Cross-trimester repeated measures testing for Down's syndrome screening: an assessment

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 06/08/01. The contractual start date was in May 2007. The draft report began editorial review in December 2008 and was accepted for publication in July 2009. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

The University of Plymouth has a patent application on the use of repeated measures in Down’s syndrome screening with David Wright named as inventor.

Copyright statement

© 2010 Queen’s Printer and Controller of HMSO. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) (http://www.publicationethics.org/). This journal may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NETSCC, Health Technology Assessment, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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General

Screening for Down’s syndrome involves the calculation of a risk based on maternal age, previous history of Down’s syndrome, measurements of biochemical markers obtained from maternal serum samples, and possibly ultrasound images. The resultant risks are compared with a threshold and, in cases where the risk is at or above the threshold, the test is deemed screen-positive. Otherwise, it is deemed screen-negative. The current policy in the NHS is to use a risk threshold of 1 in 150 for risk assessment in the first trimester of pregnancy. A risk threshold of 1 in 200 is used in the second trimester. In general, both false-positive and detection rates increase with maternal age when a screening test is applied with a fixed risk threshold. For unambiguous comparisons, it is necessary to produce estimates of standardised detection rates and false-positive rates that apply to a specific reference maternal age distribution. This report presents results for screening tests applied to the maternal age distribution of England and Wales for the 3 years from 2000 to 2002. 16 Results for this reference distribution are presented for false-positive rates and detection rates obtained using a risk cut-off of 1 in 200, and for detection rates for a fixed false-positive rate of 2%.

Risk calculation

The calculation of risk in Down’s syndrome screening is an application of Bayes’ theorem17 to combine prior information on the maternal age-specific risk18,19 with likelihoods obtained from appropriately transformed measurements of marker concentrations from maternal serum and sometimes ultrasound markers such as NT. Almost invariably the transformation involves two steps. Firstly, the measurement is expressed as a multiple of the median (MoM) value for unaffected pregnancies, standardising for gestational age and other variables such as maternal weight, smoking status and ethnicity that have effects on the marker concentrations. 20 Secondly, a log transformation is used to produce a log (MoM) value. The likelihoods are calculated under the assumption that log (MoM) values follow different multivariate Gaussian distributions21 in unaffected and in Down’s syndrome pregnancies. For first trimester markers, it has been established that the mean log (MoM) in Down’s syndrome changes with gestational age. 22 This is accommodated in the model by a linear regression relationship. In practice, the unknown parameters defining the multivariate Gaussian distributions are replaced by estimates obtained from fitting multivariate Gaussian models to data such as those collected in the SURUSS study. To deal with departures from the Gaussian form in the tails of the distribution, truncation is applied to values beyond a specified range. The established approach is to apply truncation separately to each dimension. We have explored an alternative multivariate approach, based on the Mahalanobis distance,21 truncating values that are atypical of both Down’s syndrome and unaffected distributions. 23 This avoids the production of extreme risks for atypical pregnancies.

It is notable that the so-called estimative approach24 of substituting estimates for unknown parameters takes no account of the uncertainty in the parameter estimates. A formal way of dealing with this uncertainty is to use Bayesian predictive distributions. 24 However, we restrict this report to the estimative approach.

Assessing screening performance

The conventional ‘modelling’ methodology25 for assessing screening performance assumes that the class conditional distributions fitted to unaffected and Down’s syndrome log (MoM) values perfectly match the true population distributions. In practice, the fitted distributions will differ from the population distributions to some degree because the populations are not perfectly Gaussian and the fitted parameter estimates are subject to sampling error and biases. This means that assessment of screening performance under ideal modelling assumptions is optimistically biased. This is dealt with in this report as follows:

1. By assessing the performance of existing models for risk assessment on two independent test data sets. This avoids the optimistic bias associated with assuming the same Gaussian class conditional distributions in the population and in the risk calculation.

2. Each of two test data sets is used to create new parameter estimates against which screening test performance is assessed using the other data set. This provides robust estimates of screening performance that do not rely on assumptions that the distributions are Gaussian and enables us to provide estimates of the screening parameters from the two test data sets.

3. Distributions are fitted to the combined data from the two test data sets. Point and interval estimates are obtained under the Gaussian model adopting a Bayesian approach to inference that takes account of uncertainty concerning unknown parameters. 26,27

Parameters

To date, three sets of parameter estimates, (I)–(III) below, have been published that can be used as a basis for screening tests with repeated measures of PAPP-A, hCG and uE3. All of these are based on secondary data published in appendices of the SURUSS report,4 and give very similar results when applied to the test data sets. This report also includes a fourth set of parameters obtained from the North York routine data and published meta-analysis.

1. (I) The original SURUSS parameter estimates4 with corrections. 28

2. (II) The cross-trimester ratios parameter estimates obtained from SURUSS published by Wald and colleagues. 14

3. (III) The SURUSS parameter estimates incorporating the modifications associated with measurements of PAPP-A in the second trimester reported by Palomaki and colleagues23 in 2006.

4. (IV) The model for the means of log (MoM) values taken from published meta-analyses. 22 Covariance matrices, or equivalently standard deviations and correlations, are estimated from routine data collected at North York General Hospital.

Parameter estimates for (I)–(IV) are given in Appendix 3.

In (II), measures of PAPP-A in the first trimester and uE3 and hCG in the second trimester were included as log (MoM) values. Measures of PAPP-A in the second trimester and uE3 and hCG in the first trimester were included indirectly in terms of log-transformed cross-trimester ratios of second to first trimester MoM values. The screening algorithm that results, apart from the effect of truncation, is in fact equivalent to (I). 29 However, because of the methods of estimation used, the cross-trimester ratios formulation gives different estimates of means, standard deviations and correlations. 30

With the exception of parameters involving second trimester PAPP-A, the estimates used for (III) in the validation study of Palomaki and colleagues23 were taken from SURUSS. Parameter estimates for PAPP-A were obtained from a meta-analysis and from a consecutive series of 838 women using appropriately adjusted assays. A data set comprising 34 Down’s syndrome pregnancies and 514 unaffected pregnancies was used as an independent test data set. These data were obtained from North York and the cases are a subset of those comprising our test data set. New measurements of uE3 and hCG were made on first trimester samples for this Health Technology Assessment report.

The fourth set of parameters estimates (IV) was obtained from repeated measures made on routine samples from North York General Hospital. It should be emphasised that the North York test data were not used in the estimation of (IV). Estimation for (IV) was carried out using a Bayesian analysis implemented using WinBUGS. 31

Assumptions regarding covariance structure

Some of the published correlation matrices are not positive definite14 and others are near singular. The practical consequences are that it is impossible to compute risks in cases where the correlation matrix is not positive definite and that the computed risks are implausible when the correlation matrix is near singular. Furthermore, assessment of screening performance based on models using the estimated covariance matrix may be grossly optimistic. The near singular covariance matrices arise because of the sparseness of data from affected pregnancies and the methods employed in estimation. Using computer simulation, we have demonstrated that although the standard product moment estimators are unbiased, the determinant, or generalised variance, of the covariance matrix is biased towards zero. This worsens with increasing numbers of markers and with novel combinations of markers. The approach we have taken to dealing with this is to impose structural assumptions relating the covariance matrix in Down’s syndrome to that in unaffected pregnancies. Screening performance is assessed for the following assumptions regarding covariance matrices:

1. (i) Original covariance matrices – the covariance matrix for Down’s syndrome taken directly from the original source publications.

2. (ii) Pooled covariance matrices – the population covariance matrices for Down’s syndrome and unaffected pregnancies are assumed to be equal. A pooled estimate of the common covariance matrix is used.

3. (iii) Diagonally inflated covariance matrix – although there are some exceptions, the view is that the variances in Down’s syndrome pregnancies are likely to be larger than those in unaffected pregnancies. A model where the off-diagonal elements of the covariance matrix in Down’s syndrome are the same as those in unaffected pregnancies but the diagonal elements (i.e. the variances) are inflated in Down’s syndrome is used to capture this.

For the North York routine samples training data set (IV) that is assumed to contain unaffected pregnancies only, the analysis is restricted to assumption (ii) above.

Assessment of population screening performance

Population detection rates and false-positive rates for the assumed reference distribution were estimated as follows. Likelihood ratios were computed for the assumed Gaussian model. These were used to estimate the age-specific detection rates and false-positive rates. This was achieved by computing the proportion of likelihood ratios for which the risk resulting from combining the maternal age risk with the likelihood ratio exceeded the risk threshold. Population false-positive and detection rates were obtained by taking the weighted average of these age-specific proportions with respect to the relative frequency distribution of maternal ages in the reference populations for unaffected and Down’s syndrome pregnancies respectively. This methodology has the benefit of efficiency in the sense that all of the available data are used at each maternal age. An implicit assumption involved in this calculation is that conditionally on karyotype (unaffected or Down’s syndrome), the log (MoM) values are independent of maternal age. This assumption is consistent with the available evidence. Moreover, the results we present are robust to moderate departures from this assumption. CIs were produced using non-parametric bootstrapping.

Assessment of goodness of fit

The fit of the various models to the independent test data sets was assessed using likelihood ratio-based test statistics. These were employed as a basis for comparing the goodness of fit of the different models; not as a formal hypothesis test of goodness of fit.

Model fitting

The model fitting presented in this report was carried out using Bayesian analysis implemented using WinBUGS. This approach enables missing data to be dealt with and, through the use of a mixture model with contamination, robust estimates of parameters to be obtained without the need to make arbitrary or subjective decisions about exclusion of outliers. 32 Assessment of screening performance under the Gaussian model fitted to the combined First and Second Trimester Evaluation of Risk (FaSTER) and North York data sets was carried out by sampling detection and false-positive rates from the posterior predictive distributions. Risks were calculated with the covariance matrices and means fixed at their posterior mean.

