Molecular Tests for Prenatal Diagnosis of Chromosome Abnormalities

164 Pages·2003·1.13 MB·English

Health Technology Assessment 2003;Vol.7:No.10
Evaluation of molecular tests for
prenatal diagnosis of chromosome
abnormalities
GM Grimshaw
A Szczepura
M Hultén
F MacDonald
NC Nevin
F Sutton
S Dhanjal
HTA
Health Technology Assessment
NHS R&D HTA Programme
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Evaluation of molecular tests for
prenatal diagnosis of chromosome
abnormalities
GM Grimshaw1* NC Nevin4
A Szczepura1 F Sutton5
M Hultén2 S Dhanjal2
F MacDonald3
1
Centre for Health Services Studies,University of Warwick,Coventry,UK
2
Biological Sciences,University ofWarwick,Coventry,UK
3
West Midlands Regional Genetic Laboratory and Consultancy Services,
Birmingham Womens Health Care Trust,Birmingham,UK
4
University of Belfast,Belfast,Northern Ireland
5
Statistician,Learning and Skills Council,Coventry,UK
* Corresponding author
Declared competing interests of the authors:none
Published May 2003
This report should be referenced as follows:
Grimshaw GM,Szczepura A,Hultén M,MacDonald F,Nevin NC,Sutton F,et al.Evaluation
of molecular tests for prenatal diagnosis of chromosome abnormalities.Health Technol
Assess 2003;7(10).
Health Technology Assessment is indexed in Index Medicus/MEDLINE and Excerpta Medica/
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ISSN 1366-5278
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Health Technology Assessment 2003;Vol.7:No.10
Contents
List of abbreviations .................................. i Test costs under different laboratory
conditions ...................................................... 40
Executive summary .................................... iii Discussion ...................................................... 42
5 Methods used to evaluate benefits to
1 Introduction and background.................... 1
parents and other test users...................... 45
Introduction .................................................. 1
Patient parameters ........................................ 45
Chromosome abnormalities in the fetus...... 1
Clinician surveys............................................ 47
Prenatal risk assessment................................ 3
Health commissioners surveys...................... 49
Prenatal diagnostic testing............................ 4
Summary ........................................................ 49
Developments in prenatal diagnostic
testing ............................................................ 4
6 Patient and physician choices.................... 51
Background to the current research............ 5
Introduction .................................................. 51
Aims of the research...................................... 6
Results of regional and national survey
Study design .................................................. 6
of obstetricians .............................................. 51
Obstetricians’ test choice for individual
2 Development and technical evaluation
patients .......................................................... 55
of molecular tests........................................ 9
Midwives’ test preferences............................ 57
Introduction .................................................. 9
Stakeholders’ test preferences...................... 57
Background to the FISH test........................ 9
Discussion ...................................................... 58
Background to the Q-PCR test...................... 9
Development of the Q-PCR test.................... 10
7 Estimating the cost-effectiveness of
Technical evaluation of molecular tests ...... 11
molecular tests ............................................ 61
Fineberg level 1: technical capacity of
Introduction .................................................. 61
molecular tests .............................................. 12
Cost-effectiveness of molecular tests as a
Fineberg level 2: diagnostic accuracy of
replacement for karyotyping ........................ 62
molecular tests .............................................. 16
Cost-effectiveness of molecular tests as
Sensitivity and specificity of molecular
a routine add-on to karyotyping .................. 64
tests ................................................................ 18
Cost-effectiveness of testing regimes with
Conclusions.................................................... 23
varying levels of karyotyping replacement .. 65
Costs of alternative testing regimes.............. 66
3 Current laboratory testing practices ...... 25
Incremental cost-effectiveness ratios............ 71
Introduction .................................................. 25
Discussion ...................................................... 72
UK survey of NHS genetics laboratories...... 25
Existing and planned use of molecular 8 Valuing benefits for parents and
tests in NHS cytogenetics laboratories ........ 25 other stakeholders ...................................... 75
Staffing and equipment for molecular Introduction .................................................. 75
tests in NHS cytogenetics laboratories ........ 27 Parental anxiety ............................................ 75
Prenatal services and activity in NHS Parental health status.................................... 77
cytogenetics laboratories .............................. 28 Cost–utility analysis........................................ 80
Study sites: structuring of prenatal testing Extending the cost-effectiveness analysis .... 81
services............................................................ 30 Valuing preferences: the cost–benefit
Conclusions.................................................... 32 approach ........................................................ 86
Overview of economic evaluation
4 Costs of karyotyping and molecular techniques...................................................... 91
tests................................................................ 33
Introduction .................................................. 33 9 Summary and conclusions ........................ 97
Capital costs.................................................... 34 Service delivery.............................................. 97
Labour costs .................................................. 35 Evaluation framework.................................... 99
Consumable costs.......................................... 36 Conclusions.................................................... 104
Cost per sample tested.................................. 37 Recommendations ........................................ 105
© Queen’s Printer and Controller of HMSO 2003.All rights reserved.
