vertical line. Usually, it should intersect the power functions at Ped values >0.9 (=90% for error detection).

Note: for the RE graph, the critical error line intersects most power functions at values <0.9. This indicates the generally weaker power of these rules to detect random error!

Oper. Point:RE: 2%SE: 0%



Selection of a control rule based on TEa

EXAMPLE

AnalyteCholesterol

TEa 13%: From German EQA (RILIBÄK)

Assumed stable performanceBias: 0%CVa,tot: 2%

Apply the ValidatorSee OPSpecs-chartThe Validator selects a very convenient rule: 13.5s.

Note: powerful control rules are at the right in the OPSpecs!

ConclusionIf TEa is high: «Easy» rules are selected Attractivity of the approach

WHAT, if TEa is low? Will be discussed later under the topic IQC-POLICY


The Figure shows a simplified version of an OPSpecs® chart. Construction of the lines: TE = SE + k • RE; at RE = 0: SE = TE; all lines start at {RE=0;SE=TE}; they stop at {RE=TE/k, SE=0}

According to the Westgard approach, the operating point of your test (= stable performance) should be left of the TE line with k = 4. If the operating points is located on the right, the TE cannot be controlled in 90% of the cases by IQC.

REMEMBERTEa (preselected!) = SE + k • RE (SE & RE are calculated from TEa)• For the stable process: k = 1.65 or 1.96• For the IQC controlled process: k = 4

Graphical comparison of the process at TEa and of your actual, IQC controlled process (see figure above, the two X-es)

The Figure shows the room for method instability (bias and imprecision) of a process that is controlled with the Westgard approach. Note, the process at TEa, exceeds the TEa in 5% of the cases.

REMARK: TE of the IQC controlled process is ~50% of the stable process!


The OPSpecs® chart: a more detailed look



Remark on the location of the operating point

The Figures below show the expected measurement populations (for different k values) for• an operating point with a low ratio SE/RE (upper Figure)• an operating point with a high ratio SE/RE (lower Figure).

Observations• For low SE/RE ratios, the IQC controlled process is in a robust situation: additional SE does not move it out of TEa.• For high SE/RE ratios, the IQC controlled process is in a labile situation: additional SE quickly moves it out of TEa.

CONCLUSIONThe ratio SE/RE that contributes to a TEa is important!

0-5 5 10 15

SE (%)

Moving along SE/RE = 1/16

-5 0 5 10 15SE (%)

Moving along SE/RE = 16


As already addressed before, different Validator® versions may use different default k values for the stable process: - Either 1,96: pure RE

- Or 1.65: pure SEUsually, both components are present. In practice, there is a gradual move from 1.96 to 1.65 when SE moves from 0 to SE = RE. If SE > RE, the multiplier 1.65 is justified. This has also implications for the IQC controlled process. For this reason, the STT variant was developed.

IQC decision tool – the STT variantThe variant is based on the OPSpecs® charts. From RE = 0, the lines with k = 1.65 (k = 4) are used up to SE = RE. However, from that point on, a line is drawn to the RE point that corresponds to TE/2 (TE/4.85).

IQC Decision tool - Westgard & 2-sided lines

Analyte: TE criterium:Company CV (%): 1,5 Company bias (%): 0,0

TE (%): 10

Legend:

Consulting

NNNN

Stable 1,65sStable 2s

STT

IQC 4sIQC 4,85s

Operating pointSE = RE

0123456789

10

0 1 2 3 4 5 6 7

CV (%)

Bia

s (

%)


Other selection tools

IQC Decision tool - STT

Analyte: TE criterium:Company CV (%): 1,5 Company bias (%): 0,0

TE (%): 10

Legend:

Consulting

NNNN

Stable 1,65sStable 1,65>2s

STT

SE = RE

at SE = RE

at SE = RE

IQC 4sIQC 4>4,85s

Operating point

0123456789

10

0 1 2 3 4 5 6 7

CV (%)

Bia

s (

%)

Problem of the OPSpecs® chartsWhen RE becomes > SE, one moves from the 1-sided case (k = 1,65; k = 4) to the 2-sided case (k = 2; k = 4,85)



The ratio of TEa/total-CVa (EXCEL-file)

The ratio of TEa/total-CVa allows a quick estimate of test performance. This ratio should be >4. However, the ratio depends strongly on the TEa chosen (see also discussion later: special topic TEa problematic).REMARK: bias is not considered by that tool!

