Influence of Analytical Bias and Imprecision on Guideline-Driven Medical Decision Limits Per Hyltoft...
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Transcript of Influence of Analytical Bias and Imprecision on Guideline-Driven Medical Decision Limits Per Hyltoft...
Influence of Analytical Bias and Imprecision on
Guideline-Driven Medical Decision Limits
Per Hyltoft Petersen
Hyltoft Petersen P, Klee GG.
Influence of Analytical Bias and Imprecision on the Number of False Positive Results Using Guideline-Driven Medical Decision Limits.
Clin Chem Acta 2014;430:1-8
LABMED 2014
“Guideline-Driven Medical Decision Limits”.
Diagnostic decisions based on decision limits according to medical guidelines are different from the majority of clinical decisions
due to the strict dichotomization of patients into diseased and non-diseased based on the biochemical measurement of a single component.
Background:
Consequently, the influence of analytical performance is more critical than for other diagnostic decisions where many other informations are included in the diagnosis.
Cholesterol as a screening-test for preventing coronary heart disease in adults
Decision: Cholesterol above or below 6.2 mmol/L
“Guideline-Driven Medical Decision Limits”.
HbA1c in diagnosis of diabetes mellitus
Decision: HbA1c above or below 48 mmol/mol (6.5 % HbA1c)
Examples:
Sacks et al. Diabetes Care 2011;34:c61-c99 Garber et al. Ann Intern Med.. 1996;124:515-517
“Guideline-Driven Medical Decision Limits”.
HbA1c reference interval for healthy
According to traditional IFCC criteria
CVWITHIN-SUBJECT = 1.94 % in IFCC units (~ ln = 0.0194)
HbA1c:
Recommended cut-off = 48 mmol/mol ~ ln = 3.86
Jørgensen et al. Scand J Clin Lab Invest 2002; 62:609-22.
Carlsen et al. Clin Chem Lab Med 2011;49:1501-7
Log-Gaussian distribution (natural logarithm) ln-mean = 1.727 and ln-standard deviation = 0.053
“Guideline-Driven Medical Decision Limits”.
Distribution of healthy set-points
CVWITHIN-SUBJECT = 1.94 %
HbA1c:
Distribution of Set-P oints of Reference Individuals and P robability of Results Above Cut-Off for one Sampling
5030 35 40 45
0.0
0.2
0.4
0.6
0.8
1.0
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c, mmol/mol
Fre
qu
en
cy o
r P
rob
ab
ility
Distribution of Set-Points
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
Distribution of values from a person with set-point = cut-off
Distribution of Set-P oints of Reference Individuals and P robability of Results Above Cut-Off for one Sampling
5030 35 40 45
0.0
0.2
0.4
0.6
0.8
1.0
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c, mmol/mol
Fre
qu
en
cy o
r P
rob
ab
ility
Distribution of Set-Points
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
“Guideline-Driven Medical Decision Limits”.
HbA1c:
HbA1c: Cut-off = 48 mmol/mol with Frequency and Probability due to Within-subject variation
Cut-off
Cut-off
5251504948474645
0
0.2
0.4
0.6
0.8
1
3.80 3.84 3.88 3.92 3.96
HbA1c, ln(mmol/mol)
Fre
qu
ency
or
Pro
bab
ility
frequency
cumulated
Cut-off
HbA1c, mmol/mol
Probability
Frequency
Distribution for a person with set-point = cut-off
Frequency Cumulated frequency (probability)
Probability of being measured above cut-off50 %
50 %
HbA1c: Cut-off = 48 mmol/mol with Probability for
one and two samplings
Cut-off
45 46 47 48 49 50 51 52
0
0.2
0.4
0.6
0.8
1
3.80 3.84 3.88 3.92 3.96
HbA1c, ln(mmol/mol)
Pro
ba
bil
ity
One sampling
Two samplings
Cut-off
HbA1c, mmol/mol
One sampling Two samplings
25 %
50 %
“Guideline-Driven Medical Decision Limits”.
