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The 1st Strategic Conference of the European Federation of Clinical Chemistry and Laboratory Medicine proposed a simplified hierarchy for setting analytical performance specifications (APS). The top two levels of the 1999 Stockholm hierarchy, i.e., evaluation of the effect of analytical performance on clinical outcomes and clinical decisions have been proposed to be replaced by one outcome-based model. This model can be supported by: (1a) direct outcome studies; and (1b) indirect outcome studies investigating the impact of analytical performance of the test on clinical classifications or decisions and thereby on the probability of patient relevant clinical outcomes. This paper reviews the need for outcome-based specifications, the most relevant types of outcomes to be considered, and the challenges and limitations faced when setting outcome-based APS. The methods of Model 1a and b are discussed and examples are provided for how outcome data can be translated to APS using the linked evidence and simulation or decision analytic techniques. Outcome-based APS should primarily reflect the clinical needs of patients; should be tailored to the purpose, role and significance of the test in a well defined clinical pathway; and should be defined at a level that achieves net health benefit for patients at reasonable costs. Whilst it is acknowledged that direct evaluations are difficult and may not be possible for all measurands, all other forms of setting APS should be weighed against that standard, and regarded as approximations. Better definition of the relationship between the analytical performance of tests and health outcomes can be used to set analytical performance criteria that aim to improve the clinical and cost-effectiveness of laboratory tests. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Experts recommend random effects bivariate logitnormal sensitivity and specificity estimates, rather than directly summarized univariate likelihood ratios (LRs) for diagnostic test meta-analyses. We assessed whether bivariate measures might cause different clinical conclusions compared with those from simpler univariate measures. Study Design: From two articles that described the benefits of bivariate random effects measures, we reanalyzed results and compared outcomes to univariate random effects summary estimates of sensitivity, specificity, and LRs. We also reanalyzed data from two published clinical examination studies to assess differences in the two methods. Results: The median difference between bivariate and univariate methods for sensitivity was 1.5% (range: 0–6%) and for specificity was 1.5% (range: 0–4%). Using a pretest probability of 50%, the median difference in posterior probability was 2.5% (interquartile range: 2.2–3.2%, overall range: 0–11%). For sparse data, continuity adjustment affected the differences. Adding 0.5 to each cell of studies containing at least one cell with zero patients provided the most consistent result. Conclusions: Bivariate estimates of sensitivity and specificity generate summary LRs similar to those derived with univariate methods. Our empiric results suggest that recalculating LRs in published research will not likely create dramatic changes as a function of the random effects measure chosen. [Copyright &y& Elsevier]

Abstract: Objective: To explore designs for evaluating the prognostic and predictive value of medical tests and their effect on patient outcome. Study design: Theoretical analysis with examples from the medical literature. Results: For evaluating the prognostic value of a test, one can include the test at baseline in prognostic studies. To evaluate the value of test in predicting treatment outcome, the test results can be used as baseline information in randomized controlled trials of treatment. To compare the prognostic or predictive value of two or more tests, the test result combinations can be used as baseline information. To evaluate the effect on patient outcome, randomized controlled trials of test strategies are an option. Randomization can apply to all tested or be restricted to specific subgroups, such as those with discordant test results, to increase the efficiency of trials. Conclusion: The prognostic and predictive value of medical tests can and should be evaluated, to demonstrate the test''s ability to guide clinical decision making and to improve patient outcome. Various randomized designs can be used to evaluate the effects on testing on patient outcome. [Copyright &y& Elsevier]

Abstract: Background: Several studies and systematic reviews have reported results that indicate that sensitivity and specificity may vary with prevalence. Study design and setting: We identify and explore mechanisms that may be responsible for sensitivity and specificity varying with prevalence and illustrate them with examples from the literature. Results: Clinical and artefactual variability may be responsible for changes in prevalence and accompanying changes in sensitivity and specificity. Clinical variability refers to differences in the clinical situation that may cause sensitivity and specificity to vary with prevalence. For example, a patient population with a higher disease prevalence may include more severely diseased patients, therefore, the test performs better in this population. Artefactual variability refers to effects on prevalence and accuracy associated with study design, for example, the verification of index test results by a reference standard. Changes in prevalence influence the extent of overestimation due to imperfect reference standard classification. Conclusions: Sensitivity and specificity may vary in different clinical populations, and prevalence is a marker for such differences. Clinicians are advised to base their decisions on studies that most closely match their own clinical situation, using prevalence to guide the detection of differences in study population or study design. [Copyright &y& Elsevier]

Abstract: Background. : Family screening programs for intracranial aneurysms have been considered but there are concerns about raised anxiety and depression, inadequate risk perception, and the principle of informed choice. Methods. : Observational study in 980 first-degree relatives of 172 patients with subarachnoid hemorrhage. After being informed, consenting subjects completed the Hospital Anxiety and Depression Scale (HADS), answered standardized questions on perceived risk, and responded to a list of statements about the decision-making process. Main results. : 166 subjects (21%) declined the screening offer. 12% of the participants reported HADS anxiety scores in the moderate to severe range; 2% did so for feelings of depression. All relatives substantially underestimated the risk of harboring an aneurysm and of aneurysm rupture. 98% of the participants (96% of non-participants, P = 0.60) reported feeling free to make a choice, while 31% of the participants (42% of non-participants, P = 0.16) felt more or less compelled to participate in the screening program. Conclusions. : The invitation to a family screening program for intracranial aneurysms does not lead to increased feelings of anxiety or depression. The unrealistic risk perception stresses the need of clear and detailed information. Attention should be given to factors that may interfere with the principle of informed choice. [Copyright &y& Elsevier]

The EU In-Vitro Diagnostic Device Regulation (IVDR) aims for transparent risk-and purpose-based validation of diagnostic devices, traceability of results to uniquely identified devices, and post-market surveillance. The IVDR regulates design, manufacture and putting into use of devices, but not medical services using these devices. In the absence of suitable commercial devices, the laboratory can resort to laboratory-developed tests (LDT) for in-house use. Documentary obligations (IVDR Art 5.5), the performance and safety specifications of ANNEX I, and development and manufacture under an ISO 15189-equivalent quality system apply. LDTs serve specific clinical needs, often for low volume niche applications, or correspond to the translational phase of new tests and treatments, often extremely relevant for patient care. As some commercial tests may disappear with the IVDR roll-out, many will require urgent LDT replacement. The workload will also depend on which modifications to commercial tests turns them into an LDT, and on how national legislators and competent authorities (CA) will handle new competences and responsibilities. We discuss appropriate interpretation of ISO 15189 to cover IVDR requirements. Selected cases illustrate LDT implementation covering medical needs with commensurate management of risk emanating from intended use and/or design of devices. Unintended collateral damage of the IVDR comprises loss of non-profitable niche applications, increases of costs and wasted resources, and migration of innovative research to more cost-efficient environments. Taking into account local specifics, the legislative framework should reduce the burden on and associated opportunity costs for the health care system, by making diligent use of existing frameworks. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the extent to which test accuracy studies published in two leading reproductive medicine journals in the years 1999 and 2004 adhered to the Standards for Reporting of Diagnostic Accuracy (STARD) initiative parameters, and to explore whether the introduction of the STARD statement has led to an improved quality of reporting. Design: Structured literature search. Articles that reported on the diagnostic performance of a test in comparison with a reference standard were eligible for inclusion. For each article we scored how well the 25 items of the STARD checklist were reported. These items deal with the study question, study participants, study design, test methods, reference standard, statistical methods, reporting of results, and conclusions. We calculated the total number of reported STARD items per article, summary scores for each STARD item, and the average number of reported STARD items per publication year. Setting: Not applicable. Patient(s): Not applicable. Intervention(s): Not applicable. Main Outcome Measure(s): Quality of reporting. Result(s): We found 24 studies reporting on test accuracy in reproductive medicine in 1999 and 27 studies in 2004. The mean number of reported STARD items for articles published in 1999 was 12.1 ± 3.3 (range 6.5–20) and 12.4 ± 3.2 (range 7–17.5) in 2004, after publication of the STARD statement. Overall, less than half of the studies reported adequately on 50% or more of the STARD items. The reporting of individual items showed a wide variation. There was no significant improvement in mean number of reported items for the articles published after the introduction of the STARD statement. Conclusion(s): Authors of test accuracy studies in the two leading fertility journals poorly report the design, conduct, methodology, and statistical analysis of their study. Strict adherence to the STARD guidelines should be encouraged. [Copyright &y& Elsevier]

