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Clinical Validity: Prenatal Screening for Cystic Fibrosis. Sue Richards, PhD Professor, Molecular & Medical Genetics Director, DNA Diagnostic Laboratory Oregon Health & Science University. Effective . Quality. Intervention. Assurance. (Benefit). Natural. Pilot. Clinical. History.

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clinical validity prenatal screening for cystic fibrosis

Clinical Validity: Prenatal Screening for Cystic Fibrosis

Sue Richards, PhD

Professor, Molecular & Medical Genetics

Director, DNA Diagnostic Laboratory

Oregon Health & Science University

slide2

Effective

Quality

Intervention

Assurance

(Benefit)

Natural

Pilot

Clinical

History

Trials

Sensitivity

Prevalence

Clinical

Specificity

PPV

NPV

Ethical, Legal, &

Disorder

Health

Social Implications

&

Risks

(safeguards& impediments)

Setting

Penetrance

Analytic

Assay

Sensitivity

Robustness

Analytic

Quality

Specificity

Control

Economic

Monitoring

Evaluation

&

Evaluation

Facilities

Education

Clinical Validity

  • Defines the ability of a test to detect or predict the phenotype or particular clinical outcome
  • Elements build upon analysis of analytic validity for a specific disorder in a defined setting
slide3

Clinical Sensitivity & Specificity

Disease

Phenotype

Yes No

Pos A B

NegC D

Test Result

Sensitivity:Proportion of persons with the disease who have a positive test = A / (A+C)

Specificity:Proportion of persons who do not have the diseasewho have a negative test

= D / (B+D)

issues in evaluating clinical validity
Issues in evaluating Clinical Validity
  • Study design
    • Case definitions may vary
    • Small numbers and potential biases
    • Populations may need to be stratified by variables such as gender, age, race/ethnicity
    • Testing protocols may not be comparable (e.g., numbers of mutations tested)
    • Comparability of case and control populations
  • Need to evaluate the impact of genetic and environmental modifiers
clinical sensitivity of cftr testing prenatal screening for cystic fibrosis
Clinical Sensitivity of CFTR Testing: Prenatal Screening for Cystic Fibrosis
  • Clinical sensitivity is dependent on the panel of CFTR mutations selected
    • This review will focus on the ACMG recommended panel of 25 mutations
  • Clinical sensitivity is dependent of the race/ethnicity of the population screened
    • This review will provide estimates for self-reported race/ethnic groups (i.e., Hispanic and non-Hispanic Caucasians, Ashkenazi Jewish, African Americans and Asian Americans)
  • Clinical sensitivity is not dependent on the screening model used
    • Sequential (two-step), couple (one-step) and concurrent
american college of medical genetics acmg recommended panel of 25 cftr mutations
American College of Medical Genetics (ACMG) Recommended Panel of 25 CFTR Mutations
  • 7 mutations often tested in 7-13 pilot trials
    • delF508, G551D, G542X, 621+1G>T, W1282X, N1303K, and R553X
  • 7 mutations sometimes tested (2 to 6 trials)
    • delI507, 1717+1G>T, R117H, 3849+10kbC>T, R560T, A455E, R334W
  • 11 mutations rarely or never tested (0 or 1)
    • R347P, 711+1G>T, R1162X, I148T, 2789+5G>A, 3569delC, G85E, 2184delA, 1898+1G>A, 3120+1G>T, 1078delT
to reliably estimate clinical sensitivity requires
To Reliably Estimate Clinical Sensitivity Requires
  • An unbiased set of DNA samples from individuals with clinically defined ‘classic’ cystic fibrosis
  • A set test panel of CFTR mutations
  • Two large datasets are available:
    • The Cystic Fibrosis Consortium (diagnostic laboratories)
    • The Cystic Fibrosis Foundation (clinics providing patient care)
an acce review involves a critical evaluation of the literature
An ACCE Review Involves a Critical Evaluation of the Literature
  • The CF Consortium (Kazazian et al., 1994) reported mutation frequencies in North Americans (Caucasians). However, those numbers could not be used directly for two reasons:
    • This group includes reports that focus mainly on Hispanic Caucasians, Ashkenazi Jewish or African Americans
    • There was a computational error that underestimated mutation frequencies, especially for those less common
cystic fibrosis consortium reanalysis
Cystic Fibrosis Consortium Reanalysis

Mutation Frequency (%)

MutationOriginalRevised*

delF50866.168.94

G542X 2.2 2.17

G551D 2.0 2.06

621+1G>T 1.5 1.91

?? Others 7.4 8.20

A455E 0.25 0.54

711+1G>T 0.20 0.77

R347P 0.25 0.46

All79.985.05

*After removing 15 reports and using a new denominator

mutation frequencies in non hispanic caucasians
Mutation Frequencies in Non-Hispanic Caucasians

MutationCF ConsortCF FoundAverageCumulative

delF50868.9475.9072.4272.42

G542X 2.17 2.39 2.2874.70

G551D 2.05 2.44 2.2576.95

621+1G>T 1.92 1.22 1.5778.52

W1282X 1.42 1.57 1.5080.02

20 others 8.55 8.12 8.3388.35

Total85.0591.6488.35

CF Consortium based on between 2,197 and 9,792 chromosomes

CF Foundation based on 3,938 chromosomes

which set of mutation frequencies should be used
Which Set of Mutation Frequencies Should be Used?
  • The Cystic Fibrosis Consortium data may under-represent ‘common’ mutations such as delF508 because of the ‘reference’ nature of participating laboratories
  • The Cystic Fibrosis Foundation data may over-estimate the more ‘severe’ mutations such as delF508, because they are more likely to be enrolled for services
  • The average of the two may be reasonable to use
relationship between carriers identified detection of carrier couples or affected fetuses
Relationship Between Carriers Identified & Detection of Carrier Couples (or Affected Fetuses)