HbA1c:
Distribution for a person with set-point = cut-off
Effect of one and two samplings
HbA1c: Cut-off = 48 mmol/mol with Probability for
two Samplings with Imprecision = 0, 2 and 4 %
Cut-off
5251504948474645
0
0.2
0.4
0.6
0.8
1
3.80 3.84 3.88 3.92 3.96
HbA1c, ln(mmol/mol)
Pro
bab
ility
Imprecision 0%
Imprecision 2%
Imprecision 4%
Cut-off
HbA1c, mmol/mol
Unbiased
2 %
Imprecision
4 %0 %
“Guideline-Driven Medical Decision Limits”.
HbA1c:
Distribution for two samplings with set-point = cut-off
Effect of imprecision
HbA1c: Apparant Cut-off with Probability for varying bias ± 4 % and Imprecision 0 % for two Samplings
5251504948474645
0
0.2
0.4
0.6
0.8
1
3.80 3.84 3.88 3.92 3.96
HbA1c, ln(mmol/mol)
Pro
bab
ility
Unbiased
+4 % bias
-4 % bias
Cut-off
HbA1c, mmol/mol
Unbiased
Apparant Cut-off for Bias = + 4 %
Apparant Cut-off for Bias = - 4 %
“Guideline-Driven Medical Decision Limits”.
HbA1c:
Distribution for two samplings with set-point = cut-off
Effect of Bias
“Guideline-Driven Medical Decision Limits”.
Distribution of healthy set-points
CVWITHIN-SUBJECT = 1.94 %
HbA1c:
Distribution of Set-P oints of Reference Individuals and P robability of Results Above Cut-Off for one Sampling
5030 35 40 45
0.0
0.2
0.4
0.6
0.8
1.0
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c, mmol/mol
Fre
qu
en
cy o
r P
rob
ab
ility
Distribution of Set-Points
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
Distribution of Set-P oints of Reference Individuals and P robability of Results Above Cut-Off for one Sampling
45403530 50
0.0
0.2
0.4
0.6
0.8
1.0
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c, mmol/mol
Fre
qu
en
cy o
r P
rob
ab
ility
Distribution of Set-Points
Probability of >cut-off
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
Probability for a person with set-point = cut-off to be measured above cut-off
Distribution of Set-Points of Reference Individuals and Probability of Results Above Cut-Off for one Sampling
5030 35 40 45
0.0
0.2
0.4
0.6
0.8
1.0
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c, mmol/mol
Freq
uenc
y or
Pro
babi
lity Set-point distribution
Cut-off = 3.86 = 48CVAnalytical = 0 %CVAnalytical = 1 %CVAnalytical = 2 %CVAnalytical = 3 %CVAnalytical = 4 %CVAnalytical = 5 %Mean = 3.63 = 38CVBetween = 8.38%CVWithin = 1.94%Bias % = 0.0
Distribution of Set-Points Prob of
>cut-off
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
“Guideline-Driven Medical Decision Limits”.
HbA1c:
Distribution of set-points (healthy population)
Cumulated frequency (probability functions) One sampling
Increasing imprecision
Distribution of Set-Points of Reference Individuals and Probability of Results Above Cut-Off for one Sampling
5030 35 40 45
0.0
0.2
0.4
0.6
0.8
1.0
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c, mmol/mol
Freq
uenc
y or
Pro
babi
lity Set-point distribution
Cut-off = 3.86 = 48CVAnalytical = 0 %CVAnalytical = 1 %CVAnalytical = 2 %CVAnalytical = 3 %CVAnalytical = 4 %CVAnalytical = 5 %Mean = 3.63 = 38CVBetween = 8.38%CVWithin = 1.94%Bias % = 0.0
Distribution of Set-Points Prob of
>cut-off
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
“Guideline-Driven Medical Decision Limits”.