Laboratory medicine in the European Union is at the dawn of a regulatory revolution as it reaches the end of the transition from IVDD 98/79/EC (https://eur-lex.eur-opa.eu/legal-content/EN/TXT/?uri=CELEX%3A31998L0079&qid=1628781352814) to IVDR 2017/746 https://eur-lex.europa.eu/eli/reg/2017/746. Without amendments and contingency plans, implementation of the IVDR in May 2022 will lead the healthcare sector into uncharted waters due to unpreparedness of the EU regulatory infrastructure. Prospective risk analyses were not made by the European Commission, and if nothing happens it can be anticipated that the consequences will impact all stakeholders of the medical test pipeline, may seriously harm patients and may prevent caregivers from making appropriate clinical decisions due to non-availability of medical tests. Finally, it also may discourage manufacturers and academia from developing specialty tests, thereby hampering innovation in medical diagnostic care. We hereby inform laboratory professionals about the imminent diagnostic collapse using testimonies from representative stakeholders of the diagnostic supply chain and from academia developing innovative in-house tests in domains of unmet clinical needs. Steps taken by the EFLM Task Force on European Regulatory Affairs, under the umbrella of the Biomedical Alliance in Europe, will be highlighted, as well as the search for solutions through dialogue with the European Commission. Although we recognize that the IVDR promotes positive goals such as increased clinical evidence, surveillance, and transparency, we need to ensure that the capabilities of the diagnostic sector are not damaged by infrastructural unpreparedness, while at the same time being forced to submit to a growing bureaucratic and unsupportive structure that will not support its "droit d'exister". [ABSTRACT FROM AUTHOR]

Background: Transvaginal sonography, serum human chorionic gonadotrophin (hCG) measurement, and serum progesterone measurement provide the possibility to screen symptom-free women at increased risk of ectopic pregnancy. The objective of the present study was to evaluate the cost-effectiveness of screening for ectopic pregnancy, by addressing the expected benefits and costs of screening for ectopic pregnancy.Methods: Screening programs incorporating transvaginal sonography, serum hCG measurement, and serum progesterone measurement were compared with a 'watchful waiting' strategy. Data were extracted from the literature. The strategies were compared on the expected number of prevented tubal ruptures, the expected number of false-positive diagnoses, and expected costs.Results: The cost-effectiveness of screening appeared to be strongly dependent on the prevalence of ectopic pregnancy. At a prevalence of ectopic pregnancy of 6%, a screening program with transvaginal sonography and serum hCG measurement would reduce the number of patients with ruptured ectopic pregnancy from 2.1 to 0.61 per 100 screened women. Screening was expected to cost approximately Euro 933 per prevented tubal rupture, whereas the number of expected false-positive diagnoses was 0.64 per prevented tubal rupture.Conclusion: We conclude that screening for ectopic pregnancy reduces the number of patients with tubal rupture, but only at the expense of a large false-positive rate. Although sonography in symptom-free women at risk of ectopic pregnancy might be justified for psychological reasons, the medical and economic benefits of such a policy seem to be limited. [ABSTRACT FROM AUTHOR]

Comparative diagnostic test accuracy studies assess and compare the accuracy of 2 or more tests in the same study. Although these studies have the potential to yield reliable evidence regarding comparative accuracy, shortcomings in the design, conduct, and analysis may bias their results. The currently recommended quality assessment tool for diagnostic test accuracy studies, QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2), is not designed for the assessment of test comparisons. The QUADAS-C (Quality Assessment of Diagnostic Accuracy Studies-Comparative) tool was developed as an extension of QUADAS-2 to assess the risk of bias in comparative diagnostic test accuracy studies. Through a 4-round Delphi study involving 24 international experts in test evaluation and a face-to-face consensus meeting, an initial version of the tool was developed that was revised and finalized following a pilot study among potential users. The QUADAS-C tool retains the same 4-domain structure of QUADAS-2 (Patient Selection, Index Test, Reference Standard, and Flow and Timing) and comprises additional questions to each QUADAS-2 domain. A risk-of-bias judgment for comparative accuracy requires a risk-of-bias judgment for the accuracy of each test (resulting from QUADAS-2) and additional criteria specific to test comparisons. Examples of such additional criteria include whether participants either received all index tests or were randomly assigned to index tests, and whether index tests were interpreted with blinding to the results of other index tests. The QUADAS-C tool will be useful for systematic reviews of diagnostic test accuracy addressing comparative questions. Furthermore, researchers may use this tool to identify and avoid risk of bias when designing a comparative diagnostic test accuracy study. [ABSTRACT FROM AUTHOR]

Randomized controlled trials (RCTs) are the cornerstone of evidence-based medicine. In this series in Fertility and Sterility, several aspects of RCTs are discussed, with contributions on multicenter RCTs, different international settings, and integrity of RCTs. The present contribution deals with methodologic issues. We discuss different types of RCTs based on null hypothesis (superiority vs. noninferiority vs. equivalence) as well as frequentist versus Bayesian interpretation. We also discuss the use of RCTs in the era of personalized medicine and RCTs to address diagnostic and prognostic questions. Finally, we address the use of big data compared with the use of RCTs. [ABSTRACT FROM AUTHOR]

While a reliable differentiation between viral and bacterial pneumonia is not possible with chest X-ray, this study investigates whether ultra-low-dose chest-CT (ULDCT) could be used for this purpose. In the OPTIMACT trial 281 patients had a final diagnosis of pneumonia, and 96/281 (34%) had one or more positive microbiology results: 60 patients viral pathogens, 48 patients bacterial pathogens. These 96 ULDCT's were blindly and independently evaluated by two chest radiologists, who reported CT findings, pneumonia pattern, and most likely type of pathogen. Differences between groups were analysed for each radiologist separately, diagnostic accuracy was evaluated by calculating sensitivity. The dominant CT finding significantly differed between the viral and bacterial pathogen groups (p = 0.04; p = 0.04). Consolidation was the most frequent dominant CT finding in both patients with viral and bacterial pathogens, but was observed significantly more often in those with a bacterial pathogen: 32/60 and 22/60 versus 38/48 and 31/48 (p = 0.005; p = 0.004). The lobar pneumonia pattern was more frequently observed in patients with a bacterial pathogen: 23/48 and 18/48, versus 10/60 and 8/60 for viral pathogens (p < 0.001; p = 0.004). For the bronchopneumonia and interstitial pneumonia patterns the proportions of viral and bacterial pathogens were not significantly different. Both radiologists suggested a viral pathogen correctly (sensitivity) in 6/60 (10%), for a bacterial pathogen this was 34/48 (71%). Reliable differentiation between viral and bacterial pneumonia could not be made by pattern recognition on ULDCT, although a lobar pneumonia pattern was significantly more often observed in bacterial infection. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the handling of multiple readers in imaging diagnostic accuracy systematic reviews-meta-analyses.Methods: Search was performed for imaging diagnostic accuracy systematic reviews that performed meta-analysis from 2005-2015. Handling of multiple readers was classified as: 1) averaged; 2) 'best' reader; 3) 'most experienced' reader; 4) each reader counted individually; 5) random; 6) other; 7) not specified. Incidence and reporting of multiple reader data was assessed in primary diagnostic accuracy studies that were included in a random sample of reviews.Results: Only 28/296 (9.5%) meta-analyses specified how multiple readers were handled: 7/28 averaged results, 2/28 included the best reader, 14/28 treated each reader as a separate data set, 1/28 randomly selected a reader, 4/28 used other methods. Sample of 27/268 'not specified' reviews generated 442 primary studies. 270/442 (61%) primary studies had multiple readers: 164/442 (37%) reported consensus reading, 87/442 (20%) reported inter-observer variability, 9/442 (2%) reported independent datasets for each reader. 26/27 (96%) meta-analyses contained at least one primary study with multiple readers.Conclusions: Reporting how multiple readers were treated in imaging systematic reviews-meta-analyses is uncommon and method used varied widely. This may result from a lack of guidance, unavailability of appropriate statistical methods for handling multiple readers in meta-analysis, and sub-optimal primary study reporting. [ABSTRACT FROM AUTHOR]