Proportion Identified (%)

Carrier IndividualsCarrier CouplesIncrease*

20 4

30 9 5

4016 7

5025 9

603611

704913

806415

908117

9590 9

* Increase in detection for 10% increase carriers identified

carrier couples detected clinical sensitivity among non hispanic caucasians
Carrier Couples Detected (Clinical Sensitivity) Among Non-Hispanic Caucasians

90

78%

80

75%

70

60

Clinical Sensitivity (%)

for Carrier Couples or Affected Fetuses

50

40

30

20

1

5

10

15

20

25

Number of CFTR Mutations

clinical sensitivity in other racial ethnic groups
Clinical Sensitivity in Other Racial/Ethnic Groups
  • Similar analyses are performed for individuals reported to be
    • Hispanic Caucasians
    • Ashkenazi Jewish
    • African American
    • Asian American
clinical sensitivity of prenatal cystic fibrosis screening by race ethnicity
Clinical Sensitivity of Prenatal Cystic Fibrosis Screening by Race/Ethnicity

100

Ashkenazi Jewish

90

80

Non-Hispanic Caucasian

70

Clinical Sensitivity (%)

60

Hispanic Caucasian

50

African American

40

30

Asian American

20

1

5

10

15

20

25

Number of CFTR Mutations

clinical specificity of prenatal screening for cystic fibrosis
Clinical Specificity of Prenatal Screening for Cystic Fibrosis
  • Analytic false positive results
    • Pre analytic
      • Sample mix-up prior to laboratory receipt
      • Degraded or mishandled sample
      • Non-paternity
    • Analytic
      • Sample mix-up after laboratory receipt
      • Benign polymorphism mistaken for a mutation
    • Post analytic
      • Data entry error
      • Incorrect laboratory interpretation
      • Report mix-up at the laboratory or provider site
clinical specificity of prenatal screening for cystic fibrosis17
Clinical Specificity of Prenatal Screening for Cystic Fibrosis
  • Clinical false positive results
    • Incomplete penetrance
      • Can be minimized, but not eliminated, by reflexive testing associated with R117H and I148T (D1152H is not on the panel but is likely to be of low penetrance as well)
      • A small proportion (up to 5%?) of individuals with two mutations will not have the ‘classic’ CF phenotype
    • Mutation is not disease-causing
      • Possible that I148T is a polymorphism that is tightly linked to a ‘real’ mutation
the birth prevalence of cystic fibrosis by race ethnicity
The Birth Prevalence of Cystic Fibrosis by Race/Ethnicity
  • Sources of data include:
    • prenatal (pre) screening trials
    • newborn (new) screening trials
    • population (pop) registries
  • Identified biases include:
    • number of mutations tested (pre, new)
    • race/ethnicity not accounted for (pre, new, pop)
    • prenatal screening and termination (new, pop)
    • length of follow-up (new, pop)
    • other study-specific biases (pre, new, pop)
acce methodology attempts to account for biases rather than excluding studies
ACCE Methodology Attempts to Account for Biases Rather than Excluding Studies
  • Number of mutations tested, and proportion of cases detected by race/ethnicity can be taken into account by using the race/ethnic specific mutation rates described earlier
  • Several studies provide the relative rates of prenatal screening and termination that occurs in concert with newborn screening (Europe / Australia)
  • The proportion of cases detected during reported follow-up can be adjusted using age at diagnosis information from the CF Foundation
adjusted prevalence of cf in non hispanic caucasians using prenatal screening trials
Adjusted Prevalence of CF in non-Hispanic Caucasians Using Prenatal Screening Trials

7000

5000

3000

Birth Prevalence (1:n)

2000

1:2488

1000

9B

6

10

4

13

1

9A

12

5

7

3

11

8

Consensus

Prenatal Study Number

prevalence of cystic fibrosis in non hispanic caucasians using newborn screening trials

6000

4000

3000

2000

1000

1:2509

Australia

UK

US

Europe

500

Prevalence of Cystic Fibrosis in non-Hispanic Caucasians Using Newborn Screening Trials

Birth Prevalence (1:n)

Observed

Adjusted

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

Newborn Study Number

prevalence of cystic fibrosis in non hispanic caucasians using population registries
Prevalence of Cystic Fibrosis in non-Hispanic Caucasians Using Population Registries

7000

5000

3000

Birth Prevalence (1:n)

2000

1 : 2499

1000

UK

Canada

US

Consensus

Population-Based Registry Number

summary birth prevalence of cystic fibrosis in selected racial ethnic groups
Summary: Birth Prevalence of Cystic Fibrosis in Selected Racial/Ethnic Groups

Prevalence

Racial/Ethnic GroupStudies(1:n)

Ashkenazi Jewish 4 2,271

Non-Hispanic Caucasians33 2,500

Hispanic Caucasians 313,500

African Americans 315,100

Asian Americans 131,000

genotype phenotype relationships
Genotype/Phenotype Relationships
  • ‘Classic’ cystic fibrosis phenotype occurs about 98% of the time when two mutations in the recommended mutation panel are identified.
  • Most mutations associated with pulmonary disease, but cannot accurately predict timing of onset & progression.
  • Pancreatic insufficiency in most cystic fibrosis patients, but 5 to15% have pancreatic function. Certain less common mutations are associated with pancreatic sufficiency.
  • Screening is expected to generate more information.
acknowledgements
Acknowledgements
  • ACCE Review: Population-based prenatal screening for cystic fibrosis via carrier testing (available on the CDC website)
  • ACCE Core Group
  • Slides provided by:

Glenn Palomaki & Linda Bradley