HbA1c:
Distribution of set-points (healthy population)
Cumulated frequency (probability functions) One sampling
Now we take a sample within a small interval of healthy set-pointsand multiply with the probability of these set-points exceed the cut-offto get the FP for healthy with this set-point
and by repeating the process for all intervals we get the distribution of origins of set-points of FP
Origin of set-Points Measured Above Cut-Off forno Bias and Varying Imprecision for one Sampling
5045403530
0.0000
0.0001
0.0002
0.0003
0.0004
0.0005
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c,mmol/mol
Fre
qu
en
cy
Cut-off = 3.86 = 48
CVAnalytical = 0 %CVAnalytical = 1 %
CVAnalytical = 2 %CVAnalytical = 3 %
CVAnalytical = 4 %CVAnalytical = 5 %
Mean = 3.63 = 38CVBetw een = 8.38%
CVWithin = 1.94%Bias % = 0.0
Origin of Set-Points for varying imprecision
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
“Guideline-Driven Medical Decision Limits”.
HbA1c: Varying imprecision and bias
Bias = 0 %
Bias = + 4 %
The effect of positive bias is like moving the cut-off to the left
Origin of set-Points Measured Above Cut-Off forno Bias and Varying Imprecision for one Sampling
5045403530
0.0000
0.0001
0.0002
0.0003
0.0004
0.0005
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c,mmol/mol
Fre
qu
en
cy
Cut-off = 3.86 = 48
CVAnalytical = 0 %CVAnalytical = 1 %
CVAnalytical = 2 %CVAnalytical = 3 %
CVAnalytical = 4 %CVAnalytical = 5 %
Mean = 3.63 = 38CVBetw een = 8.38%
CVWithin = 1.94%Bias % = 0.0
Origin of Set-Points for varying imprecision
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
Origin of set-Points Measured Above Cut-Off for Bias = + 4 % and Varying Imprecision for one sampling
5030 35 40 45
0.0000
0.0001
0.0002
0.0003
0.0004
0.00053.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c mmol/mol
Fre
qu
en
cy
Cut-off = 3.83 = 46.1CVAnalytical = 0 %
CVAnalytical = 1 %CVAnalytical = 2 %
CVAnalytical = 3 %CVAnalytical = 4 %CVAnalytical = 5 %
Mean = 3.63 = 38CVBetw een = 8.38%
CVWithin = 1.94%Bias % = + 4
Origin of Set-Points for Bias = + 4 % and varying imprecision and bias = + 4 %
HbA1c ln(mmol/mol)
Apparant Cut-off for Bias = +4 %
Origin of set-points for healthy individuals measured above 48 mmol/mol (healthy diagnosed as diabetics)
“Guideline-Driven Medical Decision Limits”.
HbA1c: Varying imprecision and bias
Bias = 0 %
Bias = + 4 %Origin of set-Points Measured Above Cut-Off for
Bias = + 4 % and Varying Imprecision for two samplings
50454035
0.00000
0.00010
0.00020
0.00030
0.00040
0.00050
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c mmol/mol
Fre
qu
en
cy
Cut-off = 3.83 = 46.1
CVAnalytical = 0 %
CVAnalytical = 1 %
CVAnalytical = 2 %
CVAnalytical = 3 %
CVAnalytical = 4 %
CVAnalytical = 5 %
Mean = 3.63 = 38
CVBetw een = 8.38%
CVWithin = 1.94%
Bias % = + 4
HbA1c ln(mmol/mol)
Apparant Cut-off for Bias = +4 %
Origin of Set-Points for Bias = + 4 % and varying imprecision
Bias = + 4 %
One Sampling
Two Samplings
One and two samplings
One Sampling
Origin of set-Points Measured Above Cut-Off for Bias = + 4 % and Varying Imprecision for one sampling
5030 35 40 45
0.0000
0.0001
0.0002
0.0003
0.0004
0.00053.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c mmol/mol
Fre
qu
en
cy
Cut-off = 3.83 = 46.1CVAnalytical = 0 %
CVAnalytical = 1 %CVAnalytical = 2 %
CVAnalytical = 3 %CVAnalytical = 4 %CVAnalytical = 5 %