One of the aims in reproductive medicine is to differentiate between couples that have favourable chances of conceiving naturally and those that do not. Since the development of the prediction model of Hunault, characteristics of the subfertile population have changed. The objective of this analysis was to assess whether additional predictors can refine the Hunault model and extend its applicability. Consecutive subfertile couples with unexplained and mild male subfertility presenting in fertility clinics were asked to participate in a prospective cohort study. We constructed a multivariable prediction model with the predictors from the Hunault model and new potential predictors. The primary outcome, natural conception leading to an ongoing pregnancy, was observed in 1053 women of the 5184 included couples (20%). All predictors of the Hunault model were selected into the revised model plus an additional seven (woman's body mass index, cycle length, basal FSH levels, tubal status,history of previous pregnancies in the current relationship (ongoing pregnancies after natural conception, fertility treatment or miscarriages), semen volume, and semen morphology. Predictions from the revised model seem to concur better with observed pregnancy rates compared with the Hunault model; c-statistic of 0.71 (95% CI 0.69 to 0.73) compared with 0.59 (95% CI 0.57 to 0.61). [ABSTRACT FROM AUTHOR]

Background The introduction of new biomarkers can lead to inappropriate utilization of tests if they do not fill in existing gaps in clinical care. We aimed to define a strategy and checklist for identifying unmet needs for biomarkers. Methods A multidisciplinary working group used a 4-step process: 1/ scoping literature review; 2/ face-to-face meetings to discuss scope, strategy and checklist items; 3/ iterative process of feedback and consensus to develop the checklist; 4/ testing and refinement of checklist items using case scenarios. Results We used clinical pathway mapping to identify clinical management decisions linking biomarker testing to health outcomes and developed a 14-item checklist organized into 4 domains: 1/ identifying and 2/ verifying the unmet need; 3/ validating the intended use; and 4/ assessing the feasibility of the new biomarker to influence clinical practice and health outcome. We present an outcome-focused approach that can be used by multiple stakeholders for any medical test, irrespective of the purpose and role of testing. Conclusions The checklist intends to achieve more efficient biomarker development and translation into practice. We propose the checklist is field tested by stakeholders, and advocate the role of the clinical laboratory professional to foster trans-sector collaboration in this regard. [ABSTRACT FROM AUTHOR]

Objective: Available treatment options in couples with unexplained or mild male subfertility are intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) and in vitro fertilisation (IVF). IUI-COH is a less invasive treatment that is often used before proceeding with IVF. Yet as the IVF success rates might be higher and time to pregnancy shorter, expedited access to IVF might be the preferred option. To identify couples that could benefit from immediate IVF over IUI-COH, we assessed whether female age, duration of subfertility or prewash total motile count (TMC) can help to identify couples that would benefit from IVF over IUI-COH.Study Design: We performed a secondary data-analysis of a multicentre open-label randomised controlled trial in three university and six teaching hospitals in the Netherlands. 116 couples with unexplained or mild male subfertility were randomised to one cycle of IVF with elective single embryo transfer with subsequent frozen-thawed embryo transfers or 3 cycles of IUI-COH. The primary outcome was an ongoing pregnancy within 4 months after randomisation. Our aim was to explore a possible differential effect of specific markers on the effectiveness of treatment. We chose to therefore assess female age, duration of subfertility and TMC as these have previously been identified as predictors. For each prognostic factor we developed a logistic regression model to predict ongoing pregnancy with that prognostic factor, treatment and a factor-by-treatment interaction term.Results: Female age and duration of subfertility were not associated with better ongoing pregnancy chances after IVF compared to IUI-COH (p-value for interaction=0.65 and 0.26, respectively). Only when TMC was lower than 110 (×10(6)spermatozoa/mL), the probability of ongoing pregnancy was higher in women allocated to IVF (p-value for interaction=0.06).Conclusion: In couples with unexplained or mild male subfertility, a low TMC might lead to higher pregnancy rates after IVF than after IUI-COH. This finding needs to be validated in a larger trial before it can be applied in clinical practice. [ABSTRACT FROM AUTHOR]

Objective To stratify the risk of spontaneous preterm delivery using cervical length ( CL) and fetal fibronectin ( fFN) in women with threatened preterm labor who remained pregnant after 7 days. Design Prospective observational study. Setting Nationwide cohort of women with threatened preterm labor from the Netherlands. Population Women with threatened preterm labor between 24 and 34 weeks with a valid CL and fFN measurement and remaining pregnant 7 days after admission. Methods Kaplan-Meier and Cox proportional hazards models were used to estimate cumulative percentages and hazard ratios ( HR) for spontaneous delivery. Main outcome measures Spontaneous delivery between 7 and 14 days after initial presentation and spontaneous preterm delivery before 34 weeks. Results The risk of delivery between 7 and 14 days was significantly increased for women with a CL < 15 mm or a CL ≥15 to <30 mm and a positive fFN, compared with women with a CL ≥30 mm: HR 22.3 [95% confidence interval ( CI) 2.6-191] and 14 (95% CI 1.8-118), respectively. For spontaneous preterm delivery before 34 weeks the risk was increased for women with a CL < 15 mm [ HR 6.3 (95% CI 2.6-15)] or with a CL ≥15 to <30 mm with either positive fFN [ HR 3.6 (95% CI 1.5-8.7)] or negative fFN [ HR 3.0 (95% CI 1.2-7.1)] compared with women with a CL ≥ 30 mm. Conclusions In women remaining pregnant 7 days after threatened preterm labor, CL and fFN results can be used in risk stratification for spontaneous delivery. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Do two semen analyses predict natural conception better than a single semen analysis and will adding the results of repeated semen analyses to a prediction model for natural pregnancy improve predictions? SUMMARY ANSWER A second semen analysis does not add helpful information for predicting natural conception compared with using the results of a single semen analysis and addition of the second analysis to a prediction model for natural conception did not improve predictions. WHAT IS KNOWN ALREADY A major problem with semen analyses is the large variability of results within an individual. High-quality evidence is lacking on how many semen analyses need to be performed during the fertility workup to achieve an accurate prediction of conception. STUDY DESIGN, SIZE, DURATION We conducted a prospective cohort study of 897 consecutive couples presenting with subfertility in two university hospitals in the period 2002–2004 in the Netherlands. PARTICIPANTS/MATERIALS, SETTING, AND METHODS The laboratories scored sperm parameters according to the 1999 WHO criteria. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. All assessments were performed by trained laboratory technicians. Follow-up started at the completion of the infertility workup and ended after 12 months. Primary end-point was natural conception resulting in an ongoing pregnancy. We constructed models for three strategies for the prediction of natural conception, using univariable and multivariable Cox hazard regression analyses. We evaluated the performance of the three strategies by comparing goodness-of-fit, discrimination and calibration. First, we analysed the semen parameters only. Secondly, we analysed the semen parameters in addition to the multivariable Hunault prediction model. MAIN RESULTS AND THE ROLE OF CHANCE Of the 897 couples, 132 (15%) achieved a pregnancy by natural conception. Using the results of a single semen analysis only, the calculated probabilities of natural conception within 12 months across the study population ranged from 0.12 to 0.38, with a median of 0.16 (IQR: 0.16–0.17). Using the results of two semen analyses did not lead to a better goodness-of-fit. Discriminative capacity was rather poor, with an area under the ROC curve (AUC) ranging from 0.51 to 0.56. Using the Hosmer–Lemeshow test statistic we found no signs of poor calibration. Using the results of two semen analyses in combination with the Hunault model did not significantly increase goodness-of-fit compared with using a single semen analysis. The Hunault model with the addition of the semen parameters fitted the data significantly better than the Hunault model itself (difference in −2 Log likelihood: 13; 3 df; P = 0.002). Using the Hosmer–Lemeshow test statistic we found no signs of poor calibration. LIMITATIONS, REASONS FOR CAUTION The academic setting possibly explains the relatively low natural conception rates, with only 15% achieving a natural conception within 1 year. Men with azoospermia were excluded. WIDER IMPLICATIONS OF THE FINDINGS Performing more than one semen analysis will not increase the prognostic power of the test in clinical practice. Adding the first semen analysis to the Hunault model for the prediction of natural conception improved performance significantly compared with using the Hunault model alone. External validation, in other populations, should follow to confirm our conclusions, and to evaluate the generalizability or transportability of the extended Hunault model. STUDY FUNDING/COMPETING INTEREST(S) No external funding was involved in this study. None of the authors has any conflict of interest to declare. [ABSTRACT FROM AUTHOR]

