As discussed on page 19, ‘Sensitivity and specificity of molecular tests’, molecular tests (particularly those configured to detect Down syndrome only) inevitably will have a lower relative sensitivity and specificity than karyo- typing. This means that if a molecular test were to be used on its own, some level of uncertainty would remain until the baby is born, compared to karyotyping. If it is assumed that once a baby is born the presence and nature of any abnor-
mality will be confirmed,§then there will be
no remaining uncertainty about a diagnosis.
TABLE 48 Mean time and range, in days, from reception at laboratory to posting result to patient
Type of test Mean days in laboratory (range)
Northern Ireland West Midlands
Karyotyping 20.8 (13–27) 12.8 (7–17) Molecular tests (FISH: Northern Ireland; Q-PCR:West Midlands) 1.1(1–2) 4.4 (2–8) Difference between two test types 19.7 8.4
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For the intervening period, however, a parameter best described as uncertainty days can be estimated for each of the test configurations. This can be calculated by combining two values: (i) relative sensitivity and specificity (Table 12), to express the degree of uncertainty about the presence or absence of chromosome abnormalities, and (ii) days spent in each state of uncertainty (Table 49).
Uncertainty days, calculated in this way (compared to the traditional test), are presented in Table 49 for the molecular tests as add-on (i.e. ‘new gold standard’ test regime), and in Table 50 for the molecular tests as replacement for karyotyping (i.e. ‘molecular test for all’ test regime).
Appendix 6 provides information on the detailed calculations performed.
As can be seen from Table 49, use of karyotyping is estimated to result in the largest number of uncertainty days, when compared to the various ‘new gold standard’ test regimes. This is because, if a ‘new gold standard’ test regime is used, almost all the information provided by karyo- typing is available to parents very early in the testing process.
In contrast, Table 50 shows that for the ‘molecular test for all’ regimes (i.e. molecular tests as a replacement for karyotyping), the reduced information provided by Down only
TABLE 49 Number of uncertainty days for ‘new gold standard’ test regime
Test regimes Molecular Direct cost Uncertainty Days in Uncertainty
test per patient state days
tested
‘New gold standard’ Down only FISH £131.82 1 2 7.30 0.3522 15
0.0001 158
Q-PCR £133.84 1 2 7.72 0.3804 15
0.0001 158
All commona FISH £164.75 1 2 4.11
0.1395 15 0.0001 158
Q-PCR £137.14 1 2 4.66 0.1766 15
0.0001 158
Karyotyping (status quo) £89.68 1 17 17.02 0.0001 158
a
Trisomies 21,18 and 13 and X,Y chromosome abnormalities
TABLE 50 Number of uncertainty days for ‘molecular test for all’ regime
Test regimes Molecular Direct cost Relative Uncertainty Days in Uncertainty
test per patient sensitivity state days
tested
Molecular for Down only FISH £42.14 0.6478 1 2 62.93 all replacing 0.3522 173
karyotyping Q-PCR £44.16 0.6196 1 2 67.81 0.3804 173
All commona FISH £75.07 0.8605 1 2 26.13 0.1395 173
Q-PCR £47.46 0.8234 1 2 32.55 0.1766 173
Karyotyping (status quo) £89.68 0.99 1 17 17.02 0.0001 158
a
Valuing benefits for parents and other stakeholders
84
molecular test results in the maximum number of uncertainty days for these tests. However, 5-probe FISH and, to a slightly lesser extent, multiplex Q-PCR (both configured for the five common abnormalities) approach the value for karyotyping. In these last two cases, any loss of information is compensated for by a much speedier result.
It should be noted that the values in Table 50 are estimated from the clinician’s perspective; uncertainty is calculated against perfect knowledge of how each test performs. In other words the clinician will be aware that even karyotyping can give a false result in some cases, as shown by the relative sensitivity of less than unity in Table 50 (see also page 19, ‘The gold standard, karyotyping’). If the simple cost-effectiveness ratios (cost per case detected) reported in chapter 7 are weighted by the uncertainty days in Tables 49 and 50, then a modified cost-effectiveness ratio can be estimated as given in Table 51. Once again, ‘cases detected’ are defined as all chromosome abnormalities detectable by the test configuration used and the figures given for ‘molecular test for all’ assumes that karyotyping will be replaced by molecular tests.
Table 51 presents weighted cost-effectiveness
ratios for the eight main test configurations. These weighted ratios allow for the relative costs of the test, the numbers of cases detected, and the relative time in which women remain in different states of uncertainty. Based on these ratios the ‘new gold standard’ test regime option would now appear to represent better value than karyotyping on its own. This is because the initial
(partial) information on abnormalities available quickly through the molecular tests plus the remaining information provided by karyotyping combine to give significantly better value than karyotyping alone. For the ‘new gold standard’ test regime it appears that the ‘all common’ molecular tests are the best tests to use, with their higher cost offset by the increased number of cases detected early. The extra information provided by the ‘all common’ form of the ‘new gold standard’ is reflected in the reduction of around 56–58% in the cost-effectiveness ratio compared to karyotyping.
However, if Down only molecular tests are used for the ‘new gold standard’, it appears that the loss of early information is not fully compensated for by the reduced cost, and the weighted cost- effectiveness ratio is calculated to be less favour- able – a reduction of 32–37% compared to karyotyping. The benefit of more rapid reporting is therefore undermined by the loss of infor- mation from the Down only test configuration, with fewer cases detected early, and a higher degree of uncertainty remaining until the karyotyping result.