Mean = 3.63 = 38CVBetw een = 8.38%
CVWithin = 1.94%Bias % = + 4
Origin of Set-Points for Bias = + 4 % and varying imprecision and bias = + 4 %
HbA1c ln(mmol/mol)
Apparant Cut-off for Bias = +4 %
Origin of set-Points Measured Above Cut-Off forno Bias and Varying Imprecision for one Sampling
5045403530
0.0000
0.0001
0.0002
0.0003
0.0004
0.0005
3.4 3.5 3.6 3.7 3.8 3.9 4.0
HbA1c,mmol/mol
Fre
qu
en
cy
Cut-off = 3.86 = 48
CVAnalytical = 0 %CVAnalytical = 1 %
CVAnalytical = 2 %CVAnalytical = 3 %
CVAnalytical = 4 %CVAnalytical = 5 %
Mean = 3.63 = 38CVBetw een = 8.38%
CVWithin = 1.94%Bias % = 0.0
Origin of Set-Points for varying imprecision
HbA1c ln(mmol/mol)
Cut-off = 48 mmol/mol
Origin of set-points for healthy individuals measured above 48 mmol/mol (healthy diagnosed as diabetics)
“Guideline-Driven Medical Decision Limits”.
HbA1c:
Percentage of healthy individuals measured > 48 mmol/mol (false positive diabetics)
As function of bias % for varying percentages of imprecision
Inf luence of Bias and Imprecision on Percentage Reference Individuals w ith HbA1c ≥ 48 mmol/mol in one Sample
Bias = 0%
0
2
4
6
-10 -8 -6 -4 -2 0 2 4 6 8 10Bias %
Per
cent
age
FP
CVA % = 0CVA % = 1CVA % = 2CVA % = 3CVA % = 4CVA % = 5CVA % = 6CVA % = 7CVA % = 8CVA % = 9CVA % = 10
For one sampling
“Guideline-Driven Medical Decision Limits”.
HbA1c: As function of bias % for varying percentages of imprecision
Inf luence of Bias and Imprecision on Percentage Reference Individuals w ith HbA1c ≥ 48 mmol/mol in one Sample
Bias = 0%
0
2
4
6
-10 -8 -6 -4 -2 0 2 4 6 8 10Bias %
Per
cent
age
FP
CVA % = 0CVA % = 1CVA % = 2CVA % = 3CVA % = 4CVA % = 5CVA % = 6CVA % = 7CVA % = 8CVA % = 9CVA % = 10
For one sampling
Inf luence of Bias and Imprecision on Percentage Reference Individuals w ith HbA1c ≥ 48 mmol/mol in tw o Samples
Bias = 0%
0
2
4
6
-10 -8 -6 -4 -2 0 2 4 6 8 10Bias %
Per
cent
age
FP
CVA % = 0CVA % = 1CVA % = 2CVA % = 3CVA % = 4CVA % = 5CVA % = 6CVA % = 7CVA % = 8CVA % = 9CVA % = 10
For two samplings
Percentage of healthy individuals measured > 48 mmol/mol false positive diabetics
HbA1c:
Inf luence of Bias and Imprecision on Percentage Reference Individuals w ith HbA1c ≥ 48 mmol/mol in tw o Samples
Bias = 0%
0
2
4
6
-10 -8 -6 -4 -2 0 2 4 6 8 10Bias %
Per
cent
age
FP
CVA % = 0CVA % = 1CVA % = 2CVA % = 3CVA % = 4CVA % = 5CVA % = 6CVA % = 7CVA % = 8CVA % = 9CVA % = 10
What are the recommended quality specifications from What are the recommended quality specifications from Sacks et al. Clin Chem 2011;57:793-8 Desirable specifications for HbA1c measurement are an Desirable specifications for HbA1c measurement are an intralaboratory CV < 2% and an interlaboratory CV < 3.5 % intralaboratory CV < 2% and an interlaboratory CV < 3.5 %
The CV 3.5 % DCCT units corresponds to 5.2 % at 48 The CV 3.5 % DCCT units corresponds to 5.2 % at 48 mmol/mol in IFCC units, and reduced by the 2 %, the final mmol/mol in IFCC units, and reduced by the 2 %, the final allowable bias is from ± 9 % at a 95 % intervalallowable bias is from ± 9 % at a 95 % intervaland false positives could be from 0 to 2.8 % and false positives could be from 0 to 2.8 %
Personal information from Personal information from Thomas Røraas and Sverre Sandberg, Thomas Røraas and Sverre Sandberg, NOKLUS, Bergen, NorwayNOKLUS, Bergen, Norway
“Guideline-Driven Medical Decision Limits”.