Abstract: Regulators and healthcare payers are increasingly demanding evidence that biomarkers deliver patient benefits to justify their use in clinical practice. Laboratory professionals need to be familiar with these evidence requirements to better engage in biomarker research and decisions about their appropriate use. This paper by a multidisciplinary group of the European Federation of Clinical Chemistry and Laboratory Medicine describes the pathway of a laboratory assay measuring a biomarker to becoming a medically useful test. We define the key terms, principles and components of the test evaluation process. Unlike previously described linearly staged models, we illustrate how the essential components of analytical and clinical performances, clinical and cost-effectiveness and the broader impact of testing assemble in a dynamic cycle. We highlight the importance of defining clinical goals and how the intended application of the biomarker in the clinical pathway should drive each component of test evaluation. This approach emphasizes the interaction of the different components, and that clinical effectiveness data should be fed back to refine analytical and clinical performances to achieve improved outcomes. The framework aims to support the understanding of key stakeholders. The laboratory profession needs to strengthen collaboration with industry and experts in evidence-based medicine, regulatory bodies and policy makers for better decisions about the use of new and existing medical tests. [Copyright &y& Elsevier]

Abstract: Objective: To compare accuracy and interobserver agreement between radiologists with limited experience in the evaluation of abdominal MRI (non-experts), and radiologists with longer MR reading experience (experts), in reading MRI in patients with suspected appendicitis. Methods: MR imaging was performed in 223 adult patients with suspected appendicitis and read independently by two members of a team of eight MR-inexperienced radiologists, who were trained with 100 MR examinations previous to this study (non-expert reading). Expert reading was performed by two radiologists with a larger abdominal MR experience (>500 examinations) in consensus. A final diagnosis was assigned after three months based on all available information, except MRI findings. We estimated MRI sensitivity and specificity for appendicitis and for all urgent diagnoses separately. Interobserver agreement was evaluated using kappa statistics. Results: Urgent diagnoses were assigned to 147 of 223 patients; 117 had appendicitis. Sensitivity for appendicitis was 0.89 by MR-non-expert radiologists and 0.97 in MR-expert reading (p =0.01). Specificity was 0.83 for MR-non-experts versus 0.93 for MR-expert reading (p =0.002). MR-experts and MR-non-experts agreed on appendicitis in 89% of cases (kappa 0.78). Accuracy in detecting urgent diagnoses was significantly lower in MR-non-experts compared to MR-expert reading: sensitivity 0.84 versus 0.95 (p <0.001) and specificity 0.71 versus 0.82 (p =0.03), respectively. Agreement on urgent diagnoses was 83% (kappa 0.63). Conclusion: MR-non-experts have sufficient sensitivity in reading MRI in patients with suspected appendicitis, with good agreement with MR-expert reading, but accuracy of MR-expert reading was higher. [Copyright &y& Elsevier]

Abstract: Objective: Meta-analysis of predictive values is usually discouraged because these values are directly affected by disease prevalence, but sensitivity and specificity sometimes show substantial heterogeneity as well. We propose a bivariate random-effects logitnormal model for the meta-analysis of the positive predictive value (PPV) and negative predictive value (NPV) of diagnostic tests. Study Design and Setting: Twenty-three meta-analyses of diagnostic accuracy were reanalyzed. With separate models, we calculated summary estimates of the PPV and NPV and summary estimates of sensitivity and specificity. We compared these summary estimates, the goodness of fit of the two models, and the amount of heterogeneity of both approaches. Results: There were no substantial differences in the goodness of fit or amount of heterogeneity between both models. The median absolute difference between the projected PPV and NPV from the summary estimates of sensitivity and specificity and the summary estimates of PPV and NPV was 1% point (interquartile range, 0–2% points). Conclusion: A model for the meta-analysis of predictive values fitted the data from a range of systematic reviews equally well as meta-analysis of sensitivity and specificity. The choice for either model could be guided by considerations of the design used in the primary studies and sources of heterogeneity. [Copyright &y& Elsevier]

Objective: To evaluate the capacity of the postcoital test (PCT) to predict spontaneous pregnancy in a large cohort study of subfertile couples. Design: Prospective study. Setting: Department of reproductive medicine of 38 hospitals in the Netherlands. Patient(s): Between January 2002 and February 2004, we prospectively included consecutive subfertile couples who had not been evaluated previously for subfertility. Intervention(s): We estimated the contribution of the PCT result to the existing prediction model for spontaneous pregnancy by calculating the adjusted hazard ratio (HR) of an abnormal PCT result. We constructed a second prediction model (PCT model) based on the reference model including the PCT. Main Outcome Measure(s): Primary endpoint in this study was ongoing pregnancy. We evaluated the performance of the PCT model in comparison with the reference model by calculating goodness of fit, discrimination, calibration, and the “net reclassification improvement”. Result(s): We included 3,021 couples of whom 537 (18%) had a spontaneous pregnancy and 55 (1.8%) a nonsuccessful pregnancy; 1,316 (44%) started treatment within 12 months, 824 (27%) neither started treatment nor became pregnant, and 289 (10%) became lost to follow-up within 12 months. The adjusted HR for an abnormal PCT was 0.76 (95% confidence interval [CI]: 0.62 to 0.94). The adjusted HR for an abnormal PCT was 0.63 (95% CI: 0.47 to 0.84) in case of no spermatozoa, 0.81 (95% CI: 0.57 to 1.2) in case of nonmotile spermatozoa, and 1.2 (95% CI: 0.8 to 1.8) in case of motile, nonprogressive spermatozoa. Adding the PCT result to the reference model did not improve goodness of fit. Discrimination was equally poor for the PCT model and the reference model. The calibration plots of both models showed comparably good calibration. The net reclassification improvement of the predictions of the PCT model compared with the reference model was −1.1%. Conclusion(s): This study demonstrated that the PCT has prognostic value but does not add substantially to a prognostic model for spontaneous pregnancy. [Copyright &y& Elsevier]

