The effect of the Montgomery judgment on settled claims against the National Health Service due to failure to inform before giving consent to treatment.

BACKGROUND: A landmark legal judgment in March 2015 (Montgomery) changed the test for determining negligence due to failing to inform patients before consent, by moving away from asking what a reasonable doctor should disclose and asking instead what a reasonable patient would expect to know. AIM: We sought to determine the effect Montgomery has had on settled claims due to failure to inform compared with claims for other reasons and whether legal firms are adding contributory claims of failure to inform to other principal allegations of negligence. METHODS: A Freedom of Information request to NHS Resolution provided data on the number of settled claims against the NHS (2005-19) for any cause and where failure to inform before consent was the principal or contributory cause. Time-series regression was used to compare trends before and after 31 March 2015. RESULTS: The trend in claims/year increased 4-fold for failure to inform (an increase of 9.8/year before 2015 vs. 39.5/year after 2015, P < 0.01), 2.7-fold when failure to inform was the principal cause (7.9/year vs. 21.2/year, P = 0.02) and 9.9-fold as a contributory cause (1.9/year vs. 18.3/year, P < 0.01). There was no material difference in claims due to other causes (334/year vs. 318/year, P = 0.84). CONCLUSIONS: Montgomery has led to a substantial increase in settled claims of failure to inform before consent, with no coincident change in claims for other causes. The increase in contributory compared with principal causes suggests that lawyers are using the judgment to increase the chances of a successful claim against the NHS.

Pregnancy-associated plasma protein-A truncation limits in antenatal screening for trisomy 18.

Upper and lower truncation limits are commonly applied to quantitative markers used in medical screening tests. We here examine data on 375 trisomy 18 and 522,081 unaffected singleton pregnancies, to determine if the lower truncation limit should be set below the previously specified 0.2 multiples of the median. A lower truncation limit of 0.15 would reduce the underestimation of the risk of having a trisomy 18 pregnancy in about 50% of affected pregnancies and would lead to an estimated 10 percentage point increase in the detection rate, with only a very small increase in the false-positive rate.

Presentation of meta-analysis plots.

Meta-analysis (forest) plots are widely used to show the results from multiple individual randomized trials or observational studies that address the same question, including the assessment of screening markers. They show the between study spread of results and provide a summary estimate of the results from all the studies combined. We here illustrate the advantage of ordering study results by the magnitude of the effect and including a vertical shaded band encompassing the summary 95% confidence interval of the summary estimate to emphasize the uncertainty of the estimate in a way that is more prominent than only displaying a "diamond" around its value.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study.

BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.

Is the area under an ROC curve a valid measure of the performance of a screening or diagnostic test?

OBJECTIVES: The area under a receiver operating characteristic (ROC) curve (the AUC) is used as a measure of the performance of a screening or diagnostic test. We here assess the validity of the AUC. METHODS: Assuming the test results follow Gaussian distributions in affected and unaffected individuals, standard mathematical formulae were used to describe the relationship between the detection rate (DR) (or sensitivity) and the false-positive rate (FPR) of a test with the AUC. These formulae were used to calculate the screening performance (DR for a given FPR, or FPR for a given DR) for different AUC values according to different standard deviations of the test result in affected and unaffected individuals. RESULTS: The DR for a given FPR is strongly dependent on relative differences in the standard deviation of the test variable in affected and unaffected individuals. Consequently, two tests with the same AUC can have a different DR for the same FPR. For example, an AUC of 0.75 has a DR of 24% for a 5% FPR if the standard deviations are the same in affected and unaffected individuals, but 39% for the same 5% FPR if the standard deviation in affected individuals is 1.5 times that in unaffected individuals. CONCLUSION: The AUC is an unreliable measure of screening performance because in practice the standard deviation of a screening or diagnostic test in affected and unaffected individuals can differ. The problem is avoided by not using AUC at all, and instead specifying DRs for given FPRs or FPRs for given DRs.

Improvements in antenatal screening for Down's syndrome.

OBJECTIVES: To estimate improvements to four antenatal screening tests for Down's syndrome (first trimester Combined, second trimester Quadruple, and first and second trimester Integrated and Serum Integrated tests) based on adding ductus venosus pulsatility index (DVPI), fetal nasal bone examination (NBE) and serum placental growth factor (PlGF). SETTING: Statistical analysis of data from several sources modelled using the maternal age distribution of live births in England and Wales from 2006 to 2008. METHODS: Monte Carlo simulation carried out to estimate the screening performance of tests with the addition of combinations of DVPI, NBE and PlGF. RESULTS: At a 95% detection rate (DR), with first trimester markers measured at 11 completed weeks' gestation, the addition of DVPI, NBE and PlGF decreased the false-positive rate (FPR) of the Combined test from 16.1% to 3.0%, the addition of PlGF to the Quadruple test decreased the FPR from 15.7% to 15.3%, the addition of DVPI, NBE and PlGF to the Integrated test decreased the FPR from 4.1% to 0.6% and the addition of PlGF to the Serum Integrated test decreased the FPR from 15.1% to 11.1%. At a 90% detection rate, the reductions in the FPR were from 6.8% to 0.8%, 7.7% to 7.4%, 1.2% to 0.1% and 6.2% to 4.8%, respectively. CONCLUSIONS: The addition of DVPI, NBE and PlGF to the Combined and Integrated tests significantly improves screening performance, reducing the FPRs by over 80%. The Integrated test with DVPI, NBE and PlGF is significantly better than the Combined test with DVPI, NBE and PlGF.