There is no reference interval for Cholesterol due to the strict decision limit of 6.2 mmol/L
95 % limits 150-275 mg/dL = 3.89-7.12 mmol/L
Log-Gaussian distribution (natural logarithm)
CVTOTAL =15.2 % ~ ln = 0.152
CVWITHIN-SUBJECT = 6.0 % ~ ln = 0.060
CVBETWEEN-SUBJECT = 13.9 % ~ ln = 0.139
Recommended cut-off = 6.2 mmol/L ~ ln = 1.825
Ricos et al. Scand J Clin Lab Invest 1999;59:491
Cholesterol:
But a range for the total population can be estimated
Klee et al. Scand J Clin Lab Invest 1999;59:509
“Guideline-Driven Medical Decision Limits”.
Cholesterol:
Distribution for a person with set-point = cut-off
Effect of one and two samplings
Cholesterol: Probability for Treatment with one and two Samplings as Function of Set-point
Cut-off
8.07.57.06.56.05.55.0
0.0
0.2
0.4
0.6
0.8
1.0
1.60 1.70 1.80 1.90 2.00 2.10
Cholesterol, ln(mmol/L)
Pro
bab
ility
One sampling
Two samplings
Cut-off
Cholesterol Set-point, mmol/L
One sampling Two samplings
25 %
50 %
Distribution of Set-Points of Low Risk Individuals and Probability of Results Above Cut-Off - No Bias
4.0 5.0 6.0 7.0 8.0
0.0
0.2
0.4
0.6
0.8
1.01.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
quen
cy o
r P
roba
bilit
y Set-point distributionCut-off = 1.8262 = 6.21CVAnalytical = 0 %CVAnalytical = 2 %CVAnalytical = 4 %CVAnalytical = 6 %CVAnalytical = 8 %CVAnalytical = 10 %Mean = 1.66 = 5CVBetween = 13.90%CVWithin = 6.00%Bias % = 0.0
Distribution of Low Risk Set-Points Probability of
>cut-off
ln(cholesterol)
"Cut-off" = 6.21 mmol/L
“Guideline-Driven Medical Decision Limits”.
Cholesterol:
Distribution for persons with set-points below 6.2 mmol/L
Cumulated frequency (probability functions) One sampling
“Guideline-Driven Medical Decision Limits”.