Test data

The FaSTER repeated measures data arise from a nested case–control study consisting of 78 Down’s syndrome cases and 390 matched unaffected controls, with maternal blood samples obtained at 11–13 and 15–18 weeks’ gestation. Measurements of the integrated test markers (NT and PAPP-A in the first trimester and AFP, uE3, hCG and Inhibin-A in the second trimester) were augmented by measures of PAPP-A in the second trimester and of hCG and uE3 in the first trimester. In the original FaSTER study,2 samples were obtained from 15 screening centres across the USA between October 1999 and December 2002 and analysed centrally. All centres and the central laboratory obtained institutional review board approval, and all patients provided informed consent. Outcomes were obtained in 97% of all pregnancies. Of the 117 cases of Down’s syndrome identified in this study, 25 were identified by first trimester ultrasound findings and did not have serum samples collected. Second trimester serum samples were obtained from 87 cases of Down’s syndrome. The case–control study is based on 78 of these 87 cases for which there was sufficient serum to carry out the repeated measurements. Each of the cases of Down’s syndrome was matched to five controls for gestational ages at the times of serum sampling, ethnicity, maternal age and storage duration. Serum samples were stored at –80oC. The first trimester sera were thawed and tested for uE3 and hCG. The second trimester sera were thawed and tested for PAPP-A. All measurements were made without knowledge of whether the sample was from a case or control pregnancy.

The North York repeated measures data arise from a case–control study in which cases were identified from women who received integrated prenatal screening at North York General Hospital at two time intervals: (1) between 1 December 1999 and 31 October 2003, and (2) between 1 October 2006 and 23 November 2007. Institutional review board approval was obtained for the study. After testing, first and second trimester serum samples were stored at –20°C. Demographic and pregnancy-related information, such as maternal age, gestational age, maternal weight and pregnancy outcome, including if the pregnancy was affected by Down’s syndrome, was available from the Ontario Multiple Marker Screening Database. Ultrasound-based gestational age was between 11 and 13 completed weeks for the first trimester samples and 14 and 20 completed weeks for the second trimester samples. For each pair of samples obtained from a documented singleton Down’s syndrome pregnancy (case), five paired sample sets from singleton pregnancies not known to be affected with any chromosomal abnormality were selected as controls. Cases and controls were matched for sample date, gestational age and maternal age. No data on NT and Inhibin-A were available in the database.

First trimester PAPP-A and second trimester AFP, uE3 and hCG measurements in maternal serum (PerkinElmer Life and Analytical Sciences, Woodbridge, Ontario, Canada) were already available in the Ontario Multiple Marker Screening Database. The first trimester sera were thawed and tested for uE3 and hCG. The second trimester sera were thawed and tested for PAPP-A. All measurements were made without knowledge of whether the sample was from a case or control pregnancy. The first trimester samples were tested for PAPP-A after a 1:5 dilution (according to package insert instructions). The matching second trimester samples were tested in the same manner, but at a dilution of 1:40. Measurements were converted to MoM values using medians derived from the control samples and were adjusted for maternal weight using existing equations. Because a relatively large proportion of samples was from Asian women, a separate adjustment was used for existing markers to ensure that the median MoM was 1.0 in both Asian and non-Asian women.

Training data sets

Data from two separate consecutive series screening tests from North York were used to provide evidence on the covariance matrices of marker panels involving repeated measures of PAPP-A, uE3 and hCG. Research Ethics Board approval was obtained for these studies. The same storage and assay methods as for the case–control samples were used for these samples.

Sample 1, which includes data on repeated measures of uE3, hCG and PAPP-A, was obtained from a consecutive series of 1050 women who received integrated screening between January and April 2007. The sample was restricted to singleton pregnancies with no known chromosomal anomaly for which data on maternal weights were available. Pregnancies associated with insulin-dependent diabetic mellitus were excluded. First trimester PAPP-A and second trimester AFP, uE3 and hCG measurements of these samples were already available in the Ontario Multiple Marker Screening Database. First trimester uE3 and hCG and second trimester PAPP-A concentrations were measured for this study.

Sample 2 includes repeated measures data on PAPP-A from an earlier consecutive series of 838 women. These data, reported by Palomaki and colleagues,23 were collected on women who received integrated screening during March and April 2005, reported as having a singleton pregnancy, with maternal weight and ethnicity available.

Data

Data disposition for the FaSTER and North York test data sets are shown in Table 1. Summary statistics for these data are given in Appendix 4. As can be seen, there are a number of pregnancies in the North York test data for which no second trimester sample data are available. These amount to 19% of cases of Down’s syndrome and 12% of the controls. Measurements on first trimester uE3 were missing in 10 of the cases and 50 controls in the North York sample. These data were missing because there was insufficient serum available to complete the full panel of first trimester assays. Full marker information was available on 25 cases and 123 controls.

The design used in FaSTER means that cases and controls were restricted to women for whom first and second trimester data were available. In the FaSTER repeated measures data, there was insufficient serum for assays of hCG on 9 cases and 125 controls giving full marker information on 68 cases and 224 controls. The full information data sets were used as test data for comparison of different screening strategies. Bayesian model fitting in WinBUGS used all available data.

Model data fit

The fit of the various fitted models, described in Chapter 2, was assessed using a likelihood ratio-based test statistic (see Appendix 5). This was obtained from a test of the null hypothesis that the training data arise from the specific multivariate distribution with parameters taken from Appendix 3. Under the alternative hypothesis, the data arise from a distribution with a different mean and covariance matrix. As described in Appendix 5, this statistic is partitioned into two additive components representing the lack of fit of means and of covariance matrices. The departure from the mean was represented by a linear trend with gestational age to allow for a gestational age-dependent error in mean log (MoM) values. To remove the effect of gross outliers, the likelihood ratio test statistic was computed after truncation of observations falling outside of the 99.9th contour of the fitted distribution. The results, values of –2 log likelihood ratio, are presented in Table 2.

For a situation involving p markers, under the assumption that the data arise from the particular model, the statistics presented in Table 2 are asymptotically chi-squared distributed with degrees of freedom: ν = 2p for the fit statistic for the mean and ν = p(p + 1)/2 for the fit statistic for the covariance matrix. Of course, in this analysis, the model parameters were estimated from training data and would be expected to show some departure from the true parameters, thus inflating this test statistic. Moreover, some degree of departure from a Gaussian distribution would be expected and this would further inflate the fit statistic. With p = 7 in this situation, values of 2p = 14 and p(p + 1)/2 = 28 provide a guide to interpretation, but it is the differences in the fit statistics across the different models and assumptions regarding covariance matrices that are important in the interpretation of Table 2.

The most notable feature of Table 2 is the relatively poor fit of the data from Down’s syndrome cases to the covariance matrices from the original sources (i). For parameter sets (I)–(III), the pooled covariance matrix, which is dominated by data from unaffected pregnancies, provides a better fit to the data in Down’s syndrome than the Down’s covariance matrix from the original source. It is also notable from Table 2 that the parameter sets (I)–(IV) are similar in terms of their goodness of fit to the test data. This is reflected in the similarity in screening performance when applied to the test data sets. In this report we present results of screening performance for parameter set I using truncation limits on MoM values from SURUSS.

Under assumptions (i) original covariance matrices and (ii) pooled covariance matrices, Figure 1 shows the distribution of squared Mahalanobis distances from the mean for the Down’s syndrome pregnancies. Points with the same Mahalanobis distance have the same Gaussian probability density and fall on the same contour of the probability distribution, so can be considered to be statistically equidistant from the mean. Under the Gaussian model the squared Mahalanobis distances should follow a chi-squared distribution with ν = 7 degrees of freedom as shown by the smooth curve. Under assumption (i) it is clear that the training data are generally atypical of the assumed Gaussian distribution. Under assumption (ii) the degree of lack of fit is much less pronounced. Figure 2 shows the distribution of squared Mahalanobis distances for unaffected pregnancies. This indicates that, under both sets of assumptions (i) and (ii), the fitted covariance matrices are consistent with the test data.

FIGURE 1.

Histograms of squared Mahalanobis distances of log (MoM) values of h1, p1, u1, a2, u2, h2 and p2 for Down’s syndrome pregnancies. Under the Gaussian model, the squared Mahalanobis distances should follow the chi-squared distribution with 7 degrees of freedom shown by the smooth curve. (a) North York data using SURUSS parameters with original covariance matrix; (b) North York data using SURUSS parameters with pooled covariance matrix; (c) FaSTER repeated measures data using SURUSS parameters with original covariance matrix; (d) FaSTER data using SURUSS parameters with pooled covariance matrix. Values are truncated at the 99.99th percentile.

FIGURE 2.

Histograms of squared Mahalanobis distances of log (MoM) values of h1, p1, u1, a2, u2, h2 and p2 for unaffected pregnancies. Under the Gaussian model, the squared Mahalanobis distances should follow the chi-squared distribution with 7 degrees of freedom shown by the smooth curve. (a) North York data using SURUSS parameters with original covariance matrix; (b) North York data using SURUSS parameters with pooled covariance matrix; (c) FaSTER repeated measures data using SURUSS parameters with original covariance matrix; (d) FaSTER data using SURUSS parameters with pooled covariance matrix. Values are truncated at the 99.99th percentile.

Estimation of screening performance using independent test data

Table 3 gives standardised detection rates for the two repeated measures test data sets for a 2% false-positive rate using the SURUSS screening model under the three different assumptions regarding the covariance matrix in Down’s syndrome pregnancies. Table 4 shows the marginal increase in standardised detection rates over the base test comprising PAPP-A in the first trimester, and AFP, hCG and uE3 in the second trimester. The 2% false-positive rate was chosen as it is the 2010 target set by the NHS National Programme (see Appendix 1 for National Screening Committee criteria for screening programmes). Table 5 presents standardised false-positive and detection rates using the term risk threshold of 1 in 200 to define a screen positive group. This risk threshold was chosen because it is the current threshold adopted by the NHS National Programme. Table 6 shows the marginal increases in standardised false-positive and detection rates over the base model that result from the inclusion of repeated measures markers. Whilst Tables 2 and 3 serve as a useful basis for comparing screening tests, in practice, screening is usually operated with a fixed risk threshold, so Tables 5 and 6 give a better indication of the practical consequence of incorporating repeated measures.

