Biomedical subjects

Keith R Abrams

Publications and source records attributed to Keith R Abrams.

30 records · Page 2Linked to original sources

PubMed2004

An integrated approach to the meta-analysis of genetic association studies using Mendelian randomization.

A natural randomization process, sometimes called Mendelian randomization, occurs at conception to determine a person's genotype. By combining information from genotype-disease and genotype-phenotype studies, it is possible to use this Mendelian randomization to derive an estimate of the association between phenotype (risk factor) and disease that is free of the confounding and reverse causation typical of classical epidemiology. When one is synthesizing evidence, studies evaluating genotype-phenotype associations, studies evaluating genotype-disease associations, and studies evaluating both are encountered, and methods should be used that allow for this structure. Plotting the log odds ratio of genotype-disease against the mean genotype-phenotype difference may help investigators detect departures from the assumptions underlying Mendelian randomization. Testing for differences between studies reporting on only the genotype-phenotype or genotype-disease association and those reporting on both associations may help in detecting reporting bias. This integrated approach to the meta-analysis of genotype-phenotype and genotype-disease studies is illustrated here using the example of the methylenetetrahydrofolate reductase (MTHFR) gene, homocysteine level, and coronary heart disease. An integrated meta-analytical approach may increase the precision of this estimate and provide information on the assumptions underlying Mendelian randomization. Serious biases may arise if the assumptions behind the analysis based on Mendelian randomization are not met.

Confidence Intervals↗

PubMed2004

Benefits and harms associated with hormone replacement therapy: clinical decision analysis.

OBJECTIVE: To evaluate harms and benefits associated with use of combined hormone replacement therapy (HRT) for five years in women with different baseline risks for breast cancer. DESIGN: Probabilistic clinical decision analysis. SETTING: Hypothetical population of white UK women aged 50 years with different baseline risks for breast cancer. MAIN OUTCOME MEASURE: Gain or loss in quality adjusted life years (QALYs). RESULTS: Women free of menopausal symptoms showed a net harm from HRT use, which increased for increasing baseline risk of breast cancer. Those with a baseline risk of 1.2% would expect a loss in QALYs of 0.4 months (- 0.03 QALYs, 95% credibility interval - 0.05 to - 0.01). The main analysis showed HRT to be on average beneficial in women with symptoms, with benefit decreasing with increasing baseline risk of breast cancer. The results were sensitive to the assumed value of quality of life with menopausal symptoms, therefore a contour plot was developed to show the probability of net harm for a range of different values and baseline risks. CONCLUSIONS: HRT for primary prevention of chronic diseases in women without menopausal symptoms is unjustified. Perceived quality of life in women with symptoms should be taken into account when deciding on HRT. Thus, a decision analysis tailored to an individual woman is more appropriate in clinical practice than a population based approach.

Aged↗

PubMed2004

A systematic review of molecular and biological tumor markers in neuroblastoma.

PURPOSE: The aim of this study was to conduct a systematic review, and where possible meta-analyses, of molecular and biological tumor markers described in neuroblastoma, and to establish an evidence-based perspective on their clinical value for the screening, diagnosis, prognosis, and monitoring of patients. EXPERIMENTAL DESIGN: A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. RESULTS: A total of 428 papers studying the use of 195 different tumor markers in neuroblastoma were identified. Small sample sizes, poor statistical reporting, large heterogeneity across studies (e.g., in cutoff levels), and publication bias limited meta-analysis to the area of prognosis only; MYCN, chromosome 1p, DNA index, vanillylmandelic acid:homovanillic acid ratio, CD44, Trk-A, neuron-specific enolase, lactate dehydrogenase, ferritin, and multidrug resistance were all identified as potentially important prognostic tools. CONCLUSIONS: This systematic review forms a knowledge base of the tumor markers studied thus far in neuroblastoma, and has identified some of the most important prognostic markers, which should be considered in future research and treatment strategies. Importantly, the review has also highlighted some general problems across primary tumor marker studies, in particular poor and heterogeneous reporting. These need to be addressed to allow better clinical interpretation and enable more appropriate evidence-based reviews in the future. In particular, collaboration of cancer research groups is needed to enable bigger sample sizes, standardize methods of analysis and reporting, and facilitate the pooling of individual patient data.