Cholesterol:
Distribution for persons with set-points below 6.2 mmol/L
Cumulated frequency (probability functions)
Distribution of Set-Points of Low Risk Individuals and Probability of Results Above Cut-Off - No Bias
4.0 5.0 6.0 7.0 8.0
0.0
0.2
0.4
0.6
0.8
1.01.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
quen
cy o
r P
roba
bilit
y Set-point distributionCut-off = 1.8262 = 6.21CVAnalytical = 0 %CVAnalytical = 2 %CVAnalytical = 4 %CVAnalytical = 6 %CVAnalytical = 8 %CVAnalytical = 10 %Mean = 1.66 = 5CVBetween = 13.90%CVWithin = 6.00%Bias % = 0.0
Distribution of Low Risk Set-Points Probability of
>cut-off
ln(cholesterol)
"Cut-off" = 6.21 mmol/L
For one sampling
For two samplings
Distribution of Set-Points of Low Risk Individuals and Probability of Results Above Cut-Off - No Bias
4.0 5.0 6.0 7.0 8.0
0.0
0.2
0.4
0.6
0.8
1.01.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
quen
cy o
r P
roba
bilit
y Set-point distributionCut-off = 1.8262 = 6.21CVAnalytical = 0 %CVAnalytical = 2 %CVAnalytical = 4 %CVAnalytical = 6 %CVAnalytical = 8 %CVAnalytical = 10 %Mean = 1.66 = 5CVBetween = 13.90%CVWithin = 6.00%Bias % = 0.0
Distribution of Low Risk Set-Points Probability of
>cut-off
ln(cholesterol)
"Cut-off" = 6.21 mmol/L
Distribution of Set-Points of Low Risk Individuals and Probability of Results Above Cut-Off - No Bias
4.0 5.0 6.0 7.0 8.0
0.0
0.2
0.4
0.6
0.8
1.01.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
quen
cy o
r P
roba
bilit
y Set-point distributionCut-off = 1.8262 = 6.21CVAnalytical = 0 %CVAnalytical = 2 %CVAnalytical = 4 %CVAnalytical = 6 %CVAnalytical = 8 %CVAnalytical = 10 %Mean = 1.66 = 5CVBetween = 13.90%CVWithin = 6.00%Bias % = 0.0
Distribution of Low Risk Set-Points Probability of
>cut-off
ln(cholesterol)
"Cut-off" = 6.21 mmol/L
“Guideline-Driven Medical Decision Limits”.
Cholesterol:
Distribution for persons with set-points below 6.2 mmol/L
Cumulated frequency (probability functions), one sampling
Now we take a sample within a small interval of healthy set-pointsand multiply with the probability of these set-points exceed the cut-offto get the FP for healthy with this set-point
and by repeating the process for all intervals we get the distribution of origins of set-points of FP
Distribution of Set-Points of Low Risk Individuals Measured as High Risk Above Cut-Off - No Bias
7.06.05.04.0 8.00.0000
0.0005
0.0010
0.0015
0.0020
0.00251.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
qu
en
cy
Cut-off = 1.8262 = 6.21
CVAnalytical = 0 %
CVAnalytical = 2 %
CVAnalytical = 4 %
CVAnalytical = 6 %
CVAnalytical = 8 %
CVAnalytical = 10 %
Mean = 1.66 = 5
CVBetween = 13.90%
CVWithin = 6.00%
Bias % = 0.0
Origin of Set-Points for varying imprecision
ln(Cholesterol) mmol/mol
"Cut-off" = 6.21 mmol/L
Distribution of Set-Points of Low Risk Individuals Measured as High Risk Above Cut-Off - Bias = + 4 %
8.07.06.04.0 5.0
0.0000
0.0005
0.0010
0.0015
0.0020
0.00251.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
quen
cy
Apparant Cut-off = 1.786
Assumed Cut-off = 1.826
CVAnalytical = 0.000
CVAnalytical = 0.020
CVAnalytical = 0.040
CVAnalytical = 0.060
CVAnalytical = 0.080
CVAnalytical = 0.100
'Mean' = 1.66
sBetween = 0.139
sWithin = 0.06
True Bias % = 4
ln(Cholesterol) mmol/mol
Apparant Cut-off Assumed Cut-offOrigin of Set-Points for
varying imprecision
“Guideline-Driven Medical Decision Limits”.