Objective: To evaluate the associations between the results of the male partner''s semen analysis (classified according to the World Health Organization [WHO] criteria) and fathering a child without any treatment. Design: Prospective multicenter cohort study. Setting: Twenty subfertility centers in The Netherlands. Patient(s): A total of 3,345 consecutive couples presenting for subfertility. Intervention(s): None. Main Outcome Measure(s): Associations between the results of the male partner''s semen analysis, classified according to the WHO criteria, and fathering a child without any treatment within a time horizon of 1 year. Subsequently, we redefined semen quality criteria and reevaluated the associations. Result(s): Follow-up data of 3,129 couples (94%) were available, of which 517 (17%) had a healthy pregnancy without treatment. The 1-year pregnancy rate in men with WHO normozoospermia did not differ significantly from that in men with WHO impaired semen (24% vs. 23%). In contrast, we observed lower chances of fathering a child for sperm concentrations <40 × 106/mL, total sperm count <200 × 106, and sperm morphology <20% normal forms. With a multivariable regression model based on the redefined male semen subfertility criteria we were able to make a finer differentiation between subfertile men, with probabilities of fathering a child ranging from 7% to 41%. Conclusion(s): The current WHO criteria for semen quality do not discriminate between fertile and subfertile men. Our redefined and graded semen criteria have strong predictive value. If interpreted correctly, the fast and inexpensive semen analysis remains the gold standard for defining a man''s role in subfertility. [Copyright &y& Elsevier]

Purpose: A common problem in diagnostic research is that the reference standard has not been carried out in all patients. This partial verification may lead to biased accuracy measures of the test under study. The authors studied the performance of multiple imputation and the conventional correction method proposed by Begg and Greenes under a range of different situations of partial verification. Methods: In a series of simulations, using a previously published deep venous thrombosis data set (n = 1292), the authors set the outcome of the reference standard to missing based on various underlying mechanisms and by varying the total number of missing values. They then compared the performance of the different correction methods. Results: The results of the study show that when the mechanism of missing reference data is known, accuracy measures can easily be correctly adjusted using either the Begg and Greenes method, or multiple imputation. In situations where the mechanism of missing reference data is complex or unknown, we recommend using multiple imputation methods to correct. Conclusions: These methods can easily apply for both continuous and categorical variables, are readily available in statistical software and give reliable estimates of the missing reference data. [ABSTRACT FROM AUTHOR]

Objective: To determine the precise degree of variability that is represented by the reproducibility and reliability of semen analysis. The general assumption is that semen analyses need to be repeated because of a high degree of within-individual variability. However, the precise degree of variability is not well established in male partners of subfertile couples. Design: Retrospective cohort study. Setting: Two university hospitals in the Netherlands, which routinely perform two semen analyses in the male partner of subfertile couples. Patient(s): Male partners of subfertile couples. Interventions: None. Main Outcome Measure(s): We assessed the test-retest reproducibility, by calculating the coefficient of variation (CVw) for five semen parameters. The CVw expresses, on a relative scale, the degree of closeness of repeated measurements taken in the same subject. We also estimated the reliability of these semen parameters, in terms of the intraclass correlation coefficient, which expresses the ratio of the between-subject variability over the total variability. Result(s): We analyzed the data of 5,240 men and found that the CVw of all semen parameters ranged from 28% to 34%. The intraclass correlation coefficients of these semen parameters were moderate to high: volume: 0.70; concentration: 0.89; motility: 0.58; morphology: 0.60; total motile count: 0.73. Conclusion(s): This study affirmed the presumed large within-subject variability and the limited reproducibility of semen analyses in subfertile men. Whether this degree of variability within men justifies one or more repetitions of the semen analysis in view of consequences for clinical management should be the topic of future studies. Until then it seems reasonable to perform two semen analyses. [ABSTRACT FROM AUTHOR]

Objective: To assess the time to spontaneous ongoing pregnancy after a previous miscarriage in subfertile couples. Design: A prospective cohort study. Setting: The study was conducted in 38 fertility centers in the Netherlands. Patient(s): Subfertile couples who miscarried after completing their basic fertility work-up. Intervention(s): Expectant management after a miscarriage. Main Outcome Measure(s): Spontaneous ongoing pregnancy. Result(s): We included 5,663 subfertile couples, of which 1,098 (19%) conceived spontaneously. Among these 1,098 couples, 199 (18%) miscarried and these couples were included in the present study. Follow-up was completed for 171 couples, of which 95 conceived again within 24 months of follow-up. Of these 95 pregnancies, 86 (91%) were ongoing. The cumulative spontaneous ongoing pregnancy rate (PR) after 24 months was 70% (95% confidence interval [CI] 59%–81%). Conclusion(s): Subfertile couples, who experience a treatment-independent pregnancy resulting in a miscarriage, have very good prospects of a spontaneous ongoing pregnancy in the near future. This information is useful in counseling couples who had a miscarriage after a previous period of subfertility. [Copyright &y& Elsevier]

Background: The benefits of preoperative biliary drainage, which was introduced to improve the postoperative outcome in patients with obstructive jaundice caused by a tumor of the pancreatic head, are unclear. Methods: In this multicenter, randomized trial, we compared preoperative biliary drainage with surgery alone for patients with cancer of the pancreatic head. Patients with obstructive jaundice and a bilirubin level of 40 to 250 μmol per liter (2.3 to 14.6 mg per deciliter) were randomly assigned to undergo either preoperative biliary drainage for 4 to 6 weeks, followed by surgery, or surgery alone within 1 week after diagnosis. Preoperative biliary drainage was attempted primarily with the placement of an endoprosthesis by means of endoscopic retrograde cholangiopancreatography. The primary outcome was the rate of serious complications within 120 days after randomization. Results: We enrolled 202 patients; 96 were assigned to undergo early surgery and 106 to undergo preoperative biliary drainage; 6 patients were excluded from the analysis. The rates of serious complications were 39% (37 patients) in the early-surgery group and 74% (75 patients) in the biliary-drainage group (relative risk in the early-surgery group, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). Preoperative biliary drainage was successful in 96 patients (94%) after one or more attempts, with complications in 47 patients (46%). Surgery-related complications occurred in 35 patients (37%) in the early-surgery group and in 48 patients (47%) in the biliary-drainage group (relative risk, 0.79; 95% CI, 0.57 to 1.11; P=0.14). Mortality and the length of hospital stay did not differ significantly between the two groups. Conclusions: Routine preoperative biliary drainage in patients undergoing surgery for cancer of the pancreatic head increases the rate of complications. (Current Controlled Trials number, ISRCTN31939699.) N Engl J Med 2010;362:129-37. [ABSTRACT FROM AUTHOR]

Objective: To assess whether pregnancy history can predict the occurrence of a spontaneous ongoing pregnancy in subfertile couples. Design: Prospective cohort study. Setting: Thirty fertility centers in the Netherlands. Patient(s): Subfertile, ovulatory women with at least one patent tube and male partners without severely impaired semen quality. Intervention(s): Fertility work-up, including a detailed pregnancy history. Main Outcome Measure(s): Spontaneous ongoing pregnancy. Result(s): We included 4445 couples, of whom 793 (18%) had a spontaneous ongoing pregnancy within 1 year of follow-up. Previous live birth and miscarriage in current partnership were both associated with higher fecundity as compared with primary infertility (hazard rate ratios for spontaneous pregnancy [HR] 1.4; 95% CI, 1.2–1.7 and 1.3; 95% CI, 1.0–1.5, respectively). Pregnancies in a woman''s previous partnerships did not affect the fecundity of the couple. A pregnancy in a previous partnership of the male partner was associated with lower fecundity (HR 0.76; 95% CI, 0.58–0.99). A previous pregnancy after fertility treatment also was associated with lower fecundity (HR 0.52; 95% CI, 0.30–0.90). Conclusion(s): Accurate prediction of the future fertility of a couple requires an exact assessment of the fertility history of both partners. [Copyright &y& Elsevier]