Distribution of nuchal translucency in antenatal screening for Down's syndrome.

OBJECTIVE: To determine whether the standard deviation of nuchal translucency (NT) measurements has decreased over time and if so to revise the estimate and assess the effect of revising the estimate of the standard deviation on the performance of antenatal screening for Down's syndrome. SETTING: Data from a routine antenatal screening programme for Down's syndrome comprising 106 affected and 22,640 unaffected pregnancies. METHODS: NT measurements were converted into multiple of the median (MoM) values and standard deviations of log(10) MoM values were calculated in affected and unaffected pregnancies. The screening performance of the Combined and Integrated tests (that include NT measurement) were compared using previous and revised estimates of the standard deviation. RESULTS: The standard deviation of NT in unaffected pregnancies has reduced over time (from 1998 to 2008) (e.g. from 0.1329 to 0.1105 [log(10) MoM] at 12-13 completed weeks of pregnancy, reducing the variance by about 30%). This was not observed in affected pregnancies. Compared with results from the serum, urine and ultrasound screening study (SURUSS), use of the revised NT standard deviations in unaffected pregnancies resulted in an approximate 20% decrease in the false-positive rate for a given detection rate; for example, from 2.1% to 1.7% (a 19% reduction) at a 90% detection rate using the Integrated test with first trimester markers measured at 11 completed weeks' gestation and from 4.4% to 3.5% (a 20% reduction) at an 85% detection rate using the Combined test at 11 completed weeks. CONCLUSIONS: The standard deviation of NT has declined over time and using the revised estimates improves the screening performance of tests that incorporate an NT measurement.

Evaluation of a proposed mixture model to specify the distributions of nuchal translucency measurements in antenatal screening for Down's syndrome.

OBJECTIVES: A mixture model of crown-rump length (CRL)-dependent and CRL-independent nuchal translucency (NT) measurements has been proposed for antenatal screening for Down's syndrome. We here compare the efficacy of the mixture model method with the standard method, which uses NT multiple of the median (MoM) values in a single distribution. Settings A routine antenatal screening programme for Down's syndrome comprising 104 affected and 22,284 unaffected pregnancies. METHODS: The ability of NT to distinguish between affected and unaffected pregnancies was compared using the mixture model method and the standard MoM method by using published distribution parameters for the mixture model of NT and parameters derived from these for the standard MoM method. The accuracy of the two methods was compared for NT and maternal age by comparing the median estimated risk with the prevalence of Down's syndrome in different categories of estimated risk. RESULTS: Using NT alone observed estimates of discrimination using the two methods are similar; at a 70% detection rate the false-positive rates were 12% using the mixture model method and 10% using the MoM method. Risk estimation was marginally (but not statistically significantly) more accurate using the standard MoM method. CONCLUSIONS: The mixture model method offers no advantage over the standard MoM method in antenatal screening for Down's syndrome, is more complicated and less generalizable to other data-sets. The standard MoM method remains the method of choice.

A randomized double-blind crossover trial to investigate the efficacy of screening for adult hypothyroidism.

OBJECTIVE: To assess the value of population screening for adult hypothyroidism. SETTING: Healthy people attending for a general health assessment. METHODS: A thyroid-stimulating hormone (TSH) measurement was performed on people attending for a general health assessment (women aged 50-79 [35-49 with a family history of thyroid disease] and men aged 65-79). Those with TSH levels above 4.0 mU/L were invited to join a randomized double-blind crossover trial of thyroxine and placebo, each given in random order for four months. On entry a second blood sample was collected for a TSH measurement after the end of the trial to determine whether this would help select individuals for thyroxine treatment. The daily thyroxine dose started at 50 µg and if necessary was increased to achieve a TSH level of 0.6-2.0 mU/L. RESULTS: There were 341 (8%) people with a TSH level above 4.0 mU/L, 110 met eligibility criteria (64 agreed to participate), and 56 (49 women, 7 men) completed the trial. Among the 15 individuals with a repeat TSH measurement above 4.5 mU/L, 11 reported feeling better on thyroxine than placebo and none reported feeling better on placebo (P = 0.001; four felt no different), indicating that in this group 73% benefitted (i.e. 11/15; 95% CI 45-92%). The main symptoms relieved were tiredness and loss of memory. There was no indication of harm. In the 41 individuals with a repeat serum TSH of 4.5 mU/L or less: 10 reported feeling better on thyroxine than placebo and 16 better on placebo (P = 0.42, 15 felt no different). Thus about 8% of men and women in the specified age groups had a TSH above 4.0 mU/L, and of these about a quarter had a repeat TSH above 4.5 mU/L, of whom about half would benefit from thyroxine treatment. CONCLUSION: The results indicate that screening for hypothyroidism would be worthwhile. Approximately 1% of people screened would have a better quality of life. Pilot screening programmes for adult hypothyroidism are justified.