Biomarkers, Tumor↗

PubMed2004

Comprehensive decision analytical modelling in economic evaluation: a Bayesian approach.

Decision analytical models are widely used in economic evaluation of health care interventions with the objective of generating valuable information to assist health policy decision-makers to allocate scarce health care resources efficiently. The whole decision modelling process can be summarised in four stages: (i) a systematic review of the relevant data (including meta-analyses), (ii) estimation of all inputs into the model (including effectiveness, transition probabilities and costs), (iii) sensitivity analysis for data and model specifications, and (iv) evaluation of the model. The aim of this paper is to demonstrate how the individual components of decision modelling, outlined above, may be addressed simultaneously in one coherent Bayesian model (sometimes known as a comprehensive decision analytical model) and evaluated using Markov Chain Monte Carlo simulation implemented in the specialist software WinBUGS. To illustrate the method described, it is applied to two illustrative examples: (1) The prophylactic use of neurominidase inhibitors for the prevention of influenza. (2) The use of taxanes for the second-line treatment of advanced breast cancer. The advantages of integrating the four stages outlined into one comprehensive decision analytical model, compared to the conventional 'two-stage' approach, are discussed.

Adolescent↗

PubMed2004

Sensitivity analyses allowed more appropriate and reliable meta-analysis conclusions for multiple outcomes when missing data was present.

OBJECTIVE: A major problem for meta-analysis of multiple outcomes is the unavailability of some estimates from published and unpublished studies. Dissemination bias, in how and what outcomes are reported or published, may be causing this incompleteness. This article illustrates these problems and presents possible sensitivity analyses to allow the most reliable conclusions. STUDY DESIGN AND SETTING: In a systematic review of prognostic marker MYC-N in neuroblastoma, meta-analysis for overall survival (OS) and disease-free survival (DFS) was of interest. Only 17 published studies enabled extraction of both outcome estimates, 25 enabled only DFS, 39 enabled only OS, and 70 enabled neither outcome. Unidentified unpublished studies may also exist. We assessed the robustness of the pooled estimates to the problem of missing information. Because OS and DFS estimates seemed to be related, we used the known outcome estimates to predict estimates known to be missing, and combined this approach with existing methods for assessing dissemination bias. RESULTS: The results of the sensitivity analyses suggested that the original meta-analysis results were likely to be an overestimate of the true OS and DFS effect-sizes but strengthened the belief that MYC-N is a potentially important prognostic marker in neuroblastoma. CONCLUSION: Sensitivity analyses in meta-analysis allow more appropriate and reliable conclusions when problems such as unavailable estimates and dissemination bias are present.

Biomarkers, Tumor↗

PubMed2003

Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials.

OBJECTIVE: To review the clinical effectiveness of oseltamivir and zanamivir for the treatment and prevention of influenza A and B. DESIGN: Systematic review and meta-analyses of randomised controlled trials. DATA SOURCES: Published studies were retrieved from electronic bibliographic databases; supplementary data were obtained from the manufacturers. SELECTION OF STUDIES: Randomised controlled, double blind trials that were published in English, had data available before 31 December 2001, evaluated treatment or prevention of naturally occurring influenza with zanamivir or oseltamivir (if given using the formulation and dosage licensed for clinical use), and reported at least one end point of relevance. REVIEW METHODS: The main outcome measures were the median time to the alleviation of symptoms (for treatment trials) and number of flu episodes avoided (for prevention trials). Three population groups were defined: children aged 12 years and under; otherwise healthy individuals aged 12 to 65 years; and "high risk" individuals (those with certain chronic medical conditions or aged 65 years and older). RESULTS: Seventeen treatment trials and seven prevention trials identified met the inclusion criteria. All trials included compared one of the drugs against placebo or standard care. Treatment of children, otherwise healthy individuals, and high risk populations with zanamivir reduced the median duration of symptoms in days respectively by 1.0 (95% confidence interval 0.5 to 1.5), 0.8 (0.3 to 1.3), and 0.9 (-0.1 to 1.9) for the intention to treat population. The corresponding results, in days, for oseltamivir were 0.9 (0.3 to 1.5), 0.9 (0.3 to 1.4), and 0.4 (-0.7 to 1.4). The effect of giving zanamivir and oseltamivir prophylactically resulted in a relative reduction of 70-90% in the odds of developing flu, depending on the strategy adopted and the population studied. CONCLUSIONS: Evidence from randomised controlled trials consistently supports the view that both oseltamivir and zanamivir are clinically effective for treating and preventing flu. However, evidence is limited for the treatment of certain populations and for all prevention strategies.