After randomization of subfertile couples with an isolated cervical factor to intrauterine insemination for 6 months or expectant management for 6 months, 26 women (51%) vs. 16 women (33%) conceived, respectively. Of these pregnancies, 22 (43%) vs. 13 (27%) were ongoing (relative risk, 1.6; 95% confidence interval, 0.91 to 2.8). There was one multiple pregnancy in the group that was allocated to intrauterine insemination. This trial suggests a beneficial effect of IUI in couples with an isolated cervical factor. [Copyright &y& Elsevier]

Objective: To assess the effectiveness of controlled ovarian hyperstimulation (COH) in intrauterine insemination (IUI) for subfertile couples with an abnormal postcoital test and a poor prognosis. Design: Randomized clinical trial. Setting: Twenty-four fertility centers in the Netherlands. Patient(s): Subfertile couples with a well-timed nonprogressive PCT and additional factors that reduce fertility. Intervention(s): Couples were randomly allocated to three cycles of IUI with COH or three cycles of IUI without COH. Main Outcome Measure(s): Ongoing pregnancy within three IUI cycles. Result(s): We randomly allocated 132 couples to IUI with COH, and 133, to IUI without COH. We observed 33 pregnancies (25%) in the couples allocated to IUI with COH, of which 28 were ongoing (21%), vs. 28 pregnancies (21%) in the couples allocated to IUI without COH, of which 23 were ongoing (17%; relative risk of an ongoing pregnancy, 1.2; 95% confidence interval, 0.75 to 2.0). Two multiple pregnancies occurred in the IUI with COH group, and one, in the IUI without COH group. Conclusion(s): In couples with an abnormal PCT and a poor prognosis, IUI with COH leads to pregnancy rates comparable to those for IUI without COH. We propose to perform IUI without COH in couples with an abnormal PCT. [Copyright &y& Elsevier]

Abstract: Objective. : To study the accuracy of magnetic resonance imaging (MRI) in lymph node detection in patients with vulva carcinoma. Methods. : Sixty patients with diagnosed vulva carcinoma underwent MRI examination for preoperative evaluation of lymph nodes. MRI images were read independently and retrospectively by two radiologists, both unaware of physical examination and surgery findings. The following characteristics of each lymph node with a short-axis diameter of ≥8 mm were recorded: size (axial, sagittal and coronal); aspect (homogeneous, with fatty center or partial fat); margin (smooth, lobulated/speculated or indistinct); shape: (round, ovoid or elongated). Based on these characteristics, each lymph node was classified as malignant or benign and subsequently each groin was classified as malignant or benign. Histopathology obtained at sentinel node procedure or by inguinofemoral lymphadenectomy was used as reference standard. Per groin sensitivity, specificity, positive and negative predictive values were calculated. Kappa statistics on per groin basis were calculated to express interobserver agreement. Results. : One hundred nineteen groins were examined either by sentinel node procedure or surgery, of which 23 groins were malignant. Sensitivity, specificity, positive and negative predictive values were 52%, 85%, 46% and 87% for observer 1 and 52% 89%, 52% and 89% for observer 2. The interobserver agreement was 104/119 (kappa 0.62), representing good agreement. Conclusion. : At this stage there is no role for standard MRI in evaluating lymph node involvement in patients with vulva carcinoma. [Copyright &y& Elsevier]

Summary: Experimental studies in animals show that prenatal undernutrition leads to lifelong alterations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Some studies have shown associations between low birth weight and an increased HPA response to psychological stress. We tested the hypothesis that prenatal exposure to the Dutch 1944–1945 famine leads to an elevated HPA response to psychological stress in adult life. We measured salivary cortisol responses to a psychological stress protocol among 694 adults who were born as term singletons in Amsterdam, the Netherlands, around the time of the 1944–1945 Dutch famine. We compared cortisol profiles of participants exposed to famine during late , mid , or early gestation to profiles of participants unexposed to famine during gestation . The mean increase in cortisol concentrations from baseline was 30% (95% CI 23–37). There were no statistically significant differences in the mean profile of cortisol response to the psychological stress protocol between participants exposed and unexposed to famine in utero. The mean sex and BMI adjusted difference in cortisol response for those exposed compared to those unexposed was −6% (95% CI: −15 to 2). The cortisol profiles of those exposed in late (−4% [95% CI: −16 to 7]), mid (−9% [95% CI: −22 to 3]) or early gestation (−4% [95% CI: −20 to 10]) did not differ from the profile of those unexposed to famine. We conclude that prenatal exposure to famine does not seem to be associated with the response of the HPA axis to psychological stress. However, the stress protocol we have used may have been unsuccessful in inducing a strong enough HPA axis activation to be able to detect famine related differences. [Copyright &y& Elsevier]

Objective: To investigate patient preferences and trade-offs for laparoscopic electrocautery of the ovaries relative to ovulation induction with recombinant FSH (rFSH) in patients with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). Design: Assessment of preferences and trade-offs in a randomized controlled trial. Setting: Academic hospital. Patient(s): Thirty-two CC-resistant patients with PCOS who had been randomly assigned to either laparoscopic electrocautery of the ovaries or ovulation induction with rFSH and 32 control patients with PCOS under treatment with CC. Intervention(s): Preference for laparoscopic electrocautery relative to rFSH was established during an interview. Trade-offs between treatment burden and effectiveness were evaluated by varying hypothetical pregnancy rates after laparoscopic electrocautery until patients switched in their initial preference. Main Outcome Measure(s): Preference for laparoscopic electrocautery of the ovaries; trade-off between burden and effectiveness of treatment. Result(s): The majority of the patients would prefer electrocautery of the ovaries over ovulation induction with rFSH if both treatment strategies resulted in similar pregnancy rates. However, most patients were willing to trade off their preference for increased effectiveness: the percentage of patients who preferred electrocautery over rFSH sharply declined when the difference in hypothetical pregnancy rates was more than 5% in favor of rFSH. Conclusion(s): Patients with polycystic ovary syndrome are well able to express an informed preference for laparoscopic electrocautery of the ovaries or ovulation induction with rFHS. Preferences are guided by features of the respective treatments but seem to be dominated by their effectiveness and safety. [Copyright &y& Elsevier]

Abstract: Background and objective: To review existing quality assessment tools for diagnostic accuracy studies and to examine to what extent quality was assessed and incorporated in diagnostic systematic reviews. Methods: Electronic databases were searched for tools to assess the quality of studies of diagnostic accuracy or guides for conducting, reporting or interpreting such studies. The Database of Abstracts of Reviews of Effects (DARE; 1995–2001) was used to identify systematic reviews of diagnostic studies to examine the practice of quality assessment of primary studies. Results: Ninety-one quality assessment tools were identified. Only two provided details of tool development, and only a small proportion provided any indication of the aspects of quality they aimed to assess. None of the tools had been systematically evaluated. We identified 114 systematic reviews, of which 58 (51%) had performed an explicit quality assessment and were further examined. The majority of reviews used more than one method of incorporating quality. Conclusion: Most tools to assess the quality of diagnostic accuracy studies do not start from a well-defined definition of quality. None has been systematically evaluated. The majority of existing systematic reviews fail to take differences in quality into account. Reviewers should consider quality as a possible source of heterogeneity. [Copyright &y& Elsevier]