Contents
Acknowledgements .................................... 107 Appendix 7 General public questionnaire.... 129
References .................................................... 109
Appendix 8 Willingness to pay: contingent
Appendix 1 Development and valuation and conjoint analysis ...................... 133
preliminary assessment of single Q-PCR
test for Down syndrome................................ 113 Appendix 9 Possible test strategy .............. 135
Appendix 2 The number and type of
abnormalities undetected if using 5-probe Appendix 10 Aspects of assessing
FISH or multiplex Q-PCR ............................ 117 diagnostic technologies ................................ 137
Appendix 3 First questionnaire
Appendix 11 National Screening
to women........................................................ 119
Committee’s criteria for appraising the
Appendix 4 Obstetricians’ criteria viability, effectiveness and appropriateness
for undertaking amniocentesis for of a screening programme............................ 145
specific patients.............................................. 123
Health Technology Assessment reports
Appendix 5 Influence of throughput on
published to date ........................................ 147
test costs.......................................................... 125
Appendix 6 Calculation of weighted Health Technology Assessment
cost-effectiveness analysis.............................. 127 Programme .................................................. 153
Health Technology Assessment 2003;Vol.7:No.10
List of abbreviations
CVS chorionic villus sampling QoL quality of life
FISH fluorescence in situhybridisation Q-PCR quantitative polymerase chain
reaction
HTA Health Technology Assessment
ROC receiver operating characteristic
MLA Medical Laboratory Assistant
STR small tandem repeat
MTO Medical Technical Officer
NS not significant WTP willingness to pay
QALY quality-adjusted life-year VAS visual analogue scale
All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or
it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case
the abbreviation is defined in the figure legend or at the end of the table.
i
© Queen’s Printer and Controller of HMSO 2003.All rights reserved.

Health Technology Assessment 2003;Vol.7:No.10
Executive summary
Background • assess the cost-effectiveness of molecular tests,
and consider possible changes in current
Many women undergo prenatal tests for chromo- testing protocols.
some abnormalities in their baby, usually following
identification of an increased risk of the baby
having Down syndrome. One test that can show up Design
abnormalities likely to lead to mental or physical
handicap is done by sampling the amniotic fluid Two-stage trial; technical performance assessed
that surrounds the baby, usually around 14 weeks through a blinded comparison of molecular tests
of pregnancy. There is a very small risk of mis- against the accepted gold standard (karyotyping)
carriage with this procedure and parents are in a laboratory setting in the first stage; effective-
warned of this. If the test shows there is chromo- ness and cost-effectiveness measured in a service
some abnormality, parents may want to discuss setting in the second stage. Measurement of
whether to continue with the pregnancy. anxiety and health status of women; willingness
to pay (WTP) for four stakeholder groups; and
Until now parents have had to wait for up to survey of UK obstetricians and midwives.
3 weeks for the results of this test (karyotyping),
which is based on culturing the cells sampled
from the amniotic fluid. Karyotyping allows Setting
examination of all the baby’s chromosomes.
New DNA tests have been developed that can Two study sites – the catchment areas for the
give results in 2–3 days. These new molecular West Midlands Regional Genetic Laboratory
tests, using fluorescence in situhybridisation and the Northern Ireland Regional Genetics
(FISH) or the quantitative polymerase chain Centre, Belfast.
reaction (Q-PCR), search for abnormalities in
specific chromosomes. Errors in chromosomes
other than in those tested will not be disclosed. Participants
The abnormalities not tested for are much more
rare. For example, only 4 in every 1000 babies Blinded samples: 2376 Down only molecular tests;
tested will have one of these rarer abnormalities 1576 multiplex/5-probe tests; 3952 karyotyping.
and some of these may be identified during other
examinations, for example during routine Trial: 194 women (141 intervention group;
ultrasound examinations. 53 control group).