The most notable feature of Tables 3–6 is the very poor performance associated with repeated measures with the original Down’s syndrome covariance matrix. The addition of repeated measures of uE3, hCG and PAPP-A to the base test, comprising PAPP-A in the first trimester and AFP, uE3 and hCG in the second, reduces the detection rate for a fixed 2% false-positive rate by around 30% in both FaSTER and North York data sets. This is very different from the results obtained from modelling using the fitted Gaussian model from SURUSS as presented by Wright and Bradbury13 and Wald and colleagues. 14 The poor performance, which reflects the poor fit observed in Table 2 and illustrated in Figure 1, was explored by examining the determinants of the correlation matrices of the various models given in Table 7.

These determinants provide summary measures of the multivariate spread of the fitted distribution of the standardised log (MoM) values. The smaller determinants for Down’s syndrome pregnancies relative to unaffected pregnancies means that the fitted multivariate Gaussian distribution in Down’s syndrome pregnancies is concentrated in a relatively small region of the sample space. In practice, Down’s syndrome pregnancies for which observations fall outside this region are assigned low risks. Consequently, whilst modelled performance is very good because the population distributions are assumed to be the same as the fitted distributions, performance on test data is poor. Indeed, Tables 3–6 show deterioration in performance from the addition of repeated measures when using the original covariance matrix (i) for Down’s syndrome pregnancies. This is illustrated in Figure 3, which shows the modelled receiver operating characteristic (ROC) curves with the estimates and 95% CIs for the false-positive and detection rates obtained from the test data sets with a risk threshold of 1 in 200. The evidence from the two test data sets is that screening performance in practice is likely to be much worse than that suggested by the modelling.

FIGURE 3.

Modelled receiver operating characteristics curves for screening with u1 + h1 + p1 + a2 + u2 + h2 + p2 using SURUSS parameters at 11 weeks’ (—), 12 weeks’(—) and 13 weeks’ (—) gestation with 95% CIs for false-positive and detection rates from the North York (—) and FaSTER (—) test data with a risk threshold of 1 in 200. The rectangles are the 95% CIs. The vertical and horizontal lines within these rectangles are the estimated false-positive rate and detection rate respectively for a risk threshold of 1 in 200.

Turning to the performance with pooled or diagonally inflated covariance matrices, the results from the North York and FaSTER test data sets are somewhat equivocal. Referring to Table 4, with the FaSTER test data, the addition of repeated measures of PAPP-A produces a marginal decrease in estimated detection rates for the fixed 2% false-positive rate. However, the 95% CI contains zero. For the North York test data the estimate shows a potentially important benefit for repeated measures of PAPP-A but, again, the CIs for the marginal increase in detection rates all contain zero.

The improvement in performance from assuming equal covariance matrices echoes results presented by Williams and colleagues33 in 1999, who found that, with smaller training samples, even the performance of tests with relatively few dimensions was improved by making the assumption of equal covariance matrices.

Modelling screening performance23 shows that any benefit of repeated measures diminishes as the gestational age for the first sample increases and that the modelled benefits are negligible for gestational ages of 13 weeks or older. The intuitive explanation for this is that the benefit of repeated measures depends on the difference between the means of the repeated measures. In situations where the first measurement is taken late in the first trimester, the means across the two trimesters are closer together and the discriminatory power is reduced. Tables 8–11 show screening performance for the two test data sets where the gestational age at the time of the first sample is younger than 13 weeks. Again, the original Down’s syndrome covariance matrix is associated with worsening screening performance with the addition of repeated measures. In contrast, the pooled and diagonally inflated covariance matrices show improvements, especially for repeated measures of PAPP-A.

Using the pooled covariance matrix for both FaSTER and North York data sets (see Tables 8 and 9), the use of repeated measures of PAPP-A increases the estimated detection rate for a fixed 2% false-positive rate by an estimated 5% (95% CI –2% to 13%) in the FaSTER data set and an estimated 10% (95% CI –5% to 24%) in the North York data set. Similarly, the estimates shown in Tables 10 and 11 indicate that repeated measures of PAPP-A have the potential to produce an important reduction in false-positive rates whilst maintaining or even increasing detection rates. However, because of the uncertainly reflected in the wide CIs associated with the relatively small samples of Down’s syndrome cases in the test data sets, the evidence cannot be considered conclusive.

Model fitting

The assessment of goodness of fit and screening performance with published parameters has demonstrated the limitations of the existing evidence for risk assessment using repeated measures. In particular, the correlation matrices for Down’s syndrome for training data sets (I)–(III) have unrealistically small determinants, they are a poor fit to the test data sets and produce poor screening performance. The pooled estimates provide a better fit and show some improvement in screening performance with repeated measures of PAPP-A, especially when the first sample is taken early in the first trimester. However, with the relatively small sample sizes, there is considerable uncertainty associated with these estimates. The purpose of this chapter is to show how new models were developed using the evidence available from the North York and FaSTER data sets. Three models, all based on pooled covariance matrices, were fitted within the Bayesian framework implemented using WinBUGS. One model was fitted to each of the two test data sets separately so that the other test data set could be used for independent cross-validation. A third model was fitted to the combined data set. The fitted model parameters are presented in Appendix 6.

Cross-validation

Tables 12–17 show the results of a cross-validation study using separate models fitted to each of the two test data sets using the other test data set for validation. These show similar performance to that achieved using the SURUSS data. These tables also provide estimates of screening performance when the same data set is used for training and testing. It is notable that the different results from a particular test data set are similar for the two choices of training data. The degree of optimistic bias encountered in these data is therefore small. Figure 4 shows the ROC curve produced from the model fitted to the combined data, together with estimates of screening performance from the cross-validation using the data at 12 weeks or earlier (Table 16). This shows that the estimates from the cross-validation are broadly consistent with the modelled performance. Tables 16 and 17 show that for both FaSTER and North York samples, the evidence is that repeated measures of PAPP-A improve screening performance when the first trimester sample is taken at 12 weeks’ gestation or earlier.

FIGURE 4.

Modelled receiver operating characteristics curves for screening with p1 + a2 + u2 + h2 + p2 at 11 weeks’ (—), 12 weeks’ (—) and 13 weeks’ (—) gestation. The rectangles are the 95% CIs for false-positive and detection rates from the North York (—) and FaSTER (—) test data using a risk threshold of 1 in 200. The vertical and horizontal lines within these rectangles are the estimated false-positive rate and detection rate respectively. The estimates and CIs were obtained using cross-validation. For example, the estimates and CIs for the North York test data were obtained from screening using the model fitted to the FaSTER test data.

Bayesian inference under a Gaussian model fitted to the combined data

Table 18 shows screening performance under the Gaussian model fitted to the combined test data sets from FaSTER and North York. Point estimates, together with 95% CIs, were obtained by sampling from the posterior predictive distribution of screening performance. Table 19 shows the marginal benefits of adding the sequence of repeated measures of PAPP-A (second trimester), hCG (first trimester) and then uE3 (first trimester) to the base test, comprising PAPP-A in the first trimester and AFP, hCG and uE3 in the second trimester. The evidence is that PAPP-A is the most promising marker for repeated measures. However, the benefit of this and other repeated measures markers diminishes with gestational age at the time of the first trimester sample. By 13 weeks there is no evidence of any benefit.

Figures 5–7 show ROC curves (bold) obtained from the model fitted to the combined data at 11, 12 and 13 weeks respectively for a test using first trimester PAPP-A and second trimester AFP, uE3, hCG and PAPP-A. Estimates (posterior means) and 95% credibility intervals for this test, with a risk threshold of 1 in 200, are superimposed on Figures 5–7. These were obtained from the posterior distribution under the Gaussian model. For comparison, the ROC curves of the base test (first trimester PAPP-A and second trimester AFP, hCG and uE3) are also shown.

FIGURE 5.

Receiver operating characteristic curve for the base test p1 + a2 + h2 + u2 and for the base test + p2 (bold) when the first trimester sample is taken at 11 weeks’ gestation. The rectangles show 95% credibility intervals for standardised detection rates and false-positive rates for a risk threshold of 1 in 200. These were obtained from the posterior distribution under the Gaussian model.

FIGURE 6.

Receiver operating characteristic curve for the base test p1 + a2 + h2 + u2 and for the base test + p2 (bold) when the first trimester sample is taken at 12 weeks’ gestation. The rectangles show 95% credibility intervals for standardised detection rates and false-positive rates for a risk threshold of 1 in 200. These were obtained from the posterior distribution under the Gaussian model.

FIGURE 7.

Receiver operating characteristic curve for the base test p1 + a2 + h2 + u2 and for the base test + p2 (bold) when the first trimester sample is taken at 13 weeks’ gestation. The rectangles show 95% credibility intervals for standardised detection rates and false-positive rates for a risk threshold of 1 in 200. These were obtained from the posterior distribution under the Gaussian model.

From a practical perspective, first trimester combined screening using NT, PAPP-A and β-hCG at 11–13 weeks’ gestation is the standard being adopted in the UK and elsewhere. The quadruple test comprising AFP, uE3, hCG and Inhibin-A is being adopted for women screened in the second trimester. It is therefore important to determine the role of repeated measures in tests incorporating markers from the combined test and the quadruple tests. Specific questions are:

• What is the benefit of second trimester PAPP-A when added to the markers in the combined and quadruple tests?

• What is the best subset of markers?

Using the estimates from Appendix 6 in conjunction with the mixture model for NT,34 the performance of screening using second trimester measurement of PAPP-A with the markers from the combined and quadruple tests was assessed. The results are presented in Table 20. With the inclusion of NT, the modelling produces detection rates well in excess of 90% for false-positive rates of less than 2%. The addition of PAPP-A in the second trimester increases detection rates marginally and reduces false-positive rates by 0.4% when the first trimester sample is taken at 11 weeks’ gestation and 0.2% when the first trimester sample is taken at 12 weeks. The addition of the second trimester measurement of PAPP-A is of no benefit when the first trimester sample is taken at 13 weeks’ gestation.

