20.05.16 Trials and projects e.g. EACH, RAPID etc.

Question 1

What is the EACH study

Answer 1

• Evaluation of array comparative genomic hybridisation in prenatal diagnosis of fetal anomalies.
• 2011-2014 multi centre cohort study

Question 2

Objectives of EACH study

Answer 2

• Test whether arrayCGH should replace karyotyping in prenatal diagnosis of fetal anomalies detected by routine ultrasound screening.
• Evaluate whether NIPD (non-invasive prenatal diagnosis) can reliably be used to replace conventional invasive testing for Down syndrome and other major trisomies.

Question 3

How many cases did EACH study recruit

Answer 3

-~ 1500 trios (fetus and parents) from 11 centres in England and Wales

Question 4

What was the recruitment criteria for EACH study

Answer 4

• Fetuses undergoing karyotyping by CVS or amniocentesis
  a) one or more structural anomaly identified at 11-14 or 18-21 week ultrasound scan.
  b) Isolated elevated nuchal translucency ≥3.5mm identified at 11-14 week scan.

Question 5

-Study design of EACH

Answer 5

• Informed consent obtained from women:
• to use remaining prenatal samples after conventional karyotype for EACH study
• Obtain cell-free DNA from maternal plasma (for NIPD of DS)
• QF-PCR for common aneuploidies
• Array CGH if QF-PCR normal.
• Follow up studies using FISH or MLPA if CNV identified (also on parental DNA)

Question 6

EACH study proposed primary outcomes

Answer 6

• Detection of pathogenic chromosomal imbalances by karyotyping and CNVs by array CGH. Pathogenicity determined by size, gene content and inheritance pattern.
• Sensitivity and specificity of NIPD for Down syndrome

Question 7

EACH study proposed secondary outcomes

Answer 7

• detection of VUSs by karyotyping and arrayCGH
• TATs for arrayCGH and karyotyping
• Costs to NHS and social services of arrayCGH and karyotyping and cost per additional pathogenic CNV detected by array (follow up testing) relative to karyotyping
• Parent and health professional attitudes to array CGH.

Question 8

What is the RAPID study

Answer 8

• Reliable Accurate Prenatal non-Invasive Diagnosis

- 5 year UK programme funded by NIHR (National Institute for Health Research)

Question 9

Aim of RAPID study

Answer 9

To improve the quality of NHS prenatal diagnostic services by evaluating early non-invasive prenatal testing diagnosis.

Question 10

Objectives of RAPID study

Answer 10

• Development of laboratory standards for NIPT of fetal sex determination and single gene disorders
• Evaluation of methods for the NIPT of Down’s syndrome.
• Economic evaluation of cost effectiveness of NIPT
• Study of couple’s choices, preferences and needs if NIPT is introduced. Impact on pre-test counselling.
• Development of educational material for families, healthcare professionals and general public
• Assessment of wider social and ethical issues.
• Analysis of health service needs

Question 11

Outcome of RAPID study

Answer 11

• NIPD now available for
  1. sex determination (detection of SRY-specific sequences)
  2. CAH (congenital adrenal hyperplasia)
  3. FGFR3- related skeletal dysplasias
  4. Paternal exclusion of CFTR (couples must carry different mutations)

Question 12

What is the NIPT for Down syndrome evaluation study

Answer 12

• Part of RAPID study
• To evaluate NIPT for Down syndrome.
• NIPT offered to women with >1:1,000 risk.
• Invasive testing offered to women where NIPT indicates a positive result.
• Data will be used to assess accuracy in this lower risk population

Question 13

What will the NIPT for Down syndrome evaluation study assess

Answer 13

• Uptake of NIPT
• Barriers and facilitators of implementing NIPT in NHS
• Health economic evaluation.
• Education to women and healthcare professionals
• Sensitivity and specificity of NIPT for aneuploidy

Question 14

What is the PAGE study

Answer 14

• Prenatal assessment of genomes and exomes
• Aims:
  1. to improve prenatal diagnosis of fetal structural abnormalities
  2. Evaluate the role of exome and genome sequencing and develop cost-effective assays.
  3. allowing better genetics-derived prognoses, more informed parental counselling and future management of pregnancy and childbirth.

Question 15

Study design of PAGE study

Answer 15

• 2014-2016.
• 1000 UK-based trios with abnormal ultrasound scans.
• WES (40 had WGS as well)
• Kayrotyping or NIPT has excluded major trisomies and sex chromosomal abnormalities.
• pathogenic results are validated in diagnostic setting and reported

Question 16

Results of PAGE study

Answer 16

• WES facilitated genetic diagnosis, enabling more accurate predictions as to prognosis and recurrence risk
• 8.5% diagnostic yield (pathogenic findings)
• 3.9% had VUSs (with potential clinical usefulness)
• Isolated increased nuchal translucency (≥4mm) had lowest pick up (3.2%)
• Careful consideration as to case selection to maximise clinical usefulness.