Acetamides↗

PubMed2003

Identification of previously undiagnosed left ventricular systolic dysfunction: community screening using natriuretic peptides and electrocardiography.

AIMS: We examined strategies to improve the positive predictive value of natriuretic peptides in screening for undiagnosed left ventricular systolic dysfunction (LVSD) in the community. METHODS AND RESULTS: The value of B-type(BNP), N-terminal proB-type (N-BNP) and N-terminal proAtrial(N-ANP) natriuretic peptides was prospectively assessed in 1360 subjects (45-80 years) together with echocardiography and electrocardiography. Seventeen individuals had definite and 13 had borderline, LVSD. Receiver-operating-characteristic (ROC) curve analysis showed the superiority of BNP (ROC areas 0.942 for definite LVSD, P<0.03; 0.934 for borderline LVSD, P<0.003) compared to N-BNP or N-ANP. Peptide levels, major ECG abnormality and ischaemic heart disease (IHD) history were independent predictors of LVSD. Logistic regression modelling incorporating these factors improved ROC areas for all natriuretic peptides. The specificity of all natriuretic peptides is enhanced by consideration of these factors. CONCLUSIONS: In population screening for definite LVSD, consideration of plasma natriuretic peptide levels together with the presence of major ECG abnormalities and IHD history reduces by a factor of six (in comparison to consideration of plasma natriuretic peptide levels in isolation) the number of subjects requiring echocardiography to detect one case of LVSD (for BNP, 44 falling to seven). Similar improvements were evident for N-ANP and N-BNP. Inclusion of major ECG abnormalities and IHD history improves the performance of any natriuretic peptide used in screening programmes for ruling in undiagnosed LVSD.

Aged↗

PubMed2002

Effects of decision aids for menorrhagia on treatment choices, health outcomes, and costs: a randomized controlled trial.

CONTEXT: Decision aids can increase patient involvement in treatment decision making. However, questions remain regarding their effects and cost implications. OBJECTIVE: To evaluate the effects of information, with and without a structured preference elicitation interview, on treatment choices, health outcomes, and costs. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial with 2 years of follow-up. Between October 1996 and February 1998, 894 women with uncomplicated menorrhagia were recruited from 6 hospitals in southwest England. Women were randomized to the control group, information alone group (information), or information plus interview group (interview). INTERVENTIONS: Women in both intervention groups were sent an information pack (a booklet and complementary videotape) 6 weeks before their specialist consultation. Immediately before their consultation, women in the interview group underwent structured interview, to clarify and elicit their preferences. MAIN OUTCOME MEASURES: Self-reported health status was the main outcome; secondary outcomes included treatments received and costs. Cost analyses adopted a UK health service (payer) perspective, and were based on patient-reported resource use data and are reported in 1999-2000 US dollars. RESULTS: The interventions had no consistent effect on health status. Hysterectomy rates were lower for women in the interview group (38%) (adjusted odds ratio [OR], 0.60; 95% confidence interval [CI], 0.38-0.96) than in the control group (48%) and women who received the information alone (48%) (adjusted OR, 0.52; 95% CI, 0.33-0.82). The interview group had lower mean costs ($1566) than the control group ($2751) (mean difference, $1184; 95% CI, $684-$2110) and the information group $2026 (mean difference, $461; 95% CI, $236-$696). CONCLUSIONS: Neither intervention had an effect on health status. Providing women with information alone did not affect treatment choices; however, the addition of an interview to clarify values and elicit preferences had a significant effect on women's management and resulted in reduced costs.

Adult↗

PubMed2002

Factors affecting uptake of childhood immunisation: a Bayesian synthesis of qualitative and quantitative evidence.