Many parents will welcome the quicker result from WTP: 1000 general public; 141 women;
a more focused test but some may be prepared to 84 partners; 105 health commissioners.
wait for the result of a test that examines all the
chromosomes.
Interventions (diagnostic tests)
Objectives • Molecular tests for the five most common
chromosome abnormalities.
The objectives of this study were to: • Molecular tests for Down syndrome only.
• Karyotyping.
• measure the technical performance of
FISH and Q-PCR tests versus karyotyping
• estimate the relative costs of molecular tests Main outcome measures
under various conditions
• establish the value to women, clinicians and Technical capacity, diagnostic accuracy, diagnostic
others of more rapid molecular test results impact, patient outcome and cost-effectiveness. iii
© Queen’s Printer and Controller of HMSO 2003.All rights reserved.
Executive summary
Results preferred. Five testing regimes were assessed in
terms of cost-effectiveness:
Technical capacity – does the test perform reliably
and deliver accurate (i.e. precise) information? 1. Molecular test and karyotyping for all women.
2. Molecular test as a replacement for karyotyping
FISH and Q-PCR test results are as reliable and 3. Molecular test for all plus karyotyping for
precise as karyotyping for the five most common high-risk women.
chromosome abnormalities. 4. Karyotyping for all plus molecular test for
high-risk women.
Diagnostic accuracy – does the test contribute 5. Parental choice plus karyotyping for high-
to an accurate diagnosis (of chromosome risk women.
abnormalities)?
Simple cost-effectiveness analysis based on the
The ability to detect the five most common cost per case detected (all cases) demonstrates
chromosome abnormalities, absolute sensitivity that regimes 2, 3 and 5 are more cost-effective
and specificity, are 1.00 and 1.00 for FISH and than karyotyping and 1 and 4 are not. This
0.9565 and 0.9997 for Q-PCR, respectively. pattern does not change if cost-effectiveness
analysis is limited to clinically significant
The ability to detect all clinically significant cases only.
chromosome abnormalities, relative sensitivity and
relative specificity, are 0.8605 and 0.9999 for FISH Cost–utility analysis estimates a cost per quality-
and 0.8234 and 0.9996 for Q-PCR, respectively. adjusted life-year gained of £23,542–£41,939 for
regime 1; it was not possible to assess regimes 2–5
Diagnostic impact – will the test replace other using this technique.
diagnostic tests or procedures?
Regimes 2, 3 and 5 will not detect some rare
Preferences of clinicians, women and other chromosome abnormalities (approximately 2–4,
stakeholders will influence diagnostic impact. 1–2 and 1 per 1000 women tested, respectively).
Fifty-seven per cent of obstetricians expressed a Introduction of regime 1 could increase annual
preference for molecular tests for most patients UK test costs by up to £2.8 million. Regimes 2 and
and karyotyping for a minority; only 15% would 3 should result in savings of up to £1.76 million
choose both tests. The views of midwives were per annum, and regime 5 approximately two-
similar. thirds of these savings. Regime 4 would be
largely cost neutral.
Most women (67%) and 54% of partners
expressed a pre-test preference for molecular
tests. Health commissioners were undecided. Conclusions
The general public expressed a preference for
karyotyping (60%). Implications for healthcare
In the current climate, the use of prenatal
Patient outcome – does the test contribute to testing is determined by individual clinicians,
improved health/reduced anxiety for the patient? laboratories and hospitals. There is evidence
of a lack of equity of provision, and of regional
Quality of life measure (EuroQol EQ-5D) and local variations with regard to primary risk
demonstrated significantly increased health status assessment. This may well be replicated with
linked to more rapid test results. Anxiety measure regard to final diagnosis if molecular tests are
(Speilberger) exhibited similar impact. introduced without discussion of appropriate
implementation protocols based on this report.
Cost-effectiveness – does the test use improve Debate and consensus will be necessary to develop
cost-effectiveness compared to alternative clinical protocols for introduction of molecular
interventions? tests and prevent continuation of inequities and
variations. Important ethical issues must not be
Molecular tests are less expensive than karyo- overlooked and crucial to this debate will be the
typing. As a replacement within larger laboratories needs and wishes of parents as well as the views
(> 1100 specimens per annum), Q-PCR is pre- of other stakeholders such as scientists,
iv ferred; for smaller laboratories (< 450), FISH is obstetricians and midwives.