Background: Deep-brain stimulation through an electrode implanted in the thalamus was developed as an alternative to thalamotomy for the treatment of drug-resistant tremor. Stimulation is thought to be as effective as thalamotomy but to have fewer complications. We examined the effects of these two procedures on the functional abilities of patients with drug-resistant tremor due to Parkinson's disease, essential tremor, or multiple sclerosis. Methods: Sixty-eight patients (45 with Parkinson's disease, 13 with essential tremor, and 10 with multiple sclerosis) were randomly assigned to undergo thalamotomy or thalamic stimulation. The primary outcome measure was the change in functional abilities six months after surgery, as measured by the Frenchay Activities Index. Scores for this index can range from 0 to 60, with higher scores indicating better function. Secondary outcome measures were the severity of tremor, the number of adverse effects, and patients' assessment of the outcome. Results: Functional status improved more in the thalamic-stimulation group than in the thalamotomy group, as indicated by increases in the score for the Frenchay Activities Index (from 31.4 to 36.3 and from 32.0 to 32.5, respectively; difference between groups, 4.4 points; 95 percent confidence interval, 2.0 to 6.9). After adjustment for base-line characteristics, multivariate analysis also showed that the thalamic-stimulation group had greater improvement (difference between groups, 5.1 points; 95 percent confidence interval, 2.3 to 7.9). Tremor was suppressed completely or almost completely in 27 of 34 patients in the thalamotomy group and in 30 of 33 patients in the thalamic-stimulation group. One patient in the thalamic-stimulation group died perioperatively after an intracerebral hemorrhage. With the exception of this incident, thalamic stimulation was associated with significantly fewer adverse effects than thalamotomy. Functional status was reported as improved by 8 patients in the thalamotomy group, as compared with 18 patients in the thalamic-stimulation group (P=0.01). Conclusions: Thalamic stimulation and thalamotomy are equally effective for the suppression of drug-resistant tremor, but thalamic stimulation has fewer adverse effects and results in a greater improvement in function. (N Engl J Med 2000;342:461-8.) [ABSTRACT FROM AUTHOR]

To assess the performance and clinical value of the postwash total motile sperm count (postwash TMC) as a test to predict intrauterine insemination (IUI) outcome.Meta-analysis of diagnostic tests.Tertiary fertility center.Patients undergoing IUI.None.We detected 16 studies that reported on postwash TMC at insemination and IUI outcome. Summary receiver operating characteristics (ROC) curves indicated a reasonable predictive performance toward IUI outcome, and, at cut-off levels between 0.8 to 5 million motile spermatozoa, the postwash TMC provided a substantial discriminative performance. At these cut-off levels, the specificity of the postwash TMC, defined as the ability to predict failure to become pregnant, was as high as 100%; the sensitivity of the test, defined as the ability to predict pregnancy, was limited.The postwash TMC at insemination could potentially be used in counseling patients for either IUI or IVF. However, to enable patient counseling before the start of treatment, further studies are needed to establish the accuracy of a postwash TMC during the fertility workup rather than at insemination. [Copyright &y& Elsevier]

Effect of starting with hemodialysis compared with peritoneal dialysis in patients new on dialysis treatment: A randomized controlled trial. Background. Up-until-now, the survival and health-related quality of life of hemodialysis and peritoneal dialysis patients has only been compared in observational studies. These studies have reported small and opposing differences between both modalities. The aim of this study was to compare the outcome of hemodialysis as initial chronic dialysis treatment with that of peritoneal dialysis in a randomized controlled trial. Methods. All new dialysis patients from 38 dialysis centers in The Netherlands without indications against either modality were invited to participate. Patients were assigned to start with hemodialysis or peritoneal dialysis. The primary outcome was mean quality-adjusted life year (QALY) score. Secondary outcome was survival. Results. Due to the low inclusion rate, the trial was prematurely stopped after which 38 patients had been randomized: 18 patients to hemodialysis and 20 to peritoneal dialysis. The mean QALY score in the first 2 years was 59.1 (SD 12) for hemodialysis patients versus 54.0 (SD 19) for peritoneal dialysis patients, which constitutes a small difference in favor of hemodialysis of 5.1 (95%CI −7.3 to 17.6) After 5 years of follow-up, nine hemodialysis and five peritoneal dialysis patients had died, a significant difference in survival; hazard ration of hemodialysis versus peritoneal dialysis of 3.8 (95%CI 1.1 to 12.6). After adjustment for age, comorbidity, and primary kidney disease the hazard ratio was 3.6 (0.8 to 15.4). Conclusion. Only a small difference in QALY score was observed between patients who started with hemodialysis compared to patients who started with peritoneal dialysis, lending support for the equivalence hypothesis. The significant difference in longer-term survival, which favored peritoneal dialysis in this small group of patients, could be used to posit that incident dialysis patients might benefit from starting on peritoneal dialysis. [ABSTRACT FROM AUTHOR]

Diagnostic testing can be used to discriminate subjects with a target disorder from subjects without it. Several indicators of diagnostic performance have been proposed, such as sensitivity and specificity. Using paired indicators can be a disadvantage in comparing the performance of competing tests, especially if one test does not outperform the other on both indicators. Here we propose the use of the odds ratio as a single indicator of diagnostic performance. The diagnostic odds ratio is closely linked to existing indicators, it facilitates formal meta-analysis of studies on diagnostic test performance, and it is derived from logistic models, which allow for the inclusion of additional variables to correct for heterogeneity. A disadvantage is the impossibility of weighing the true positive and false positive rate separately. In this article the application of the diagnostic odds ratio in test evaluation is illustrated. [Copyright &y& Elsevier]

: ObjectiveThe goal of this article is to systematically review the available evidence on the diagnostic performance of computed tomography (CT) and magnetic resonance imaging (MRI) in staging of cervical carcinoma.: MethodsA comprehensive computer literature search was performed in MEDLINE and EMBASE databases from January 1985 to May 2002. Two reviewers independently scored methodological quality of included studies and extracted relevant data for data analysis. A bivariate random effect approach was used to summarize estimates of sensitivity and specificity values. Covariates were added to this model to study the influence of sample size, publication year, methodological criteria, and MRI techniques on summary estimates.: ResultsFifty-seven articles were included. In 49 articles one imaging modality was evaluated (MRI, 38; CT, 11), and in 8 articles, both. Inclusion criteria were: minimum of 10 patients included, histopathology as reference standard, sufficient data presented to construct 2(×) 2 tables. The exclusion criterion was: data reported elsewhere in more detail. Sensitivity estimates for parametrial invasion were 74% (95% C: 68–79%) for MRI and 55% (95% CI: 44–66%) for CT, and for lymph node involvement, 60% (95% CI 52%–68%) and 43% (95% CI: 37–57%), respectively. MRI and CT had comparable specificities for parametrial invasion and lymph node involvement. For bladder invasion and rectum invasion the sensitivities for MRI were respectively 75% (95% CI: 66–83%) and 71% (95% CI: 53–83%), higher compared with CT. The specificity in evaluating bladder invasion for MRI was significantly higher compared with CT: 91% (95% CI: 83–95%) for MRI and 73% (95% CI: 52–87%) for CT. The specificities for rectum invasion were comparable. Differences in patient sample size, publication year, methodological criteria, and MRI techniques had no effect on the summary estimates.: ConclusionFor overall staging of cervical carcinoma, MRI is more accurate than CT. [Copyright &y& Elsevier]