Contribution of authors

The data which made this study possible were provided from the FaSTER study, represented by F Malone and M D’Alton, and North York General Hospital, Toronto, by A Summers and T Huang. The analysis was conducted by D Wright and I Bradbury, with S Ball and A Baker assisting with the analysis. The report was drafted by D Wright and I Bradbury. B Nix, D Aitken, J Crossley, H Cuckle and K Spencer worked on the design of the study. All authors contributed to the writing of the report.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Ideally all the following criteria should be met before screening for a condition is initiated:

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   By Hobbs FDR, Delaney BC, Fitzmaurice DA, Wilson S, Hyde CJ, Thorpe GH, et al.

6. Systematic review of outpatient services for chronic pain control.

   By McQuay HJ, Moore RA, Eccleston C, Morley S, de C Williams AC.

7. Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

   A review by Pollitt RJ, Green A, McCabe CJ, Booth A, Cooper NJ, Leonard JV, et al.

8. Preschool vision screening.

   A review by Snowdon SK, Stewart-Brown SL.

9. Implications of socio-cultural contexts for the ethics of clinical trials.

   A review by Ashcroft RE, Chadwick DW, Clark SRL, Edwards RHT, Frith L, Hutton JL.

10. A critical review of the role of neonatal hearing screening in the detection of congenital hearing impairment.

    By Davis A, Bamford J, Wilson I, Ramkalawan T, Forshaw M, Wright S.

11. Newborn screening for inborn errors of metabolism: a systematic review.

    By Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, Cockburn F, et al.

12. Routine preoperative testing: a systematic review of the evidence.

    By Munro J, Booth A, Nicholl J.

13. Systematic review of the effectiveness of laxatives in the elderly.

    By Petticrew M, Watt I, Sheldon T.

14. When and how to assess fast-changing technologies: a comparative study of medical applications of four generic technologies.

    A review by Mowatt G, Bower DJ, Brebner JA, Cairns JA, Grant AM, McKee L.

1. Antenatal screening for Down’s syndrome.

   A review by Wald NJ, Kennard A, Hackshaw A, McGuire A.

2. Screening for ovarian cancer: a systematic review.

   By Bell R, Petticrew M, Luengo S, Sheldon TA.

3. Consensus development methods, and their use in clinical guideline development.

   A review by Murphy MK, Black NA, Lamping DL, McKee CM, Sanderson CFB, Askham J, et al.

4. A cost–utility analysis of interferon beta for multiple sclerosis.

   By Parkin D, McNamee P, Jacoby A, Miller P, Thomas S, Bates D.

5. Effectiveness and efficiency of methods of dialysis therapy for end-stage renal disease: systematic reviews.

   By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M, Daly C, et al.

6. Effectiveness of hip prostheses in primary total hip replacement: a critical review of evidence and an economic model.

   By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M, Bevan G.

7. Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomised controlled trials.

   By Song F, Glenny AM.

8. Bone marrow and peripheral blood stem cell transplantation for malignancy.

   A review by Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA.

9. Screening for speech and language delay: a systematic review of the literature.

   By Law J, Boyle J, Harris F, Harkness A, Nye C.

10. Resource allocation for chronic stable angina: a systematic review of effectiveness, costs and cost-effectiveness of alternative interventions.

    By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR, Buxton MJ.

11. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review.

    By Ebrahim S.

12. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review.

    By McQuay HJ, Moore RA.

13. Choosing between randomised and nonrandomised studies: a systematic review.

    By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C.

14. Evaluating patient-based outcome measures for use in clinical trials.

    A review by Fitzpatrick R, Davey C, Buxton MJ, Jones DR.

15. Ethical issues in the design and conduct of randomised controlled trials.

    A review by Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J.

16. Qualitative research methods in health technology assessment: a review of the literature.

    By Murphy E, Dingwall R, Greatbatch D, Parker S, Watson P.

17. The costs and benefits of paramedic skills in pre-hospital trauma care.

    By Nicholl J, Hughes S, Dixon S, Turner J, Yates D.

18. Systematic review of endoscopic ultrasound in gastro-oesophageal cancer.

    By Harris KM, Kelly S, Berry E, Hutton J, Roderick P, Cullingworth J, et al.

19. Systematic reviews of trials and other studies.

    By Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F.

20. Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses.

    A review by Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, et al.

1. Informed decision making: an annotated bibliography and systematic review.

   By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J, Robinson MB, et al.

2. Handling uncertainty when performing economic evaluation of healthcare interventions.

   A review by Briggs AH, Gray AM.

3. The role of expectancies in the placebo effect and their use in the delivery of health care: a systematic review.

   By Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H.

4. A randomised controlled trial of different approaches to universal antenatal HIV testing: uptake and acceptability. Annex: Antenatal HIV testing – assessment of a routine voluntary approach.

   By Simpson WM, Johnstone FD, Boyd FM, Goldberg DJ, Hart GJ, Gormley SM, et al.

5. Methods for evaluating area-wide and organisation-based interventions in health and health care: a systematic review.

   By Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Burney PGJ.

6. Assessing the costs of healthcare technologies in clinical trials.

   A review by Johnston K, Buxton MJ, Jones DR, Fitzpatrick R.

7. Cooperatives and their primary care emergency centres: organisation and impact.

   By Hallam L, Henthorne K.

8. Screening for cystic fibrosis.

   A review by Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J.

9. A review of the use of health status measures in economic evaluation.

   By Brazier J, Deverill M, Green C, Harper R, Booth A.

10. Methods for the analysis of quality-of-life and survival data in health technology assessment.

    A review by Billingham LJ, Abrams KR, Jones DR.

11. Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis.

    By Zeuner D, Ades AE, Karnon J, Brown J, Dezateux C, Anionwu EN.

12. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses.

    A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, Jones A, et al.

13. ‘Early warning systems’ for identifying new healthcare technologies.

    By Robert G, Stevens A, Gabbay J.

14. A systematic review of the role of human papillomavirus testing within a cervical screening programme.

    By Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, et al.

15. Near patient testing in diabetes clinics: appraising the costs and outcomes.

    By Grieve R, Beech R, Vincent J, Mazurkiewicz J.

16. Positron emission tomography: establishing priorities for health technology assessment.

    A review by Robert G, Milne R.

17. The debridement of chronic wounds: a systematic review.

    By Bradley M, Cullum N, Sheldon T.

18. Systematic reviews of wound care management: (2) Dressings and topical agents used in the healing of chronic wounds.

    By Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.

19. A systematic literature review of spiral and electron beam computed tomography: with particular reference to clinical applications in hepatic lesions, pulmonary embolus and coronary artery disease.

    By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

20. What role for statins? A review and economic model.

    By Ebrahim S, Davey Smith G, McCabe C, Payne N, Pickin M, Sheldon TA, et al.

21. Factors that limit the quality, number and progress of randomised controlled trials.

    A review by Prescott RJ, Counsell CE, Gillespie WJ, Grant AM, Russell IT, Kiauka S, et al.

22. Antimicrobial prophylaxis in total hip replacement: a systematic review.

    By Glenny AM, Song F.

23. Health promoting schools and health promotion in schools: two systematic reviews.

    By Lister-Sharp D, Chapman S, Stewart-Brown S, Sowden A.

24. Economic evaluation of a primary care-based education programme for patients with osteoarthritis of the knee.

    A review by Lord J, Victor C, Littlejohns P, Ross FM, Axford JS.

1. The estimation of marginal time preference in a UK-wide sample (TEMPUS) project.

   A review by Cairns JA, van der Pol MM.

2. Geriatric rehabilitation following fractures in older people: a systematic review.

   By Cameron I, Crotty M, Currie C, Finnegan T, Gillespie L, Gillespie W, et al.

3. Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research.

   By Davies SC, Cronin E, Gill M, Greengross P, Hickman M, Normand C.

4. Community provision of hearing aids and related audiology services.

   A review by Reeves DJ, Alborz A, Hickson FS, Bamford JM.

5. False-negative results in screening programmes: systematic review of impact and implications.

   By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

6. Costs and benefits of community postnatal support workers: a randomised controlled trial.

   By Morrell CJ, Spiby H, Stewart P, Walters S, Morgan A.

7. Implantable contraceptives (subdermal implants and hormonally impregnated intrauterine systems) versus other forms of reversible contraceptives: two systematic reviews to assess relative effectiveness, acceptability, tolerability and cost-effectiveness.

   By French RS, Cowan FM, Mansour DJA, Morris S, Procter T, Hughes D, et al.

8. An introduction to statistical methods for health technology assessment.

   A review by White SJ, Ashby D, Brown PJ.

9. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review.

   By Clegg A, Bryant J, Milne R.

10. Publication and related biases.

    A review by Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ.

11. Cost and outcome implications of the organisation of vascular services.

    By Michaels J, Brazier J, Palfreyman S, Shackley P, Slack R.

12. Monitoring blood glucose control in diabetes mellitus: a systematic review.

    By Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R.

13. The effectiveness of domiciliary health visiting: a systematic review of international studies and a selective review of the British literature.

    By Elkan R, Kendrick D, Hewitt M, Robinson JJA, Tolley K, Blair M, et al.

14. The determinants of screening uptake and interventions for increasing uptake: a systematic review.

    By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J.

15. The effectiveness and cost-effectiveness of prophylactic removal of wisdom teeth.

    A rapid review by Song F, O’Meara S, Wilson P, Golder S, Kleijnen J.

16. Ultrasound screening in pregnancy: a systematic review of the clinical effectiveness, cost-effectiveness and women’s views.

    By Bricker L, Garcia J, Henderson J, Mugford M, Neilson J, Roberts T, et al.

17. A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.

    By Lister-Sharp D, McDonagh MS, Khan KS, Kleijnen J.

18. Liquid-based cytology in cervical screening: a rapid and systematic review.

    By Payne N, Chilcott J, McGoogan E.

19. Randomised controlled trial of non-directive counselling, cognitive–behaviour therapy and usual general practitioner care in the management of depression as well as mixed anxiety and depression in primary care.

    By King M, Sibbald B, Ward E, Bower P, Lloyd M, Gabbay M, et al.

20. Routine referral for radiography of patients presenting with low back pain: is patients’ outcome influenced by GPs’ referral for plain radiography?