The EXCEL-file contains a nearly complete list of TEa and state-of-the-art CVa values for the following analyte groups:• Ion selective electrode (ISE)• Substrates• Enzymes• Specific proteins• Therapeutic drug monitoring (TDM)

TEa criteria are:• Ricos et al., or• 1/6th of the reference (therapeutic) interval

CVa data• State-of-the-art

Summary

IQC rule selection can proceed via• Statistics• TEa and statistics

Development of an IQC policy has to consider both possibilities.

Conclusion

Because regulation and manufacturer recommendations describe minimum IQC, only, the laboratory has to develop an IQC policy itself.

The IQC-policy of the laboratory has to respect statistical and medical aspects and should be developed according to the needs of the laboratory, naturally, respecting the guiding rules of regulation.

Development of IQC policy Laboratory task


IQC policy

IQC policy

Introduction

Software

Samples

Frequency (& location) of IQC measurements

Performance (State-of-the-art)

IQC rule selection– Patient release– Process control– Examples

IQC rules for state-of-the-art performance– Screening with TEa/CVa,tot

– STT IQC decision tool– EZ rules/Validator

Special topics– Calculation of an actual TE[a]– Rule “n” and patient release– Dealing with a bias– IQC rules with wide limits (e.g. 6s) and lot variations– “Fine-tuning” of IQC according to instability

Remedial actions &– Pfr of the IQC rule and frequency of remedial actions

– CVa,tot /CVa,w ratio

– Inspecting IQC charts

Summary


IQC policy

Introduction

The IQC policy will be developed on the basis of the Belgian situation:

RECALL: Koninklijk Besluit

Art. 34. §1. The laboratory director has to organize IQC in all disciplines.

§3. IQC consists of several procedures which allow, before the release of patient results, to detect all significant within- or between-day variations: Remedial actions policy/rule selection

Art. 35. §1. The frequency of control measurements has to be such that it can guarantee a clinically acceptable imprecision. This frequency depends on the characteristics of the method and/or the instrument: Additional: PraktijkrichtlijnControl rules used for start and for acceptance of a run at least 2 IQC events.Rule selection/frequency

§2. The control material, … must be stable within a defined period of time. Different aliquots of the same lot must be homogeneous;Concentrations: Praktijkrichtlijn.Sample requirements

§3. For each new lot, the mean and the SD have to be determined. … IQC materials may, at the same time, not be used as calibrator and control material: Establish stable performance: own targets!


IQC policy

Introduction

On the basis of the Belgian regulation, we will apply all input elements that we have seen to the analytes ISE; substrates; enzymes, specific proteins; TDM.

The elements we have seen (see also “ckecklists”) were:

“Knowledge-base”• -Statistics• -Rule selection• -Metrology/Error concept for IQC• -TEa data, biological variation

State-of-the-art performance data• -CVa,tot, CVa,w

• -Experience from "Peer-IQC"• -Laboratory experience• (also: Questionnaire to participants)

Software tools• -Laboratory IQC software• -EZ-rules• -IQC decision tool/Ratio TEa/CVa,tot

From established rules, we look at the magnitude of undetected errors (e.g., in 10% of the cases)Additionally, we will address the topic

-Remedial actions.

We will develop the policy in an interactive way.

We start with the Laboratory IQC software (see also checklist).


IQC policy

IQC-software

Discussion

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“IQC”-capabilities-Transparent & efficient data presentation-Great variety of rules-Rule selection logic-Automatic release-Automatic “flags” and remedial action(but with open decision logic)


IQC policy

The IQC sample

Samples: §2. The control material, … must be stable within a defined period of time. Different aliquots of the same lot must be homogeneous.Concentrations: PraktijkrichtlijnSee also checklist – Samples Select commercial oneNote: In principle, their target and range cannot be used by the laboratory (Art. 35. §3.) (§3. For each new lot, the mean and the SD have to be determined).