Cholesterol:
Origin of set-points
Cumulated frequency (probability functions), one sampling
Distribution of Set-Points of Low Risk Individuals Measured as High Risk Above Cut-Off - No Bias, Two samplings
7.06.05.04.0 8.00.0000
0.0005
0.0010
0.0015
0.0020
0.00251.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
qu
en
cy
Cut-off = 1.8262 = 6.21
CVAnalytical = 0 %
CVAnalytical = 2 %
CVAnalytical = 4 %
CVAnalytical = 6 %
CVAnalytical = 8 %
CVAnalytical = 10 %
Mean = 1.66 = 5
CVBetween = 13.90%
CVWithin = 6.00%
Bias % = 0.0
Origin of Set-Points for varying imprecision
ln(Cholesterol) mmol/mol
"Cut-off" = 6.21 mmol/L
Distribution of Set-Points of Low Risk Individuals Measured as High Risk, Bias = + 4 %, Two samplings
8.07.06.04.0 5.0
0.0000
0.0005
0.0010
0.0015
0.0020
0.00251.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
quen
cyApparant Cut-off = 1.786
Assumed Cut-off = 1.826
CVAnalytical = 0.000
CVAnalytical = 0.020
CVAnalytical = 0.040
CVAnalytical = 0.060
CVAnalytical = 0.080
CVAnalytical = 0.100
'Mean' = 1.66
sBetween = 0.139
sWithin = 0.06
True Bias % = 4
ln(Cholesterol) mmol/mol
Apparant Cut-off Assumed Cut-offOrigin of Set-Points for
varying imprecision
One sampling
Two samplings
Bias = 0 % Bias = +4 %
Apparent cut-off
Assumed cut-off
Distribution of Set-Points of Low Risk Individuals Measured as High Risk Above Cut-Off - No Bias
7.06.05.04.0 8.00.0000
0.0005
0.0010
0.0015
0.0020
0.00251.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1
Cholesterol, mmol/L
Fre
qu
en
cy
Cut-off = 1.8262 = 6.21
CVAnalytical = 0 %
CVAnalytical = 2 %
CVAnalytical = 4 %
CVAnalytical = 6 %
CVAnalytical = 8 %
CVAnalytical = 10 %
Mean = 1.66 = 5
CVBetween = 13.90%
CVWithin = 6.00%
Bias % = 0.0
Origin of Set-Points for varying imprecision
ln(Cholesterol) mmol/mol
"Cut-off" = 6.21 mmol/L
“Guideline-Driven Medical Decision Limits”.
Cholesterol:
For one sampling
For two samplings
Percentage of false positive
As function of bias % for varying percentages of imprecision
Inf luence of Bias and Imprecision on Percentage Low Risk
Individuals w ith Cholesterol above 6.2 mmol/L for one Sample
Bias = 0%
0
5
10
15
20
25
-10 -8 -6 -4 -2 0 2 4 6 8 10Bias %
Per
cent
age
FP
CVA % = 0CVA % = 1CVA % = 2CVA % = 3CVA % = 4CVA % = 5CVA % = 6CVA % = 7CVA % = 8CVA % = 9CVA % = 10
Influence of Bias and Imprecision on Percentage of Low Risk Individuals w ith Cholesterol above 6.2 mmol/L, tw o Samples
Bias = 0%
0
5
10
15
20
25
-10 -8 -6 -4 -2 0 2 4 6 8 10Bias %
Per
cent
age
FP
CVA % = 0CVA % = 1CVA % = 2CVA % = 3CVA % = 4CVA % = 5CVA % = 6CVA % = 7CVA % = 8CVA % = 9CVA % = 10
“Guideline-Driven Medical Decision Limits”.
Biological Variables: HbA1c and Cholesterol
Age and Gender
Within- and Between-Subject Biological Variation
Ethnicity, Lifestyle, Environment, Subclinical Diseases, etc.
Seasonal variation
CholesterolHbA1c
Garde et al. Clin Chem 2000;46:551
1. Sharp decision limits are extremely sensitive to analytical bias
2. Use of two measurements in diagnosis reduces the effect of performance errors
3. Separate specifications for analytical bias and imprecision is recommended
4. Biological variation and other information should be considered in decision limits
5. A concentration related probability function as an alternative to sharp decision limit is proposed
Conclusions
“Guideline-Driven Medical Decision Limits”.