Falls in levels of measles, mumps, and rubella (MMR) immunisation in the UK and the continuing debate on how to respond to this situation emphasise the importance of identifying and understanding the factors that affect the uptake of recommended childhood immunisations. Both qualitative and quantitative evidence could be useful in this process. We aimed to explore the feasibility and value of an approach to formal synthesis of qualitative and quantitative evidence in the context of factors affecting the uptake of childhood immunisation in developed countries. We used a Bayesian approach to meta-analysis. Evidence from 11 qualitative and 32 quantitative studies of factors affecting uptake of childhood immunisation was combined and assessed. We conclude that use of either qualitative or quantitative research alone might not identify all relevant factors, or might result in inappropriate judgments about their importance, and could thus lead to inappropriate formulation of evidence-based policy. Further development of our methods might enable rigorous synthesis of qualitative and quantitative evidence in this and other contexts.

Bayes Theorem↗

PubMed2002

Generalized synthesis of evidence and the threat of dissemination bias. the example of electronic fetal heart rate monitoring (EFM).

Assessment of the potential impact of dissemination bias is necessary for meta-analysis. When evidence is available from studies of different designs, the different study types may be affected by dissemination bias to differing degrees. The evidence relating to electronic fetal heart rate monitoring (EFM) for preventing perinatal mortality is used to explore the feasibility of carrying out a dissemination bias assessment in a generalized synthesis of evidence (gse) framework. Visual inspection of funnel plots, statistical tests, and methods to "adjust" the results of a meta-analysis are all used in an extensive sensitivity analysis. The potential impact of dissemination bias on gse models synthesizing all the evidence together is also reported. Detailed consideration is given to the influence of meta-analysis model choice, and outcome scale used. Using the risk difference scale, funnel plots of the observational studies appeared highly asymmetric. However, further explorations show these conclusions are not robust over use of different outcome measures or different meta-analysis models. Researchers should be aware that dissemination bias may affect different sources of evidence differently. Although assessments such as those described here are recommended, awareness of their lack of robustness to outcome scale and model choice is important. Further research into methods to assess dissemination bias that are invariant to these factors is needed.

Cardiotocography↗

PubMed2002

Cyclooxygenase-2 expression is a novel prognostic factor in malignant mesothelioma.

Malignant mesothelioma (MM) is a fatal tumor of increasing incidence, which is resistant to current therapy. Cyclooxygenase-2 (COX-2) plays an important role in solid tumor growth, invasiveness, and angiogenesis, in part through the synthesis of prostaglandins such as prostaglandin E(2) (PGE(2)). In a prospective study, we evaluated COX-2 expression in snap-frozen, surgically resected MM tissue specimens using immunohistochemistry and semiquantitative Western blotting. PGE(2) was assessed by enzyme immunoassay. Thirty epithelioid, 10 biphasic, and 8 sarcomatoid tumors were evaluated. Immunohistochemistry demonstrated strong cytoplasmic tumor cell and variable stromal staining in all of the cases. COX-2 protein levels were correlated with clinicopathological prognostic factors using Kaplan-Meier and Cox proportional hazards models. High COX-2 band densitometry values correlated with poor survival (P = 0.008). In multivariate analysis, high COX-2 expression (P = 0.0005), nonepithelioid cell type (P = 0.002), and chest pain (P = 0.04) were independent predictors of poor prognosis. Furthermore, COX-2 expression contributed in multivariate analysis to both European Organization for Research and Treatment of Cancer (P = 0.001) and Cancer and Leukemia Group B (P = 0.003) prognostic scoring systems. The presence of PGE(2) was demonstrated in all of the samples. These results suggest that COX-2 expression is a prognostic factor in MM. COX-2 is a potential therapeutic target in MM, and trials are required of COX-2 inhibitors alone or in combination with existing treatment modalities.

Biomarkers, Tumor↗

PubMedDate not supplied

Use of Bayesian Markov Chain Monte Carlo methods to model cost-of-illness data.

It is well known that the modeling of cost data is often problematic due to the distribution of such data. Commonly observed problems include 1) a strongly right-skewed data distribution and 2) a significant percentage of zero-cost observations. This article demonstrates how a hurdle model can be implemented from a Bayesian perspective by means of Markov Chain Monte Carlo simulation methods using the freely available software WinBUGS. Assessment of model fit is addressed through the implementation of two cross-validation methods. The relative merits of this Bayesian approach compared to the classical equivalent are discussed in detail. To illustrate the methods described, patient-specific non-health-care resource-use data from a prospective longitudinal study and the Norfolk Arthritis Register (NOAR) are utilized for 218 individuals with early inflammatory polyarthritis (IP). The NOAR database also includes information on various patient-level covariates.

Arthritis↗