    By Kerry S, Hilton S, Patel S, Dundas D, Rink E, Lord J.

21. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration.

    By O’Meara S, Cullum N, Majid M, Sheldon T.

22. Using routine data to complement and enhance the results of randomised controlled trials.

    By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

23. Coronary artery stents in the treatment of ischaemic heart disease: a rapid and systematic review.

    By Meads C, Cummins C, Jolly K, Stevens A, Burls A, Hyde C.

24. Outcome measures for adult critical care: a systematic review.

    By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM, Daly K, et al.

25. A systematic review to evaluate the effectiveness of interventions to promote the initiation of breastfeeding.

    By Fairbank L, O’Meara S, Renfrew MJ, Woolridge M, Sowden AJ, Lister-Sharp D.

26. Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

    By Parkes J, Bryant J, Milne R.

27. Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

    By Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C.

28. Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial.

    By Baxter-Jones ADG, Helms PJ, Russell G, Grant A, Ross S, Cairns JA, et al.

29. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis.

    By Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HAW.

30. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists in the medical management of unstable angina.

    By McDonagh MS, Bachmann LM, Golder S, Kleijnen J, ter Riet G.

31. A randomised controlled trial of prehospital intravenous fluid replacement therapy in serious trauma.

    By Turner J, Nicholl J, Webber L, Cox H, Dixon S, Yates D.

32. Intrathecal pumps for giving opioids in chronic pain: a systematic review.

    By Williams JE, Louw G, Towlerton G.

33. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review.

    By Shepherd J, Waugh N, Hewitson P.

34. A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

    By MacLehose RR, Reeves BC, Harvey IM, Sheldon TA, Russell IT, Black AMS.

35. Intravascular ultrasound-guided interventions in coronary artery disease: a systematic literature review, with decision-analytic modelling, of outcomes and cost-effectiveness.

    By Berry E, Kelly S, Hutton J, Lindsay HSJ, Blaxill JM, Evans JA, et al.

36. A randomised controlled trial to evaluate the effectiveness and cost-effectiveness of counselling patients with chronic depression.

    By Simpson S, Corney R, Fitzgerald P, Beecham J.

37. Systematic review of treatments for atopic eczema.

    By Hoare C, Li Wan Po A, Williams H.

38. Bayesian methods in health technology assessment: a review.

    By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

39. The management of dyspepsia: a systematic review.

    By Delaney B, Moayyedi P, Deeks J, Innes M, Soo S, Barton P, et al.

40. A systematic review of treatments for severe psoriasis.

    By Griffiths CEM, Clark CM, Chalmers RJG, Li Wan Po A, Williams HC.

1. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease: a rapid and systematic review.

   By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al.

2. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review.

   By Stewart A, Sandercock J, Bryan S, Hyde C, Barton PM, Fry-Smith A, et al.

3. Equity and the economic evaluation of healthcare.

   By Sassi F, Archard L, Le Grand J.

4. Quality-of-life measures in chronic diseases of childhood.

   By Eiser C, Morse R.

5. Eliciting public preferences for healthcare: a systematic review of techniques.

   By Ryan M, Scott DA, Reeves C, Bate A, van Teijlingen ER, Russell EM, et al.

6. General health status measures for people with cognitive impairment: learning disability and acquired brain injury.

   By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

7. An assessment of screening strategies for fragile X syndrome in the UK.

   By Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G.

8. Issues in methodological research: perspectives from researchers and commissioners.

   By Lilford RJ, Richardson A, Stevens A, Fitzpatrick R, Edwards S, Rock F, et al.

9. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy.

   By Cullum N, Nelson EA, Flemming K, Sheldon T.

10. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

    By Hampson SE, Skinner TC, Hart J, Storey L, Gage H, Foxcroft D, et al.

11. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

    By Jobanputra P, Parry D, Fry-Smith A, Burls A.

12. Statistical assessment of the learning curves of health technologies.

    By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT.

13. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review.

    By Dinnes J, Cave C, Huang S, Major K, Milne R.

14. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wounds healing by secondary intention.

    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

    By Scott DA, Loveman E, McIntyre L, Waugh N.

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Riemsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda^®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera^®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris^®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.

1. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease.

   By Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al.

2. FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke.

   By Dennis M, Lewis S, Cranswick G, Forbes J.

3. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews.

   By Black C, Bagust A, Boland A, Walker S, McLeod C, De Verteuil R, et al.

4. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

   By Whiting P, Gupta R, Burch J, Mujica Mota RE, Wright K, Marson A, et al.

5. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

   By Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR.

6. Systematic review and evaluation of methods of assessing urinary incontinence.

   By Martin JL, Williams KS, Abrams KR, Turner DA, Sutton AJ, Chapple C, et al.

7. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

   By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

8. Surveillance of Barrett’s oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

   By Garside R, Pitt M, Somerville M, Stein K, Price A, Gilbert N.

9. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

   By Main C, Bojke L, Griffin S, Norman G, Barbieri M, Mather L, et al.

10. Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

    By Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M.

11. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

    By Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, et al.

12. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.

    By Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al.

13. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

    By Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

14. The cost-effectiveness of screening for oral cancer in primary care.

    By Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, et al.

15. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

    By Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton A, Thomas S, et al.

16. Systematic review of the effectiveness and cost-effectiveness of HealOzone^® for the treatment of occlusal pit/fissure caries and root caries.

    By Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al.

17. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

    By Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Kerwin R, et al.

18. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation.

    By Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, et al.

19. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

    By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

20. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1.

    By Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al.

21. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

    By Wright M, Grieve R, Roberts J, Main J, Thomas HC, on behalf of the UK Mild Hepatitis C Trial Investigators.

22. Pressure relieving support surfaces: a randomised evaluation.

    By Nixon J, Nelson EA, Cranny G, Iglesias CP, Hawkins K, Cullum NA, et al.

23. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

    By King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al.

24. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.

    By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

25. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

    By Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, et al.

26. A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

    By Robinson L, Hutchings D, Corner L, Beyer F, Dickinson H, Vanoli A, et al.

27. A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost–utility for these groups in a UK context.

    By Buxton M, Caine N, Chase D, Connelly D, Grace A, Jackson C, et al.

28. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Takeda A, Davidson P, Price A.

29. An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

    By Harvey S, Stevens K, Harrison D, Young D, Brampton W, McCabe C, et al.

30. Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

    By Wardlaw JM, Chappell FM, Stevenson M, De Nigris E, Thomas S, Gillard J, et al.

31. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

    By Woolacott N, Bravo Vergel Y, Hawkins N, Kainth A, Khadjesari Z, Misso K, et al.

32. The cost-effectiveness of testing for hepatitis C in former injecting drug users.

    By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al.

33. Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation.

    By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M, Beverley C, et al.

34. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

    By Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, et al.

35. Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

    By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al.

36. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

    By Whiting P, Westwood M, Bojke L, Palmer S, Richardson G, Cooper J, et al.

37. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

    By O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A.

38. A comparison of the cost-effectiveness of five strategies for the prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

    By Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al.

39. The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease: systematic review.

    By Waugh N, Black C, Walker S, McIntyre L, Cummins E, Hillis G.

40. What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).

    By Williams J, Russell I, Durai D, Cheung W-Y, Farrin A, Bloor K, et al.

41. The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

    By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P.

42. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

    By Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al.

43. Telemedicine in dermatology: a randomised controlled trial.

    By Bowns IR, Collins K, Walters SJ, McDonagh AJG.

44. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

    By Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C.

45. Clinical effectiveness and cost-effectiveness of laparoscopic surgery for colorectal cancer: systematic reviews and economic evaluation.

    By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C, McKinley A, et al.

46. Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

    By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

47. Systematic reviews of clinical decision tools for acute abdominal pain.

    By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al.

48. Evaluation of the ventricular assist device programme in the UK.

    By Sharples L, Buxton M, Caine N, Cafferty F, Demiris N, Dyer M, et al.

49. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

    By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al.

50. Amniocentesis results: investigation of anxiety. The ARIA trial.

    By Hewison J, Nixon J, Fountain J, Cocks K, Jones C, Mason G, et al.

1. Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

   By Dundar Y, Bagust A, Dickson R, Dodd S, Green J, Haycox A, et al.

2. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.

   By Collins R, Fenwick E, Trowman R, Perard R, Norman G, Light K, et al.

3. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

   By Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al.

4. The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women.

   By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.

5. A systematic review of quantitative and qualitative research on the role and effectiveness of written information available to patients about individual medicines.

   By Raynor DK, Blenkinsopp A, Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

6. Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.

   By Adi Y, Juarez-Garcia A, Wang D, Jowett S, Frew E, Day E, et al.

7. Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

   By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

8. Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection.

   By Low N, McCarthy A, Macleod J, Salisbury C, Campbell R, Roberts TE, et al.

9. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

   By Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al.

10. Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.

    By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D, Harridge SDR, et al.

11. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N.

12. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

    By Tappenden P, Jones R, Paisley S, Carroll C.

13. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.

    By Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, et al.

14. A systematic review and economic evaluation of statins for the prevention of coronary events.

    By Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan A, et al.

15. A systematic review of the effectiveness and cost-effectiveness of different models of community-based respite care for frail older people and their carers.

    By Mason A, Weatherly H, Spilsbury K, Arksey H, Golder S, Adamson J, et al.

16. Additional therapy for young children with spastic cerebral palsy: a randomised controlled trial.

    By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ.

17. Screening for type 2 diabetes: literature review and economic modelling.

    By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A, Goyder E, et al.

18. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Mealing S, Roome C, Snaith A, et al.

19. The clinical effectiveness and cost-effectiveness of gemcitabine for metastatic breast cancer: a systematic review and economic evaluation.

    By Takeda AL, Jones J, Loveman E, Tan SC, Clegg AJ.

20. A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease.

    By Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, et al.

21. The clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review.

    By Colquitt JL, Kirby J, Green C, Cooper K, Trompeter RS.

22. A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.

    By Fayter D, Nixon J, Hartley S, Rithalia A, Butler G, Rudolf M, et al.

23. Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

    By McCormack K, Rabindranath K, Kilonzo M, Vale L, Fraser C, McIntyre L, et al.

24. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis.

    By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D, et al.

25. A randomised controlled trial and economic evaluation of direct versus indirect and individual versus group modes of speech and language therapy for children with primary language impairment.

    By Boyle J, McCartney E, Forbes J, O’Hare A.

26. Hormonal therapies for early breast cancer: systematic review and economic evaluation.

    By Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L.

27. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

    By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

28. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.

    By McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, et al.

29. Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses.

    By Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et al.

30. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review.

    By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al.

31. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

    By Prescott RJ, Kunkler IH, Williams LJ, King CC, Jack W, van der Pol M, et al.

32. Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.

    By Bamford J, Fortnum H, Bristow K, Smith J, Vamvakas G, Davies L, et al.

33. The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

    By Black C, Cummins E, Royle P, Philip S, Waugh N.

34. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis.

    By Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, et al.

35. The Birmingham Rehabilitation Uptake Maximisation Study (BRUM). Homebased compared with hospital-based cardiac rehabilitation in a multi-ethnic population: cost-effectiveness and patient adherence.

    By Jolly K, Taylor R, Lip GYH, Greenfield S, Raftery J, Mant J, et al.

36. A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.

    By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

37. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

    By Marson AG, Appleton R, Baker GA, Chadwick DW, Doughty J, Eaton B, et al.

38. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anti-coagulation therapy: a systematic review and economic modelling.

    By Connock M, Stevens C, Fry-Smith A, Jowett S, Fitzmaurice D, Moore D, et al.

39. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

    By Soares-Weiser K, Bravo Vergel Y, Beynon S, Dunn G, Barbieri M, Duffy S, et al.

40. Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

    By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

41. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

    By Burr JM, Mowatt G, Hernández R, Siddiqui MAR, Cook J, Lourenco T, et al.

42. Acceptability, benefit and costs of early screening for hearing disability: a study of potential screening tests and models.

    By Davis A, Smith P, Ferguson M, Stephens D, Gianopoulos I.

43. Contamination in trials of educational interventions.

    By Keogh-Brown MR, Bachmann MO, Shepstone L, Hewitt C, Howe A, Ramsay CR, et al.

44. Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

    By Facey K, Bradbury I, Laking G, Payne E.

45. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Rogers G, Dyer M, Mealing S, et al.

46. Drug-eluting stents: a systematic review and economic evaluation.

    By Hill RA, Boland A, Dickson R, Dündar Y, Haycox A, McLeod C, et al.

47. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model.

    By Fox M, Mealing S, Anderson R, Dean J, Stein K, Price A, et al.

48. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study.

    By Campbell MK, Snowdon C, Francis D, Elbourne D, McDonald AM, Knight R, et al.

49. Cost-effectiveness of functional cardiac testing in the diagnosis and management of coronary artery disease: a randomised controlled trial. The CECaT trial.

    By Sharples L, Hughes V, Crean A, Dyer M, Buxton M, Goldsmith K, et al.

50. Evaluation of diagnostic tests when there is no gold standard. A review of methods.

    By Rutjes AWS, Reitsma JB, Coomarasamy A, Khan KS, Bossuyt PMM.

51. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding.

    By Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al.

52. A review and critique of modelling in prioritising and designing screening programmes.

    By Karnon J, Goyder E, Tappenden P, McPhie S, Towers I, Brazier J, et al.

53. An assessment of the impact of the NHS Health Technology Assessment Programme.

    By Hanney S, Buxton M, Green C, Coulson D, Raftery J.

1. A systematic review and economic model of switching from nonglycopeptide to glycopeptide antibiotic prophylaxis for surgery.

   By Cranny G, Elliott R, Weatherly H, Chambers D, Hawkins N, Myers L, et al.

2. ‘Cut down to quit’ with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.

   By Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D.

3. A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management.

   By Thornton J, Ashcroft D, O’Neill T, Elliott R, Adams J, Roberts C, et al.

4. Does befriending by trained lay workers improve psychological well-being and quality of life for carers of people with dementia, and at what cost? A randomised controlled trial.

   By Charlesworth G, Shepstone L, Wilson E, Thalanany M, Mugford M, Poland F.

5. A multi-centre retrospective cohort study comparing the efficacy, safety and cost-effectiveness of hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids. The HOPEFUL study.

   By Hirst A, Dutton S, Wu O, Briggs A, Edwards C, Waldenmaier L, et al.

6. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

   By Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, et al.

7. The use of economic evaluations in NHS decision-making: a review and empirical investigation.

   By Williams I, McIver S, Moore D, Bryan S.

8. Stapled haemorrhoidectomy (haemorrhoidopexy) for the treatment of haemorrhoids: a systematic review and economic evaluation.

   By Burch J, Epstein D, Baba-Akbari A, Weatherly H, Fox D, Golder S, et al.

9. The clinical effectiveness of diabetes education models for Type 2 diabetes: a systematic review.

   By Loveman E, Frampton GK, Clegg AJ.

10. Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

    By Raftery J, Bryant J, Powell J, Kerr C, Hawker S.

11. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation.

    By Chen Y-F, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al.

12. The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation.

    By Hockenhull JC, Dwan K, Boland A, Smith G, Bagust A, Dundar Y, et al.

13. Stepped treatment of older adults on laxatives. The STOOL trial.

    By Mihaylov S, Stark C, McColl E, Steen N, Vanoli A, Rubin G, et al.

14. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

    By Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al.

15. The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation.

    By Hind D, Tappenden P, Tumur I, Eggington E, Sutcliffe P, Ryan A.

16. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: a systematic review and economic evaluation.

    By Colquitt JL, Jones J, Tan SC, Takeda A, Clegg AJ, Price A.

17. Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease.

    By Mowatt G, Cummins E, Waugh N, Walker S, Cook J, Jia X, et al.

18. Structural neuroimaging in psychosis: a systematic review and economic evaluation.

    By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al.

19. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in adults and children aged 12 years and over.

    By Shepherd J, Rogers G, Anderson R, Main C, Thompson-Coon J, Hartwell D, et al.

20. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in children under the age of 12 years.

    By Main C, Shepherd J, Anderson R, Rogers G, Thompson-Coon J, Liu Z, et al.

21. Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

    By Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al.

22. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

    By Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross P, Harding G, et al.

23. A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial.

    By George S, Pockney P, Primrose J, Smith H, Little P, Kinley H, et al.

24. A review and critical appraisal of measures of therapist–patient interactions in mental health settings.

    By Cahill J, Barkham M, Hardy G, Gilbody S, Richards D, Bower P, et al.

25. The clinical effectiveness and cost-effectiveness of screening programmes for amblyopia and strabismus in children up to the age of 4–5 years: a systematic review and economic evaluation.

    By Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J.

26. A systematic review of the clinical effectiveness and cost-effectiveness and economic modelling of minimal incision total hip replacement approaches in the management of arthritic disease of the hip.

    By de Verteuil R, Imamura M, Zhu S, Glazener C, Fraser C, Munro N, et al.

27. A preliminary model-based assessment of the cost–utility of a screening programme for early age-related macular degeneration.

    By Karnon J, Czoski-Murray C, Smith K, Brand C, Chakravarthy U, Davis S, et al.

28. Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A.

29. Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product categories.

    By Fader M, Cottenden A, Getliffe K, Gage H, Clarke-O’Neill S, Jamieson K, et al.

30. A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.

    By French B, Leathley M, Sutton C, McAdam J, Thomas L, Forster A, et al.

31. The effectiveness and cost-effectivness of minimal access surgery amongst people with gastro-oesophageal reflux disease – a UK collaborative study. The reflux trial.

    By Grant A, Wileman S, Ramsay C, Bojke L, Epstein D, Sculpher M, et al.

32. Time to full publication of studies of anti-cancer medicines for breast cancer and the potential for publication bias: a short systematic review.

    By Takeda A, Loveman E, Harris P, Hartwell D, Welch K.

33. Performance of screening tests for child physical abuse in accident and emergency departments.

    By Woodman J, Pitt M, Wentz R, Taylor B, Hodes D, Gilbert RE.

34. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

    By Rodgers M, McKenna C, Palmer S, Chambers D, Van Hout S, Golder S, et al.

35. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

    By Lourenco T, Armstrong N, N’Dow J, Nabi G, Deverill M, Pickard R, et al.

36. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

    By Wang D, Cummins C, Bayliss S, Sandercock J, Burls A.

1. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation.

   By McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al.

2. Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis.

   By Simpson EL, Stevenson MD, Rawdin A, Papaioannou D.

3. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs.

   By Main C, Liu Z, Welch K, Weiner G, Quentin Jones S, Stein K.

4. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis.

   By McDaid C, Griffin S, Weatherly H, Durée K, van der Burgt M, van Hout S, Akers J, et al.

5. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.

   By Sutcliffe P, Hummel S, Simpson E, Young T, Rees A, Wilkinson A, et al.

6. The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

   By Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, et al.

7. Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients.

   By Mowatt G, Houston G, Hernández R, de Verteuil R, Fraser C, Cuthbertson B, et al.

8. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.

   By Taylor RS, Elston J.

9. Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) – a randomised controlled trial.

   By Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al.

10. Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

    By Pilgrim H, Lloyd-Jones M, Rees A.

11. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

    By Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al.

12. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods.

    By Hobart J, Cano S.

13. Treatment of severe ankle sprain: a pragmatic randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of three types of mechanical ankle support with tubular bandage. The CAST trial.

    By Cooke MW, Marsh JL, Clark M, Nakash R, Jarvis RM, Hutton JL, et al. , on behalf of the CAST trial group.

14. Non-occupational postexposure prophylaxis for HIV: a systematic review.

    By Bryant J, Baxter L, Hird S.

15. Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial.

    By Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, et al.

16. How far does screening women for domestic (partner) violence in different health-care settings meet criteria for a screening programme? Systematic reviews of nine UK National Screening Committee criteria.

    By Feder G, Ramsay J, Dunne D, Rose M, Arsene C, Norman R, et al.

17. Spinal cord stimulation for chronic pain of neuropathic or ischaemic origin: systematic review and economic evaluation.