Ductus venosus pulsatility index as an antenatal screening marker for Down's syndrome: use with the Combined and Integrated tests.

OBJECTIVES: To assess the value of ductus venosus blood flow (expressed as pulsatility index, DVPI) in antenatal Down's syndrome screening when used with the Combined and Integrated tests. METHODS: DVPI measurements between 10 and 13 weeks' gestation in 66 Down's syndrome and 7184 unaffected pregnancies were collected from women attending the Hospital Clinic, Barcelona, for antenatal care from 1999 to 2007 and combined with the Serum Urine and Ultrasound Screening Study (SURUSS) data to model screening performance, safety and cost-effectiveness of the screening tests with and without DVPI. RESULTS: The median DVPI multiple of the normal median in Down's syndrome pregnancies was 1.55 (95% CI 1.36-1.73). As a single screening marker without using maternal age, DVPI has a 62% detection rate for a 5% false-positive rate. At a 90% detection rate (first trimester measurements at 11 weeks' gestation) the addition of DVPI reduced the false-positive rate of the Combined test from 8.5% to 4.6% and the Integrated test from 2.0% to 1.1%, with a corresponding reduction in fetal losses from diagnostic procedures. There was no material loss of cost-effectiveness. CONCLUSION: Addition of DVPI measurements to the Combined and Integrated tests substantially improves the efficacy and safety of antenatal Down's syndrome screening.

Antenatal screening for Down's syndrome using the Integrated test at two London hospitals.

We carried out an audit of antenatal screening for Down's syndrome using the Integrated test (which provides a single screening result from information collected in the late first and early second trimesters of pregnancy) which was introduced into routine antenatal care at two London hospitals, University College Hospital (UCH) and St Mary's Hospital, in 2003-4. The audit was based on 15,888 women who accepted screening and booked in the first trimester. The Down's syndrome detection rate was 87% (95% confidence interval [CI], 74-95) consistent with an expected detection rate of 89% based on applying the estimates of screening performance of the Serum, Urine and Ultrasound Screening Study (SURUSS) to the maternal age distribution of women who were screened at UCH and St Mary's. The observed false-positive rate was 2.1% (95% CI, 1.9-2.3), compared with an expected of 2.5% for women of the same age. An audit trail (conducted at UCH) indicated that 98% (10,746/10,961) of women accepted integrated screening (2% having a first trimester test) and of these, 94% (10,116) completed both stages of the test. The audit demonstrated that it is feasible to conduct integrated screening within the NHS with a high acceptance rate and a screening performance consistent with that determined from previous research studies.

Validation plots in antenatal screening for Down's syndrome.

OBJECTIVE: To validate empirically the accuracy of antenatal Down's syndrome screening using the Integrated test, to compare this with other screening tests (including the Integrated test with the addition of cross trimester [CT] marker ratios) and to suggest how such validation analyses should be presented and interpreted. METHODS: Using data from 7809 unaffected and 27 Down's syndrome pregnancies that had had an Integrated test, risk estimates for various screening tests (maternal age, Double, Triple, Quadruple, Combined, Integrated and serum Integrated tests) that use Integrated test markers were categorized according to quintile categories of risk estimates of the 27 affected pregnancies. For each screening test, the median risk estimate for each category was plotted against the observed prevalence within each category. Such validation plots were also produced for the Integrated test with CT marker ratios by measuring the level of the serum markers in the trimester of pregnancy not already measured in stored samples of all affected and a one-in-five sample of unaffected pregnancies. The robustness of the method was assessed by repeating the analysis for the Integrated test after re-classifying affected pregnancies with low risk estimates as unaffected, simulating the underascertainment of cases. RESULTS: The validation plots (i) confirmed the accuracy of risk estimation for the different tests (by how close the points lay to the line of identity between predicted risk and observed prevalence), (ii) demonstrated the differences in screening performance of the different tests (by the range of risk spanned by the points and, in particular, the separation between the points representing the lowest risk and the next point), and (iii) are robust to underascertainment of affected pregnancies (by having little influence on the closeness of the points to the line of identity). CONCLUSION: The validation plot is a useful, simple and robust way to assess the validity of new screening methods, to assess the accuracy of risk estimation and to audit the performance of screening programmes.