Consider participation in an IQC "Peer"-systemSample advantages due to the high number of participants• System specific target means and SDs • Low target uncertainty• Control of sample stability

Discussion…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………

• Nature-Correspond with patient sample-Compatible with the test

• Concentration: medically relevant-Number of levels

• Stability (liquid versus lyophilized)• Lyophilized

-Variation in fill content-Accuracy of reconstitution

• Target mean-Sufficient digits-System specific-Uncertainty

• Target SD-Representative for system-Uncertainty


IQC policy

Frequency of measurement and location

Frequency: Art. 35. §1. The frequency of control measurements has to be such that it can guarantee a clinically acceptable imprecision. This frequency depends on the characteristics of the method and/or the instrument.

PraktijkrichtlijnControl rules used for start and for acceptance of a run. Frequency: at least 2 IQC events Location: at least at start and end

See also checklist – Frequency and location

Discussion…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….……………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………

• Minimum: 2 samples per run

• Desirable: ~1-2% of patient samples-Make a cost/benefit calculation

• Frequency should be related to test stability: requires knowledge of instrument and test

• Consider “dummy” measurements before 1st IQC

• Frequency may depend on the control rule

• Block: Maximizes chance of assignable cause of variability between subgroups

• Continuous: Maximizes chance of assignable cause of variability within subgroups


IQC policy

Stable performance

Stable performance §3. For each new lot, the mean and the SD have to be determined.The laboratory has to establish its own stable performance data.

REMEMBERThe target SD (= stable imprecision) is the cornerstone of IQC. It deserves special attention. All instabilities (random and systematic) are compared relative to the stable imprecision.

Recommendation 1• Compare your performance with your colleagues (IQC-"Peer")

Advantages due to the high number of participants• Better IQC-sample • Easier set-up of IQC (more reliable estimates of stable performance) • Easier troubleshooting by direct comparison with “peer”

Recommendation 2• Compare your performance with the data from the manufacturer!

See EXCEL-file for an overview about “state-of-the-art” performance data for the Analyte groups• Ion selective electrode (ISE)• Substrates/Enzymes• Specific proteins• Therapeutic drug monitoring (TDM)

A list of total and within-run CV data for analyte concentrations in the reference interval (RI) can be found in the EXCEL-file (sorted by biological CVw).

See also Checklist “stable” imprecision

Note: CV data from concentrations in the RI have been chosen because they will be compared with TEa goals derived from biological variation, which apply to concentrations within the RI.


IQC policy

Stable performance

Discussion

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Gather as much information as possibleInstrument stability (general system robustness), e.g.:• Pipetting• Temperature• Photometer (wavelength/intensity/sensor)

Test stability & reproducibility (individual test robustness)• Total/within-day CV (CVa,tot/CVa,w ratio)• Calibration tolerance (within/between lot), -function• Reagent (within/between lot)• Test robustness

Ideally, a GUM type variance analysis should be available for all important elements.

Decide about approaching the variations by IQC and/or quality assurance.


IQC policy

IQC rule selection

Generally, IQC rule selection can be done on:• Statistical basis: A rule is chosen based on Pfr and Ped. SD-limits are taken from

stable performance.

• TEa basis: From a specification for TEa, critical error values can be calculated. From the critical error values, adequate IQC rules can be selected,

naturally, on statistical basis.

Selection tools are: power functions, OPSpecs, critical error graphs, the TEa/CVa,tot ratio; the IQC decision tool

See also checklists basic statistics; power of control rules; metrology.

Belgian regulation, however …§3. IQC consists of several procedures which allow, before the release of patient results, to detect all significant within- or between-day variations

Art. 35. §1. … guarantee clinically acceptable imprecision?

What is significant; what is clinically acceptable? We need a goal for TEa!

… requires, in principle, IQC rule selection on the TEa basis. see also TEa checklist


Selection of TEa

Discussion

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IQC policy

Apply TEa values from the following hierarchy

• 1. Clinical models (e.g., cholesterol; glucose)

• 2. Biological variation (obtain the database)-Bottom-line values

• No numbers from 1-2: 3. Expert models

• No numbers from 1-3: 4. Regulation

• No numbers from 1-4: 5. Better state-of-the-art

Note: Critically review the proposed numbers.