    By Simpson, EL, Duenas A, Holmes MW, Papaioannou D, Chilcott J.

18. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and cost-effectiveness and natural history.

    By Fortnum H, O’Neill C, Taylor R, Lenthall R, Nikolopoulos T, Lightfoot G, et al.

19. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study.

    By Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, et al.

20. Systematic review of respite care in the frail elderly.

    By Shaw C, McNamara R, Abrams K, Cannings-John R, Hood K, Longo M, et al.

21. Neuroleptics in the treatment of aggressive challenging behaviour for people with intellectual disabilities: a randomised controlled trial (NACHBID).

    By Tyrer P, Oliver-Africano P, Romeo R, Knapp M, Dickens S, Bouras N, et al.

22. Randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care: the THREAD (THREshold for AntiDepressant response) study.

    By Kendrick T, Chatwin J, Dowrick C, Tylee A, Morriss R, Peveler R, et al.

23. Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation.

    By Bryant J, Cooper K, Picot J, Clegg A, Roderick P, Rosenberg W, et al.

24. Enhanced external counterpulsation for the treatment of stable angina and heart failure: a systematic review and economic analysis.

    By McKenna C, McDaid C, Suekarran S, Hawkins N, Claxton K, Light K, et al.

25. Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).

    By Donnan PT, McLernon D, Dillon JF, Ryder S, Roderick P, Sullivan F, et al.

26. A systematic review of presumed consent systems for deceased organ donation.

    By Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A.

27. Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial.

    By Hay AD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S, et al.

28. A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the management of insulin-treated diabetes mellitus (MITRE).

    By Newman SP, Cooke D, Casbard A, Walker S, Meredith S, Nunn A, et al.

29. Sensitivity analysis in economic evaluation: an audit of NICE current practice and a review of its use and value in decision-making.

    By Andronis L, Barton P, Bryan S.

30. Trastuzumab for the treatment of primary breast cancer in HER2-positive women: a single technology appraisal.

    By Ward S, Pilgrim H, Hind D.

31. Docetaxel for the adjuvant treatment of early node-positive breast cancer: a single technology appraisal.

    By Chilcott J, Lloyd Jones M, Wilkinson A.

32. The use of paclitaxel in the management of early stage breast cancer.

    By Griffin S, Dunn G, Palmer S, Macfarlane K, Brent S, Dyker A, et al.

33. Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma.

    By Dundar Y, Bagust A, Hounsome J, McLeod C, Boland A, Davis H, et al.

34. Bortezomib for the treatment of multiple myeloma patients.

    By Green C, Bryant J, Takeda A, Cooper K, Clegg A, Smith A, et al.

35. Fludarabine phosphate for the firstline treatment of chronic lymphocytic leukaemia.

    By Walker S, Palmer S, Erhorn S, Brent S, Dyker A, Ferrie L, et al.

36. Erlotinib for the treatment of relapsed non-small cell lung cancer.

    By McLeod C, Bagust A, Boland A, Hockenhull J, Dundar Y, Proudlove C, et al.

37. Cetuximab plus radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck.

    By Griffin S, Walker S, Sculpher M, White S, Erhorn S, Brent S, et al.

38. Infliximab for the treatment of adults with psoriasis.

    By Loveman E, Turner D, Hartwell D, Cooper K, Clegg A

39. Psychological interventions for postnatal depression: cluster randomised trial and economic evaluation. The PoNDER trial.

    By Morrell CJ, Warner R, Slade P, Dixon S, Walters S, Paley G, et al.

40. The effect of different treatment durations of clopidogrel in patients with non-ST-segment elevation acute coronary syndromes: a systematic review and value of information analysis.

    By Rogowski R, Burch J, Palmer S, Craigs C, Golder S, Woolacott N.

41. Systematic review and individual patient data meta-analysis of diagnosis of heart failure, with modelling of implications of different diagnostic strategies in primary care.

    By Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, et al.

42. A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO trial.

    By Gray AJ, Goodacre S, Newby DE, Masson MA, Sampson F, Dixon S, et al. , on behalf of the 3CPO study investigators.

43. Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation.

    By Ara R, Pandor A, Stevens J, Rees A, Rafia R.

44. Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation.

    By Jones J, Shepherd J, Baxter L, Gospodarevskaya E, Hartwell D, Harris P, et al.

45. Methods to identify postnatal depression in primary care: an integrated evidence synthesis and value of information analysis.

    By Hewitt CE, Gilbody SM, Brealey S, Paulden M, Palmer S, Mann R, et al.

46. A double-blind randomised placebo-controlled trial of topical intranasal corticosteroids in 4- to 11-year-old children with persistent bilateral otitis media with effusion in primary care.

    By Williamson I, Benge S, Barton S, Petrou S, Letley L, Fasey N, et al.

47. The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model.

    By Bond M, Pitt M, Akoh J, Moxham T, Hoyle M, Anderson R.

48. Rehabilitation of older patients: day hospital compared with rehabilitation at home. A randomised controlled trial.

    By Parker SG, Oliver P, Pennington M, Bond J, Jagger C, Enderby PM, et al.

49. Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis.

    By Renfrew MJ, Craig D, Dyson L, McCormick F, Rice S, King SE, et al.

50. The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation.

    By Picot J, Jones J, Colquitt JL, Gospodarevskaya E, Loveman E, Baxter L, et al.

51. Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness.

    By Daniels J, Gray J, Pattison H, Roberts T, Edwards E, Milner P, et al.

52. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

    By Honest H, Forbes CA, Durée KH, Norman G, Duffy SB, Tsourapas A, et al.

53. The effectiveness and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults: a systematic review and economic model.

    By Bond M, Mealing S, Anderson R, Elston J, Weiner G, Taylor RS, et al.

54. Gemcitabine for the treatment of metastatic breast cancer.

    By Jones J, Takeda A, Tan SC, Cooper K, Loveman E, Clegg A.

55. Varenicline in the management of smoking cessation: a single technology appraisal.

    By Hind D, Tappenden P, Peters J, Kenjegalieva K.

56. Alteplase for the treatment of acute ischaemic stroke: a single technology appraisal.

    By Lloyd Jones M, Holmes M.

57. Rituximab for the treatment of rheumatoid arthritis.

    By Bagust A, Boland A, Hockenhull J, Fleeman N, Greenhalgh J, Dundar Y, et al.

58. Omalizumab for the treatment of severe persistent allergic asthma.

    By Jones J, Shepherd J, Hartwell D, Harris P, Cooper K, Takeda A, et al.

59. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma.

    By Boland A, Bagust A, Hockenhull J, Davis H, Chu P, Dickson R.

60. Adalimumab for the treatment of psoriasis.

    By Turner D, Picot J, Cooper K, Loveman E.

61. Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal.

    By Holmes M, C Carroll C, Papaioannou D.

62. Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura: a single technology appraisal.

    By Mowatt G, Boachie C, Crowther M, Fraser C, Hernández R, Jia X, et al.

63. Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

    By Bond M, Hoyle M, Moxham T, Napier M, Anderson R.

64. Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

    By Stevenson M, Lloyd-Jones M, Papaioannou D.

65. The effects of biofeedback for the treatment of essential hypertension: a systematic review.

    By Greenhalgh J, Dickson R, Dundar Y.

66. A randomised controlled trial of the use of aciclovir and/or prednisolone for the early treatment of Bell’s palsy: the BELLS study.

    By Sullivan FM, Swan IRC, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al.

67. Lapatinib for the treatment of HER2-overexpressing breast cancer.

    By Jones J, Takeda A, Picot J, von Keyserlingk C, Clegg A.

68. Infliximab for the treatment of ulcerative colitis.

    By Hyde C, Bryan S, Juarez-Garcia A, Andronis L, Fry-Smith A.

69. Rimonabant for the treatment of overweight and obese people.

    By Burch J, McKenna C, Palmer S, Norman G, Glanville J, Sculpher M, et al.

70. Telbivudine for the treatment of chronic hepatitis B infection.

    By Hartwell D, Jones J, Harris P, Cooper K.

71. Entecavir for the treatment of chronic hepatitis B infection.

    By Shepherd J, Gospodarevskaya E, Frampton G, Cooper, K.

72. Febuxostat for the treatment of hyperuricaemia in people with gout: a single technology appraisal.

    By Stevenson M, Pandor A.

73. Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal.

    By Stevenson M, Scope A, Holmes M, Rees A, Kaltenthaler E.

74. Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

    By Greenhalgh J, Bagust A, Boland A, Fleeman N, McLeod C, Dundar Y, et al.

75. Mifamurtide for the treatment of osteosarcoma: a single technology appraisal.

    By Pandor A, Fitzgerald P, Stevenson M, Papaioannou D.

76. Ustekinumab for the treatment of moderate to severe psoriasis.

    By Gospodarevskaya E, Picot J, Cooper K, Loveman E, Takeda A.

77. Endovascular stents for abdominal aortic aneurysms: a systematic review and economic model.

    By Chambers D, Epstein D, Walker S, Fayter D, Paton F, Wright K, et al.

78. Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation.

    By Chen Y-F, Jowett S, Barton P, Malottki K, Hyde C, Gibbs JSR, et al.

79. Cessation of attention deficit hyperactivity disorder drugs in the young (CADDY) – a pharmacoepidemiological and qualitative study.

    By Wong ICK, Asherson P, Bilbow A, Clifford S, Coghill D, R DeSoysa R, et al.

80. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening.

    By Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, et al.

81. The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a systematic review and economic evaluation.

    By Black C, Clar C, Henderson R, MacEachern C, McNamee P, Quayyum Z, et al.

82. Randomised preference trial of medical versus surgical termination of pregnancy less than 14 weeks’ gestation (TOPS).

    By Robson SC, Kelly T, Howel D, Deverill M, Hewison J, Lie MLS, et al.

83. Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes.

    By Jeffcoate WJ, Price PE, Phillips CJ, Game FL, Mudge E, Davies S, et al.

84. VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers.

    By Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, et al.

