**15-English version**

**Improving detection of biochemical significant changes**

(B RCV: biochemical reference change value)

It has been seen that, when expressing an analyte measurement as the average of two results obtained from samples withdrawn within 15 days, the probability that the information from that measurement to the real homeostatic condition of the patient, is improved.

Biochemical uncertainty, by this procedure, is reduced in 30%; the equivalent happens with the minimal statistically significant change, turning this analytical procedure in a more sensitive system to be able to detect changes in the homeostatic condition of the patient.

Likewise, it must be remembered that, when two results cannot be averaged, this procedure allows detecting serious errors in the pre-analytical phase as well as accelerated changes in the homeostatic condition of the patient. In both cases, obtain new samples to make a careful study of the patient is needed.

As an example, let´s take total PSA measurements performed within 6 months period.

__Current procedure:__
Results obtained with a single measurement from a single sample

1st measurement, sample 1: February, 2011

2nd measurement, sample 2: July, 2011

**Analyte:**total PSA

**Result from sample 1: 2.5 ng/ml**

**Result from sample 2: 3.5 ng/ml**

Method analytical performance: CV

_{A}%: 5%; Bias %: 0%
Biological variability: CV

_{I}% = 18%
N: number of replicates for each measurement. N= 1

Z: (95% confidence limit) = 1.96

CV

_{B}%: biochemical variation coefficient- Minimal biochemical significant change (BRCV: biochemical reference change value) analysis

B RCV % = Z · 1.41 · CV

_{B}%
CV

_{B}% = (CV_{I}%^{2}+CV_{A}%^{2})^{0.5}/ N^{0.5}
Since the determination is performed on a single sample, N = 1.

Then

B RCV % = Z · 1.41 · (CV

_{I}%

^{2}+CV

_{A}%

^{2})

^{0.5}

For a 95 % confidence level Z = 1.96

^{}
B RCV % = 1.96 · 1.41 · (CV

_{I}%^{2}+CV_{A}%^{2})^{0.5}B RCV % = 2.76 · (CV

_{I}%

^{2}+CV

_{A}%

^{2})

^{0.5}replacing

B RCV % = 2.76 · (18 %

^{2 }+ 5.0 %

^{2})

^{0.5}= 2.76 · 18.7 % = 51.6%

- Interpretation:

To consider, with a 95% confidence level, that the biochemical change is significant, the difference between both measurements must be greater than 51.6%

__Suggested procedure__
Measurements performed as the averages of two results obtained from two samples withdrawn within 15 days.

1st measurement from sample 1: February 5

^{th}, 2011

sample 2: February 20th, 2011

2nd measurement from sample 3: July 7

^{th}, 2011
sample 4: July 22nd, 2011

**Analyte**: total PSA

Result from sample 1: 2.4 ng/ml

Result from sample 2: 2.6 ng/ml

**Result from 1st measurement: 2.5 ng/ml**

Result from sample 3: 3.3 ng/ml

Result from sample 4: 3.7 ng/ml

**Result from 2nd measurement: 3.5 ng/ml**

Method analytical performance: CV

_{A}%: 5%; Bias %: 0%

Biological variability: CV

_{I}% = 18%
N: number of replicates for each measurement. N= 2

Z: (95% confidence limit) = 1.96

CV

_{B}%: biochemical variation coefficient- Minimal biochemical significant change (B RCV: biochemical reference change value) analysis

B RCV % = Z · 1.41 · CV

_{B}%
CV

_{B}% = (CV_{I}%^{2}+CV_{A}%^{2})^{0.5}/ N^{0.5}
Since the result of the measurement is the average of the results from two samples, N = 2. Then

^{}

B RCV % = Z · 1.41 · (CV

_{I}%^{2}+CV_{A}%^{2})^{0.5}/ 2^{0.5}B RCV % = Z · 1.41 · (CV

_{I}%

^{2}+CV

_{A}%

^{2})

^{0.5}/ 1.41

^{}

B RCV % = Z . (CV

_{I}%

^{2}+CV

_{A}%

^{2})

^{0.5}

^{}

For a 95 % confidence level Z = 1.96

^{}
B RCV % = 1.96 · (CV

_{I}%^{2}+CV_{A}%^{2})^{0.5}B RCV % = 1.96 · (CV

_{I}%

^{2}+CV

_{A}%

^{2})

^{0.5}replacing

B RCV % = 1.96 · (18 %

^{2 }+ 5.0 %

^{2})

^{0.5}= 1.96 ·18.7 % = 36.6%

- Interpretation:

To consider, with a 95% confidence level, that the biochemical change is significant, the difference between both measurements must be greater than 36.6%

__Comparison between both procedures:__
The difference between both measurements is the same in both procedures, meaning 3.5 ng/ml - 2.5 ng/ml =

__1 ng/ml.__
Let´s analyze the meaning of that difference between both procedures:

(result from a single sample)__Current procedure__

For the first case the biochemical significant change (B RCV: biochemical reference change value) is 51.6% (rounded up to 52%).

Subsequently, the absolute difference D for the change is

D = 52 /100 · [(2.5ng/ml +3.5ng/ml ) /2] = 0.52· 3 ng/ml = 1.6 ng/ml

1ng/ml < D

**Conclusion**: the biochemical difference between February and July is NOT significant.

(average results from two samples)__Suggested procedure__

For the second case the biochemical significant change (B RBCV: biochemical reference change value) is 36.6% (rounded up to 37%).

Subsequently, the absolute difference D for the change is

D = 37 /100 · [(2.5ng/ml +3.5ng/ml ) /2] = 0.37 · 3 ng/ml = 1.1 ng/ml

1ng/ml aprox.= D

**Conclusion**: the biochemical difference between February and July is doubtful!!! and requires a new study in a shorter time.

Notice that, the same difference between measurements, has a different meaning when performed on a single sample or as an average between two samples in each month when the study was performed.

**Final conclusion:**

Performing measurements with two samples and averaging the obtained results for the laboratory report, not only improves the probability of knowing the real biochemical condition of the patient, but also improves the sensitivity of the study to be able to detect significant changes in the patient homeostatic condition.

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