IQC policy

Example

Selection of the TEa

We select TEa from biology

• TEa from the Ricos concept, and• The most stringent TEa, with bottom-line

We apply TEa to manufacturer’s performance

ExampleSerum GlucoseRicos TEa: 6.3%CVa,tot : 2%

Bias: 0%

ExerciseSTT IQC decision tool

EZ Rules selection: NONE with 90%: see OPSpec (note TEa/CVa,tot = 3.2)

Conclusion from the example: It did not work! We need a “modified TEa approach”


Apply the TEa approach (TEa/CVa,tot ratio; the Validator®/EZ rules; IQC decision

tool) as evaluation tool for current quality.

Analytes that cannot fulfill the TE specifications Decide on the most stringent rule you want to apply (Pfr; n)

Analytes that fulfill TE very easy Decide on the most loose rule you want to apply

All others: decide whether you want to use individually optimized rules:– Different rules– Same rule, but movement– Adapt the frequency (less/more measurements)

• Problem• Optimization always should consider individual test stability!

Example 1: most stringent rule (left)Westgard multirule: 13s / 22s / R4s / 41s

n = 4 (required for full power)Pfr: 3%Relatively high!

Ped for a 2.5s-shift ~90%

Ped for 3 RE ~90%

Example: the most loose rule (right)13.5s

n = 4Pfr: 0,2%; Ped for a 2.5s-shift ~50%

Ped for 3 RE ~70%

NOTEFor what concerns n, the rule can be applied flexible (e.g., n = 1).

IQC policy

The modified TEa approach

Power of rules with n = 4(mean; 13s/22s/R4s/41s; 3.5s)

0,0

0,2

0,4

0,6

0,8

1,0

0 1 2 3 4 SE (in units of s)

Pe

d

Mean

Multirule

3.5s

Mean

3.5 s

Power of rules with n = 4(13s/22s/R4s/41s; 3.5s)

0,0

0,2

0,4

0,6

0,8

1,0

1 1,5 2 2,5 3 3,5 4 4,5 5

RE (in units of s)

Pe

d

Multirule

3,5s

3.5 s


Example 2 for the most stringent rule (left)Westgard multirule: 13s / 22s

n = 4Pfr: 1%

Ped for a 2.5s-shift ~83%

Ped for 3 RE ~83%

Example for the most loose rule (right)13.5s

n = 4Pfr: 0,2%; Ped for a 2.5s-shift ~50%

Ped for 3 RE ~70%

NOTEFor what concerns n, the rule can be applied flexible (e.g., n = 1).

Note (most stringent rule): The Westgard multirules have been chosen because of their widespread availability in IQC software programmes. When possible, choose others: Think of control rules with variable limits, or mean and variance rules!

We will go further with The modified TEa approach

IQC policy

The modified TEa approach

Power of rules with n = 4(mean; 13s/22s; 3.5s)

0,0

0,2

0,4

0,6

0,8

1,0

0 1 2 3 4 SE (in units of s)

Pe

d

Mean

Multirule

3.5s

13s/22s

3.5 s

Power of rules with n = 4(13s/22s; 3.5s)

0,0

0,2

0,4

0,6

0,8

1,0

1 1,5 2 2,5 3 3,5 4 4,5 5 RE (in units of s)

Pe

d

Multirule

3,5s

13s/22s

3.5 s


IQC policy

IQC rule selection – Process control

Basic ideaIndependent of using IQC for patient release, we may want to use it for process control! For process control, each test could be controlled by the same IQC procedure. For process control, higher Pfr values can be accepted. However, Ped should be

considerably higher than for patient release.