85. A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: the VULCAN trial

    By Michaels JA, Campbell WB, King BM, MacIntyre J, Palfreyman SJ, Shackley P, et al.

86. Communication of carrier status information following universal newborn screening for sickle cell disorders and cystic fibrosis: qualitative study of experience and practice.

    By Kai J, Ulph F, Cullinan T, Qureshi N.

87. Antiviral drugs for the treatment of influenza: a systematic review and economic evaluation.

    By Burch J, Paulden M, Conti S, Stock C, Corbett M, Welton NJ, et al.

88. Development of a toolkit and glossary to aid in the adaptation of health technology assessment (HTA) reports for use in different contexts.

    By Chase D, Rosten C, Turner S, Hicks N, Milne R.

89. Colour vision testing for diabetic retinopathy: a systematic review of diagnostic accuracy and economic evaluation.

    By Rodgers M, Hodges R, Hawkins J, Hollingworth W, Duffy S, McKibbin M, et al.

90. Systematic review of the effectiveness and cost-effectiveness of weight management schemes for the under fives: a short report.

    By Bond M, Wyatt K, Lloyd J, Welch K, Taylor R.

91. Are adverse effects incorporated in economic models? An initial review of current practice.

    By Craig D, McDaid C, Fonseca T, Stock C, Duffy S, Woolacott N.

1. Multicentre randomised controlled trial examining the cost-effectiveness of contrast-enhanced high field magnetic resonance imaging in women with primary breast cancer scheduled for wide local excision (COMICE).

   By Turnbull LW, Brown SR, Olivier C, Harvey I, Brown J, Drew P, et al.

2. Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation.

   By Thompson Coon J, Hoyle M, Green C, Liu Z, Welch K, Moxham T, et al.

3. The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation.

   By Fleeman N, McLeod C, Bagust A, Beale S, Boland A, Dundar Y, et al.

4. Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer.

   By Mowatt G, Zhu S, Kilonzo M, Boachie C, Fraser C, Griffiths TRL, et al.

5. Effectiveness and cost-effectiveness of arthroscopic lavage in the treatment of osteoarthritis of the knee: a mixed methods study of the feasibility of conducting a surgical placebo-controlled trial (the KORAL study).

   By Campbell MK, Skea ZC, Sutherland AG, Cuthbertson BH, Entwistle VA, McDonald AM, et al.

6. A randomised 2 × 2 trial of community versus hospital pulmonary rehabilitation for chronic obstructive pulmonary disease followed by telephone or conventional follow-up.

   By Waterhouse JC, Walters SJ, Oluboyede Y, Lawson RA.

7. The effectiveness and cost-effectiveness of behavioural interventions for the prevention of sexually transmitted infections in young people aged 13–19: a systematic review and economic evaluation.

   By Shepherd J, Kavanagh J, Picot J, Cooper K, Harden A, Barnett-Page E, et al.

8. Dissemination and publication of research findings: an updated review of related biases.

   By Song F, Parekh S, Hooper L, Loke YK, Ryder J, Sutton AJ, et al.

9. The effectiveness and cost-effectiveness of biomarkers for the prioritisation of patients awaiting coronary revascularisation: a systematic review and decision model.

   By Hemingway H, Henriksson M, Chen R, Damant J, Fitzpatrick N, Abrams K, et al.

10. Comparison of case note review methods for evaluating quality and safety in health care.

    By Hutchinson A, Coster JE, Cooper KL, McIntosh A, Walters SJ, Bath PA, et al.

11. Clinical effectiveness and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes: systematic review and economic evaluation.

    By Cummins E, Royle P, Snaith A, Greene A, Robertson L, McIntyre L, et al.

12. Self-monitoring of blood glucose in type 2 diabetes: systematic review.

    By Clar C, Barnard K, Cummins E, Royle P, Waugh N.

13. North of England and Scotland Study of Tonsillectomy and Adeno-tonsillectomy in Children (NESSTAC): a pragmatic randomised controlled trial with a parallel non-randomised preference study.

    By Lock C, Wilson J, Steen N, Eccles M, Mason H, Carrie S, et al.

14. Multicentre randomised controlled trial of the clinical and cost-effectiveness of a bypass-surgery-first versus a balloon-angioplasty-first revascularisation strategy for severe limb ischaemia due to infrainguinal disease. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial.

    By Bradbury AW, Adam DJ, Bell J, Forbes JF, Fowkes FGR, Gillespie I, et al.

15. A randomised controlled multicentre trial of treatments for adolescent anorexia nervosa including assessment of cost-effectiveness and patient acceptability – the TOuCAN trial.

    By Gowers SG, Clark AF, Roberts C, Byford S, Barrett B, Griffiths A, et al.

16. Randomised controlled trials for policy interventions: a review of reviews and meta-regression.

    By Oliver S, Bagnall AM, Thomas J, Shepherd J, Sowden A, White I, et al.

17. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery: a systematic review.

    By McDaid C, Maund E, Rice S, Wright K, Jenkins B, Woolacott N.

18. A systematic review of outcome measures used in forensic mental health research with consensus panel opinion.

    By Fitzpatrick R, Chambers J, Burns T, Doll H, Fazel S, Jenkinson C, et al.

19. The clinical effectiveness and cost-effectiveness of topotecan for small cell lung cancer: a systematic review and economic evaluation.

    By Loveman E, Jones J, Hartwell D, Bird A, Harris P, Welch K, et al.

20. Antenatal screening for haemoglobinopathies in primary care: a cohort study and cluster randomised trial to inform a simulation model. The Screening for Haemoglobinopathies in First Trimester (SHIFT) trial.

    By Dormandy E, Bryan S, Gulliford MC, Roberts T, Ades T, Calnan M, et al.

21. Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis.

    By Black C, Sharma P, Scotland G, McCullough K, McGurn D, Robertson L, et al.

22. A randomised controlled trial of cognitive behaviour therapy and motivational interviewing for people with Type 1 diabetes mellitus with persistent sub-optimal glycaemic control: A Diabetes and Psychological Therapies (ADaPT) study.

    By Ismail K, Maissi E, Thomas S, Chalder T, Schmidt U, Bartlett J, et al.

23. A randomised controlled equivalence trial to determine the effectiveness and cost–utility of manual chest physiotherapy techniques in the management of exacerbations of chronic obstructive pulmonary disease (MATREX).

    By Cross J, Elender F, Barton G, Clark A, Shepstone L, Blyth A, et al.

24. A systematic review and economic evaluation of the clinical effectiveness and cost-effectiveness of aldosterone antagonists for postmyocardial infarction heart failure.

    By McKenna C, Burch J, Suekarran S, Walker S, Bakhai A, Witte K, et al.

25. Avoiding and identifying errors in health technology assessment models: qualitative study and methodological review.

    By Chilcott JB, Tappenden P, Rawdin A, Johnson M, Kaltenthaler E, Paisley S, et al.

26. BoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type A.

    By Shaw L, Rodgers H, Price C, van Wijck F, Shackley P, Steen N, et al. , on behalf of the BoTULS investigators.

27. Weighting and valuing quality-adjusted life-years using stated preference methods: preliminary results from the Social Value of a QALY Project.

    By Baker R, Bateman I, Donaldson C, Jones-Lee M, Lancsar E, Loomes G, et al.

28. Cetuximab for the first-line treatment of metastatic colorectal cancer.

    By Meads C, Round J, Tubeuf S, Moore D, Pennant M and Bayliss S.

29. Infliximab for the treatment of acute exacerbations of ulcerative colitis.

    By Bryan S, Andronis L, Hyde C, Connock M, Fry-Smith A and Wang D.

30. Sorafenib for the treatment of advanced hepatocellular carcinoma.

    By Connock M, Round J, Bayliss S, Tubeuf S, Greenheld W and Moore D.

31. Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection.

    By Jones J, Colquitt J, Shepherd J, Harris P and Cooper K.

32. Prasugrel for the treatment of acute coronary artery syndromes with percutaneous coronary intervention.

    By Greenhalgh J, Bagust A, Boland A, Saborido CM, Fleeman N, McLeod C, et al.

33. Alitretinoin for the treatment of severe chronic hand eczema.

    By Paulden M, Rodgers M, Griffin S, Slack R, Duffy S, Ingram JR, et al.

34. Pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer.

    By Fleeman N, Bagust A, McLeod C, Greenhalgh J, Boland A, Dundar Y, et al.

35. Topotecan for the treatment of recurrent and stage IVB carcinoma of the cervix.

    By Paton F, Paulden M, Saramago P, Manca A, Misso K, Palmer S, et al.

36. Trabectedin for the treatment of advanced metastatic soft tissue sarcoma.

    By Simpson EL, Rafia R, Stevenson MD and Papaioannou D.

37. Azacitidine for the treatment of myelodysplastic syndrome, chronic myelomonocytic leukaemia and acute myeloid leukaemia.

    By Edlin R, Connock M, Tubeuf S, Round J, Fry-Smith A, Hyde C, et al.

38. The safety and effectiveness of different methods of earwax removal: a systematic review and economic evaluation.

    By Clegg AJ, Loveman E, Gospodarevskaya E, Harris P, Bird A, Bryant J, et al.

39. Systematic review of the clinical effectiveness and cost-effectiveness of rapid point-of-care tests for the detection of genital chlamydia infection in women and men.

    By Hislop J, Quayyum Z, Flett G, Boachie C, Fraser C, Mowatt G.

40. School-linked sexual health services for young people (SSHYP): a survey and systematic review concerning current models, effectiveness, cost-effectiveness and research opportunities

    By Owen J, Carroll C, Cooke J, Formby E, Hayter M, Hirst J, et al.

41. Systematic review and cost-effectiveness evaluation of ‘pill-in-the-pocket’ strategy for paroxysmal atrial fibrillation compared to episodic in-hospital treatment or continuous antiarrhythmic drug therapy.

    By Martin Saborido C, Hockenhull J, Bagust A, Boland A, Dickson R, Todd D.

42. Chemoprevention of colorectal cancer: systematic review and economic evaluation.

    By Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan, RF, et al.

Health Technology Assessment programme

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Director, Medical Care Research Unit, University of Sheffield