Unlike add-on tests, the use of molecular tests as a replacement for karyotyping (‘molecular test for all’ regime) is calculated to be a less cost-effective strategy than karyotyping, substantially increasing the weighted cost per case detected (by between about 55% and 412%). This is because limited information is available with all molecular tests and therefore high levels of uncertainty about other abnormalities remain to the end of pregnancy. Even with the extra information provided by the ‘all common’ form of the ‘molecular test for all’
TABLE 51 Comparative cost-effectiveness of tests weighted for uncertainty days
Test configuration Ratio of Cost per case detected
uncertainty days (% change from status quo) to karyotyping
Unweighted Weighted
‘New gold standard’ Down only FISH 0.36 £3,184 (+47%) £1,366 (–37%) Q-PCR 0.38 £3,232 (+49%) £1,467 (–32%) All commona FISH 0.20 £3,979 (+84%) £960 (–56%) Q-PCR 0.23 £3,312 (+53%) £908 (–58%) Karyotyping (status quo) 1.00 £2,166 (0%) £2,166 (0%) ‘Molecular test for all’ Down only FISH 2.66 £2,657 (+23%) £9,826 (+354%)
Q-PCR 2.87 £2,784 (+29%) £11,096 (+412%) All commona FISH 1.11 £2,768 (+28%) £4,250 (+96%)
Q-PCR 1.38 £1,750 (–19%) £3,347 (+55%)
85
regime there is a calculated increase of between 55% (Q-PCR) and 96% (FISH) in the cost- effectiveness ratio compared with karyotyping. As explained, the values in Table 51 are based on the assumption of ‘perfect knowledge’ of the test and its performance (or the clinician’s perspec- tive). These values may therefore change if calculated from a patient’s perspective, dependent on what information individuals expect from the test result. In particular, if women expect, and want, only a test result for Down syndrome, the relative values would change as shown in Table 52.
Table 52 shows values for the weighted cost-
effectiveness ratios based on the assumption that a test for Down syndrome alone is requested or expected. As can be seen, in this situation the ‘molecular test for all’ regimes are more cost- effective than karyotyping or the ‘new gold standard’. The Down only test configuration of the ‘molecular test for all’ regime is the most cost-effective. This is because all molecular tests are technically equivalent in performance for the detection of Down syndrome and the ‘new gold standard’ and the ‘all common’ configuration of the ‘molecular test for all’ regime have a higher cost per sample tested than the Down only ‘molecular test for all’ regime.
In the situation depicted in Table 52, the un- weighted cost per case detected also changes compared to Table 51, because the intention is only to detect Down syndrome and thus the number of abnormalities to be detected falls by 60%. Therefore, for karyotyping, the unweighted cost per case detected rises by 161%, from £2166
to £5654 per Down syndrome case detected. This reflects the relative inefficiency of this test, which is, in effect, over-diagnosing. Similarly, the unweighted cost per case of Down syndrome detected in Table 52 for the ‘molecular test for all’ regime rises for the ‘all common’ test configuration, while remaining the same for the Down only configuration compared to Table 51.
Table 52 also shows that in a situation where women
are only expecting a test for Down syndrome, use of molecular tests alone is seen to be much more cost-effective than use of the ‘new gold standard’. This reflects the more expensive test cost of the ‘new gold standard’ regime compared to the information expected. Although all molecular test configurations demonstrate better weighted cost- effectiveness ratios than karyotyping, because the test results are received within 2 days rather than 13–21 days, the Down only ‘molecular test for all’ regime (FISH or Q-PCR) is the most cost-effective as it minimises waiting and has the smallest direct cost (weighted cost per case detected, 95% lower than for karyotyping).
The assumptions on which the weighted cost- effectiveness calculation are based are untested and need validation. In their current form, however, the assumptions highlight the sensitivity of the cost-effectiveness approach in terms of the outcomes chosen. In the unweighted cost- effectiveness it is assumed that the outcome of the number of cases detected is the sole outcome. Even this simple outcome is not without problems as it may be asked what outcomes the women tested were expecting and whether there is a complete match in expectations between clinician
TABLE 52 Comparative cost-effectiveness of tests weighted for uncertainty days (for Down syndrome only)
Test configuration Ratio of Cost per case detected
uncertainty days (% change from status quo) to karyotyping
Unweighted Weighted
‘New gold standard’ Down only FISH 0.10 £8,311(+47%) £902 (–84%) Q-PCR 0.10 £8,439 (+49%) £916 (–84%) All commona FISH 0.10 £10,388 (+84%) £1,128 (–80%) Q-PCR 0.10 £8,647 (+53%) £939 (–83%) Karyotyping (status quo) 1.00 £5,654b(0%) £5,654 (0%) ‘Molecular test for all’ Down only FISH 0.10 £2,657 (–53%) £288 (–95%)
Q-PCR 0.10 £2,784 (–51%) £302 (–95%) All commona FISH 0.10 £4,733 (–16%) £514 (–91%) Q-PCR 0.10 £2,992 (–47%) £325 (–94%)
a
Trisomies 21,18,13 and X, Y chromosome abnormalities
b
Valuing benefits for parents and other stakeholders
86
and patient, where for example the women has entered a screening programme for Down syn- drome. The weighted cost-effectiveness analysis modifies some of the conclusions, but at the expense of invalidated extended outcome measures.