Examples• Westgard multirules with high n Ped (90%) ~1.8 SE (see Figure); for the logic of

Westgard multirules: lower Figure• Mean and variance rules with high n

Logic scheme for applying the Westgard multirule

X

ControlData

12s

13s 22s R4s 41s 10

In-control Accept run

Out-of-control Reject run

No

YesNo No No No

Yes Yes Yes Yes Yes

No

12s/13s/22s/R4s/41s/10x(mean)

Pfr: ~3%, Ped for a 2.5s shift: 90% (for n = 4, without the mean rule)


IQC policy

Rule selection

Discussion

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• Ped should be 90%• Realistic errors to be detected by IQC are

• SE = >2• RE = >3 • REstable

• Ped AND Pfr increase with• lower -limits (2 > 3)• n (note, some rules are connected to the number of materials: multiples of 2, 3 with 2 or 3 materials)

• Generally, do not consider rules with Pfr >1%• Ped increases by combination of rules• Ped of mean and variance rules > than single or combined rules• Ped for SE > RE• Pfr at non-zero can be minimized by movement of the power curve• The power curve should have a good steepness


IQC policy

Selection of IQC rules – Tools & Examples

Tools• The ratio of TEa/total-CVa: should be 4• The STT IQC decision tool• The Westgard software tools (Validator/EZ Rules)

EXERCISESSodiumWe apply the modified TEa approach, the “most stringent TE” (with bottom-line), and the state-of-the-art CV data

1. Select TEa: Bottom-line: 3.2%2. Apply the IQC decision tool

- Set stable Bias = 0- Stable CV (total) = 1%

3. “Sort of analyte?”4. Apply Validator® for individual rule selection

OUTCOMEThe IQC tool and the Validator® show that sodium, with the values chosen, cannot be controlled according to the TEa concept.The ratio of TEa/total-CVa is 3.2.

TriglyceridesStrategy as before(see Figures on the right)TEa: 13.8 (most stringent)Bias: 0%CVa,tot: 1.7%

Ratio TEa/CVa,tot: 8.1

OUTCOMEThe IQC tool and the Validator® show that, even with the most stringent TEa, triglycerides can be controlled easily with the TEa concept: The Validator® selects the 13.5s rule (n = 2)

NOTEIn the EXCEL-file, you find for ISE, substrates, enzymes, specific proteins, TDM a list of• CVw, CVb• TE for IQC decision

- Ricos et al.• State-of-the-art CV data


IQC policy

IQC rule selection – Applications

First, we screen the analytes with the Ricos-TEa/CVa,tot ratio

The tables show analytes with ratios <4 (full list in EXCEL-file).In principle, the most stringent IQC rule should be applied for all these analytes.Example: 13s/22s (n = 4)

Note on low TEa/CVa,tot ratios

Low TEa/CVa,tot ratios are usually associated with analytes that have narrow

biological variation.Current state-of-the-art technology is unable to reach the goals for these

analytes. This holds true for all companies.

ISESodium 0,9Chloride 1,5SubstratesCalcium 1,2Fructosamine 1,8Bicarbonate 2,3Magnesium 2,4Protein 2,6Glucose 3,2Albumin 3,3Creatinine 3,5EnzymesCholinesterase 2,8CK-MB (activity) 3,4

Spec. proteinsHbA1c 1,5Ceruloplasmin 2,2Transferrin 2,5IgG 3,2C3c 3,4 -2-Microglobulin 3,6Rheumatoid factor 3,9APO B 3,9

TDMDigitoxin 1,6Valproic Acid 2,8Digoxin 3,1Carbamazepin 3,6Procainamide 3,6Phenytoin-1 3,7

TEa/CVa,tot ratio TEa/CVa,tot ratio


IQC policy


The tables below show analytes with ratios 4 (full list in EXCEL-file).In principle, individually optimized IQC rules can be applied for all of these analytes (note: most loose = 13.5s).

Now, we will apply the STT IQC decision tool for some analytes with ratios from 4-7.

APO A1 (4,3): TEa: 9.1 CVa,tot: 2.1

-1-Antitrypsin (5,1) TEa: 9.2 CVa,tot: 1.8

IgA (6,8) TEa: 13.5 CVa,tot: 2.0

We observe: from ratios >~5-6, IQC should be relatively easy! We verify this with the EZ rules (note: fill in all fields; if appropriate, use dummy values).

