Skip to main content

Table 3 Carrier test accuracies for frequent and rare autosomal recessive diseases [20]

From: Analyzing the most frequent disease loci in targeted patient categories optimizes disease gene identification and test accuracy worldwide

Disease

Disease frequency

98% Accurate* 100,000 tested

99.9% Accurate** 100,000 tested

Carrier frequency

Cystic Fibrosis

~1/3364

~3279 Correct

~3445 Correct

~1/29

  

~2067 Incorrect

~103 Incorrect

 
  

(2000 + 67 = 2067)

(100 + 3.3 = 103.3)

 

PKU

~1/10,000

~1960 Correct

~1998 Correct

~1/50

  

~2040 Incorrect

~102 Incorrect

 
  

(200 + 40 = 2040)

(100 + 2 = 102)

 

Arylsulfatase A

~1/100,000

~619 Correct

~632 Correct

~1/158

Deficiency

 

~2012 Incorrect

~101 Incorrect

 
  

(2000 + 12.4 = 2012.4)

(100 + .6 = 100.6)

 

Fumarese

~1/60,000,000

~25 Correct

~26 Correct

~1/3873

Deficiency

 

~2000 Incorrect

~100 Incorrect

 
  

(2000 + .5 = 2000.5)

(100 + .026 = 100.026)

 
  1. *A 96% to 98% accurate cystic fibrosis result frequency was initially reported by CAP certified testing laboratories.
  2. **A 99.5% accurate result frequency was estimated by one commercial microarray manufacturer.
  3. These data illustrate the prudence of testing maternal and fetal samples together.
  4. LEGEND: One first reason for targeting the most frequent genetic diseases is illustrated by the calculated differences between correct and incorrect test results for diseases with different frequencies given the same test accuracies. For instance, considerably higher test accuracies are observed when calculated for screening of the more frequent autosomal recessive diseases in unselected asymptomatic carriers. The proportion of incorrectly detected carriers increases substantially for rare autosomal recessive diseases like Fumarase deficiency.
  5. Clinical test accuracy is optimized during laboratory validation according to College of American Pathology guidelines. An illustrative 98% test accuracy has been arbitrarily selected for comparison of a Standard of Care test based upon the 96% to 98% accurate cystic fibrosis results reported by CAP certified clinical laboratories initially screening for the 23 most common cystic fibrosis mutations. Given a test accuracy of 98% for cystic fibrosis would identify ~3279 cystic fibrosis carriers correctly and ~67 carriers and ~2000 noncarriers incorrectly among 100,000 people. The same test accuracy applied to the rare autosomal recessive fumarase deficiency with a frequency of ~1 in 60,000,000 would identify 25 of 26 fumarase deficiency carriers correctly but also identify 1 carrier and ~2000 noncarriers incorrectly.
  6. DNA sequencing platforms themselves are anticipated to be substantially more accurate, while entire test accuracy is also modified by sample collection, laboratory manipulation, and reporting. An arbitrarily selected 99.9% accurate test would decrease the incorrectly identified noncarriers for each genetic disease from ~2000 to ~100 among 100,000 patients tested. At the same time the number of correctly detected cystic fibrosis carriers would increase by 66 to 3445. In contrast, the 26 true carriers of the rare fumarase deficiency with a frequency of 1 in 60,000,000 would be identified correctly among the 100 incorrectly identified carriers. Compare these to the calculated 99.9% accurate test results for autosomal recessive Arylsulfatase A deficiency with an affected frequency of 1 in 100,000 that would identify 632 carriers correctly along with 1 carrier and 100 noncarriers incorrectly.
  7. The ~50-fold enriched frequency of most frequent deletions found among all patients submitted for microarray analysis (Additional file 3: Table S3B, top) illustrates the principle that testing clinically suspicious phenotypes substantially enhances the affected patient frequency among tested samples. Prior screening test results like hemoglobin electrophoresis for sickle cell anemia and the hemoglobinopathies will further enrich for abnormal patient samples submitted for DNA analysis.
Back to article page

Journal of Translational Medicine

ISSN: 1479-5876

Contact us