Background Ankle decision rules help to determine which patients with ankle injuries should undergo radiography. However, these rules are limited by imperfect generalizability and sensitivity. The judgement of physicians, aided by structured data collection, is a potential alternative. We compared the diagnostic performance of 2 decision rules with the performance of physicians, aided by structured data collection, in ruling out fracture in patients with acute ankle injury. Methods Consecutive patients with acute ankle injury who visited the emergency department of a teaching community hospital in Amsterdam were included in the study. After taking the patient's history and performing a physical examination, the surgical resident in each case completed a specially developed structured data form incorporating all of the variables in the Ottawa and Leiden ankle rules, as well as some additional variables. The form then asked whether the resident thought radiography was necessary. Each patient then underwent ankle and midfoot radiography. The films were independently interpreted by a radiologist and a trauma surgeon, who were both blinded to the information on the data form. Sensitivity, specificity and the percentage of patients for whom radiography was recommended were the main outcome measures. Results Of 690 consecutive patients, 647 met the inclusion criteria. Fractures were observed in 74 (11%) of these patients. Sensitivity was 89% (95% confidence interval [CI] 80% to 95%) for the Ottawa ankle rules, 80% (95% CI 69% to 88%) for the Leiden ankle rule and 82% (95% CI 72% to 90%) for physicians' judgement. Specificity was 26% (95% CI 23% to 30%), 59% (95% CI 55% to 63%) and 68% (95% CI 64% to 71%) respectively. Radiography was recommended in 76% (95% CI 72% to 79%), 46% (95% CI 42% to 50%) and 38% (95% CI 34% to 42%) of cases respectively. The Ottawa rules missed 8 fractures, of which 1 was clinically significant, the Leiden rule missed 15 fractures, of which 5... [ABSTRACT FROM AUTHOR]

Reports on a study of the diagnostic performance of magnetic resonance angiography (MRA) in patients with lower extremity arterial disease. Data Sources; Study Selection; Data extraction; Data synthesis; Conclusion.

Objective: To evaluate whether ovarian reserve tests (ORTs) add prognostic value to patient characteristics, such as female age, in the prediction of excessive response to ovarian hyperstimulation in patients undergoing IVF, and whether their performance differs across clinical subgroups. Design: Authors of studies reporting on basal FSH, antimüllerian hormone (AMH), or antral follicle count (AFC) in relation to ovarian response to ovarian hyperstimulation were invited to share original data. Random intercept logistic regression models were used to estimate added value of ORTs on patient characteristics, while accounting for between-study heterogeneity. Receiver operating characteristic regression analyses were performed to study the effect of patient characteristics on ORT accuracy. Setting: In vitro fertilization clinics. Patient(s): A total of 4,786 women for the main analysis, with a subgroup of 1,023 women with information on all three ORTs. Intervention(s): None. Main Outcome Measure(s): Excessive response prediction. Result(s): We included 57 studies reporting on 32 databases. Female age had an area under the receiver operating characteristic curve of 0.61 for excessive response prediction. Antral follicle count and AMH significantly added prognostic value to this. A model with female age, AFC, and AMH had an area under the receiver operating characteristic curve of 0.85. The combination of AMH and AFC, without age, had similar accuracy. Subgroup analysis indicated that FSH performed significantly worse in predicting excessive response in higher age groups, AFC did significantly better, and AMH performed the same. Conclusion(s): We demonstrate that AFC and AMH add value to female age in the prediction of excessive response and that, for AFC and FSH, the discriminatory performance is affected by female age. [ABSTRACT FROM AUTHOR]

Objective: To evaluate to what extent couples carrying a balanced structural chromosome abnormality follow up the advice to opt for invasive prenatal diagnosis (PND) in subsequent pregnancies. Design: Index–control study. Setting: Six centers for Clinical Genetics in The Netherlands. Patient(s): Couples referred for chromosome analysis after recurrent miscarriage between 1992 and 2001 and with at least one pregnancy after disclosure; 239 carrier couples and 389 noncarrier couples. Intervention(s): Questionnaire, medical record checking. Main Outcome Measure(s): Uptake of invasive PND. Result(s): Only 53 of 239 (22%) carrier couples underwent a PND procedure (CVS or amniocentesis) in all subsequent pregnancies. A relatively high number, 105 (44%) carrier couples, refrained from PND in all subsequent pregnancies. More carrier couples with maternal age ≥36 years (20/33 = 61%) refrained from PND, compared with carrier couples with maternal age <36 years (85/206 = 41%). In women ≥36 years, an equal proportion of carrier and noncarrier couples refrained from PND (61% vs. 54%). Conclusion(s): The advice to opt for invasive PND in carrier couples is poorly followed, especially in carrier couples with maternal age ≥36 years. The motivations of carrier couples to opt for or refrain from invasive PND procedures should be the topic for further research to optimize clinical care and informative decision making. [Copyright &y& Elsevier]

Background: Methotrexate and cyclosporine are well-known systemic therapies for moderate-to-severe chronic plaque psoriasis. We conduced a randomized, controlled trial comparing methotrexate and cyclosporine in terms of effectiveness, side effects, and the quality of life. Methods: A total of 88 patients with moderate-to-severe psoriasis were randomly assigned to treatment for 16 weeks with either methotrexate (44 patients; initial dose, 15 mg per week) or cyclosporine (44 patients; initial dose, 3 mg per kilogram of body weight per day) and were followed for another 36 weeks. The primary outcome was the difference between groups in the psoriasis area-and-severity index after 16 weeks of treatment, after adjustment for base-line values; scores were determined in a blinded fashion by trained observers. Results: Two patients were excluded from the analysis after randomization because they were found to be ineligible, and one patient withdrew his consent. Twelve patients in the methotrexate group had to discontinue treatment because of reversible elevations in liver-enzyme levels, and 1 patient in the cyclosporine group had to do so because of an elevation in the bilirubin level, but all 13 were included in the analysis. After 16 weeks of treatment, the mean (±SE) score for the psoriasis area-and-severity index decreased from 13.4±3.6 at base line to 5.0±0.7 among 43 patients treated with methotrexate, whereas the score decreased from 14.0±6.6 to 3.8±0.5 among 42 patients treated with cyclosporine. After adjustment for base-line values, the mean absolute difference in values at 16 weeks was 1.3 (95 percent confidence interval, –0.2 to 2.8; P=0.09). The physician's global assessment of the extent of psoriasis, the time to and the rates of remission, and the quality of life were similar in the two groups. Conclusions: No significant differences in efficacy were found between methotrexate and cyclosporine for the treatment of moderate-to-severe psoriasis. N Engl J Med 2003;349:658-65. [ABSTRACT FROM AUTHOR]

Background: Port-wine stains can be treated with a flash-lamp–pumped pulsed-dye laser, but it is uncertain whether this treatment is more effective if administered early in life, when the skin is thinner and the lesion is smaller. Methods: We prospectively studied 100 patients with a previously untreated port-wine stain of the head or neck. They were treated with the flash-lamp–pumped pulsed-dye laser and divided into four age groups (0 to 5, 6 to 11, 12 to 17, and 18 to 31 years). The outcome measure was lightening of the port-wine stain (reduction in the difference in color between the skin with the stain and contralateral healthy skin) as measured with a colorimeter after an average of five treatments (range, three to seven) of the entire lesion. Results: Of the 100 patients, 11 could not be included in the analysis because they had received fewer than three or more than seven treatments, had an erroneous base-line color measurement, or were lost to follow-up. The sizes, locations, and colors of the port-wine stains were similar among the groups. When all 89 patients were analyzed together, the average reduction in the difference in color between the skin with the port-wine stain and contralateral healthy skin was 40 percent. The differences between age groups in the average reduction in color differences were not significant (P = 0.26). By the end of the study, only 7 of 89 patients had completed laser therapy, and in no case was clearance complete. Treatment was discontinued in all seven because the last three treatments did not lead to further lightening. Conclusions: We found no evidence that treatment of port-wine stains with the flash-lamp–pumped pulsed-dye laser in early childhood is more effective than treatment at a later age. (N Engl J Med 1998;338:1028-33.) [ABSTRACT FROM AUTHOR]