ISEPotassium 5,8SubstratesUIBC 4,5Phosphate 5,1HDL cholesterol 5,6Cholesterol 6,0Ammonia 7,7Urea 7,9Uric acid 7,9LDL cholesterol 9,1Bilirubin 10,4Lactate 10,5Bilirubin direct 11,1Triglycerides 16,4Iron, total 20,5EnzymesLD-1 4,1LDH 4,8HBDH 4,8Alk. Phosph. 5,9Amylase pancr. 5,9Acid Phosph. 6,9AST 7,6 -Amylase 7,9GGT 7,9ALT 10,7Lipase 11,6GLDH 11,9CK 16,8

Spec. proteinsKappa 4,0Prealbumin 4,1Lambda 4,3APO A1 4,3Ferritin 4,3 -1-Antitrypsin 5,1Myoglobin 5,6C4 6,4IgA 6,8Lp(a) 7,1IgM 8,4IgE 9,5 -1-Acid Glycopr. 10,8ASLO 13,3Haptoglobin 13,6CRP 27,3

TDMTobramycin 4,6Gentamicin 4,9Phenobarbital 5,1Theophylline-2 5,1NAPA 5,4Salicylate 5,6



IQC policy


Excercises with the EZ rules, using the specific protein examples (ratios from ~4-7).Note: all fields must be filled in (may be dummy values)!Selection criteria: 2 materials, SE detection 90%APO A1 (4.3) Rule: 12.5s n=4 Pfr: 4%

-1-Antitrypsin (5.1) Rule: 13s/ 22s n=2 Pfr: 1%

IgA (6.8) Rule: 13.5s n=2 Pfr: <0.1%

Example (6) Rule: 13.5s n=2 Pfr: <0.1%

Observation: from ratios >6, the process can be controlled very easy! 6 sigma process We take the 13.5s (n=4) rule for all analytes with a TEa/CVa,tot ratio 6SubstratesCholesterol 6,0Ammonia 7,7Urea 7,9Uric acid 7,9LDL cholesterol 9,1Bilirubin 10,4Lactate 10,5Bilirubin direct 11,1Triglycerides 16,4Iron, total 20,5EnzymesAcid Phosph. 6,9AST 7,6 -Amylase 7,9GGT 7,9ALT 10,7Lipase 11,6GLDH 11,9CK 16,8

Specific proteinsC4 6,4IgA 6,8Lp(a) 7,1IgM 8,4IgE 9,5 -1-Acid Glycopr. 10,8ASLO 13,3Haptoglobin 13,6CRP 27,3



IQC policy


Screening with the Ricos-TEa/CVa,tot ratio: all 4 - <6

The table shows examples where optimized rules could be used. However, • Consider: Is it worth?• Should one use the most stringent IQC rule?

REMARKRemember process control.One stringent rule could be used for all analytes.ISEPotassium 5,8SubstratesUIBC 4,5Phosphate 5,1HDL cholesterol 5,6EnzymesLD-1 4,1LDH 4,8HBDH 4,8Alk. Phosph. 5,9Amylase pancr. 5,9

Spec. proteinsKappa 4,0Prealbumin 4,1Lambda 4,3APO A1 4,3Ferritin 4,3 -1-Antitrypsin 5,1Myoglobin 5,6

TDMTobramycin 4,6Gentamicin 4,9Phenobarbital 5,1Theophylline-2 5,1NAPA 5,4Salicylate 5,6

TEa/CVa,tot ratio


IQC policy

VARIA

• Calculation of an actual TE• Rule “n” and patient release• Dealing with a bias• Rules with wide limits (e.g. 6s) & lot variations• “Fine-tuning” of IQC according to instability

Calculation of an actual TEWhen actual performance does not satisfy the TEa requirement, and one selects the most stringent rule, one can calculate (or extract with EZ rules) the real TE for the actual performance and the rule chosen.

Examples, IQC rule 13s/22s (n = 4)

CVa Ricos TEa Real TE (%) (%) (%)

Chloride: 1.0 1.5 ~4.3Albumin: 1.2 3.9 ~5.2Calcium: 2.0 2.4 ~8.6Note: with this rule (without bias), actual TE = 4.3 • CVa

Rule “n” and patient releaseWhen IQC rules with higher number of n are selected, and IQC measurements are done continuous, patient release has to be postponed until the full power of the rule is reached (cumulation needed).

However, at the end of the day, cumulation is not possible anymore. Consequently, it may be required to increase the frequency of measurement per IQC event (1 = usual, 2 = last but two, 3 = last but one, 4 = final event).

This is not necessary when block measurement is performed.

Dealing with a biasIt is not recommended to work with the bias in the QC chart: Increases Pfr

Bias should be addressed during rule selection via TEa.A bias will require more stringent IQC rules.


IQC policy

VARIA

IQC rules with wide limits (e.g. 6s) and lot variationsWhen rules with wide limits are used, significant lot-to-lot variations may be recognized in the chart, but may not cause rule violations (see Figure below).

Decide about• the medical relevance of the variations• whether you want to pick them up by the process control• whether you address them with quality assurance means.

Note: Similar may happen when you overestimated CVa (for example, high

CVa,tot/CVa,w ratios).

“Fine-tuning” of IQC according to type of instability• Steadily increasing• Abrupt changes• Fluctuating• Intermittent (sporadic)IQC is strong in detecting steadily increasing instability or abrupt changes. This, in particular, when patient release can be postponed until the IQC procedure reaches its full power. Namely, after error detection and correction, patient samples can be remeasured.

IQC is weak in detecting fluctuating or intermittent (sporadic) instability. This the more, the less IQC measurements are performed.

“Fine-tuning” of IQC according to instability requires in-depth knowledge about the weak points of the analytical process (error frequency; expected error types).“Fine tuning” may consider:• IQC sample concentration• Rule selection• Frequency of measurement• Location (block or continuous)

-6-5-4-3-2-10123456

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Measurement number

Sta

nd

ard

dev

iati

on


IQC policy

Varia

Discussion

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• Calculation of TEa from IQC rule and performance

• Power at the end of the run (high n-rules)

• Dealing with a bias

• Rules with high s (or: overestimation of CVa)-How to deal with lot-to-lot variations

• IQC “fine tuning” & system experience-Quality assurance versus quality control


IQC policy

Remedial actions

EXCERCISESInspecting IQC charts

Note in advance: «When results of controls fail to meet the laboratory's established criteria for acceptability, all patient test results obtained in the unacceptable run must be evaluated to determine if patient results have been adversely affected and the laboratory must take remedial actions to ensure the reporting of accurate and reliable patient test results»

“Westgard philosophy” (Basic QC Practices)• Don’t simply rerun the control• Don’t simply “try a new bottle” Identify the problem (inspect the chart) and correct it• Which type of error (concentration dependent, SE, RE)

Relate the error to a potential cause• Consider common factors (temperature; pipetting: volumes; kind of test: kinetic/endpoint; wavelength)• Relate to recent changes (operator, calibration, reagent, IQC-material, maintenance, etc.)

Demonstrate and document that the error was fixed• Run controls after fixing the problem

Acceptability limits

• Duplicates (Note: s = “within day”) z• 2 • s, for 95%: 1.96 • 2 • s : 2.77• s

• New control samples, recalibration For n measurements, decrease the limit with a

factor of 1/n Case n = 3, limit = 2.5s, new limit = 2.5 • [1/3] = 1.44, Because of practical considerations one may

choose 1.5s

• New batches (immunoassays), • Control of target values

Basic formula:

x t

s

n( , )

Example: n = 10, 95%-level: ±0.715 s, simplified:±0.7 s


IQC policy

Pfr of the IQC rule and frequency of remedial actions

When you compare your actual short-to-medium term frequency of remedial actions with the Pfr you expect from the IQC rule, consider the nature of the CVa,tot

you chose. The more variations you included, the lower the frequency of remedial actions will be.

If actual remedial actions frequency << rule Pfr

• Consider to pick up certain variations by IQC Consequence: reduces your CVa,tot that you use for IQC

May allow a different rule when the TEa concept was used.• Consider that you used a wrong CVa,tot

The “state-of-the-art” exampleWe have ~40 analytes with the rule 13s/22s, Pfr: 1% (n = 4), ~30 analytes with the

rule 13.5s, Pfr: 0,2% (n = 4), and assume 8 IQC measurements per day. Then,

we expect ~80% chance for a false rejection Under stable conditions, we expect at maximum 1 remedial action per day,• More, if system is unstable

• Less, if Cva,tot > CVa short-to-medium term.

CVa,tot /CVa,w ratio

Note: Troubleshooting is facilitated by increased CVa,tot /CVa,w ratios.


IQC policy

Remedial actions

Note: Either the measurement procedure or the control procedure can be faulty.

Release of patient results

You suspect the QC sample was the reason for failure• Take a new bottle.• Remeasure with n = 4, for example. If the IQC rule is not violated, assume the IQC sample caused the problem.• However, realize the uncertainty of your estimate!Keep an eye on the process for a while.

You suspect a calibration problem• Recalibrate the system, however, document the post-calibration status by a sufficient number of control measurements (for example: 4).• The system is under control again when the IQC rule is not violated. However, realize the uncertainty of your estimate!• Remeasure the patient samples between the last in-control event and the out-of-control event.• Compare the mean of the new patient results with that of the old results. When there was a calibration problem, this should be reflected in the difference of both means.

You suspect other problems• Look at patient data• Investigate all IQC levels (= IQC across materials), check other analytes (= IQC across analytes).• Investigate related analytes (e.g., all enzymes: could be temperature related).• Compare the actual CV with the expected one, and compare the IQC results with appropriate IQC-"Peer" (EQA) data.• Look at “electronic” QC data.• Check instrument (maintenance), reagents, operator change.• Locate and fix the problem and document that the problem was solved (perform IQC).• Remeasure the patient samples between the last in-control event and the out-of-control event.• Compare the mean of the new patient results with that of the old results. When there was an SE problem, this should be reflected in the difference of both means.


IQC policy

Remedial actions

Process control• Rules with higher Pfr (e.g. 2.5s, Westgard multirules, or others) can be used for

closely monitoring the analytical process.• In case that these rules are violated, patient results can still be reported. However, when time, the analytical process (calibration, reagent, instrument) or the IQC material should be investigated.

Possibilities• Look at patient data• Check “electronic” QC data• Investigate all IQC levels (= IQC across materials), check other analytes (= IQC across analytes).• Invstigate related analytes (e.g., all enzymes: could be temperature related).• Compare the actual CV with the expected one, and compare the IQC results with appropriate IQC-"Peer" (EQA) data.• When necessary, recalibrate the system and check the success of recalibration as described above.• Check instrument (maintenance), reagents, operator change.

In general, trouble-shooting should be done with an increased number of control measurements, however, higher CVa,tot/CVa,w ratios facilitate troubleshooting.

Over the time, check the success of your remedial actions.

CAUTIONThe described strategy is an extremely simplified one.

• In practice, problems have a great variety of origins and require different trouble-shooting strategies (“mans phantasy is too limited to imagine beforehand what the problem might be”).

• Only an experienced analyst will be able to solve serious problems in a reasonable time. System experience is invaluable!


IQC policy

Remedial actions

Discussion

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IQC policy

Internal Quality Control

General discussion

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IQC policy

Reminders

Reminder 1Troubleshooting should be done with replicates!

Reminder 2Don’t forget proactive quality assurance• A new lot (bottle) of IQC material is introduced• The operator changed• Instrument was calibrated or underwent major maintenance• New lots (bottles) of reagents or calibrators

Overall summary• The guiding rule (regulation) • Knowledge

– Basic statistics– Power functions– TE error concept (metrology)– TEa (critical errors, specifications)– Selection of TEa values (and problems)

• IQC Software– Additional: rule selection tools

• Adequate samples (sort, targets, concentration)• Adequate frequency (and location) policy

– Cost/benefit calculations• Instrument stability data & test stability & reproducibility data

– Stable performance: Compared to manufacturer/peers• Integrated rule selection (TEa; statistics; costs)

– Distinguish: Release of patient data/Process control• Remedial actions policy

– Distinguish: Release of patient data/Process control– Compare expected Pfr with actual rejection rate

– Investigate success rate• Integration of IQC in the overall quality management• Dedicated personnel

statistics & graphics for the laboratory 54 metrological basis of iqc introduction the error...

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