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Background Diagnostic tests play a crucial role during an epidemic or a pandemic, both for individual patient care, and as a tool in population-level non-pharmaceutical interventions. The development and evaluation of such tests during epidemics faces numerous challenges, including short timeframes, and changing disease prevalence, pathogen characteristics, and testing applications. In this position paper, we describe these challenges through an interdisciplinary lens and present potential solutions, based on experiences during the SARS-CoV-2 pandemic. Methods We conducted a workshop that brought together experts from various disciplines involved in diagnostic test development and evaluation, from molecular test development to public health decision-making. The challenges and potential solutions we discuss are derived from discussions had and conclusions drawn in the workshop. Results We identified a feedback loop between evaluation of test accuracy, integration of test accuracy estimates in modelling studies for public health decision-making, and population-level interventions that determine testing strategies, and can define how diagnostic tests might need re-evaluation. Incorporating this feedback loop into test evaluation can help diagnostic test development be optimised for both individual patient care and population level measures. Furthermore, adaptive and seamless designs for diagnostic studies provide a promising methodological solution to narrow timeframes and the need for continuous re-evaluation of diagnostic tests during epidemic or pandemic situations. Conclusions We present a framework for diagnostic test development and evaluation that acknowledges the feedback loop between diagnostic test studies and infectious disease modelling studies, and provides solutions to challenges faced in test development and evaluation during outbreaks of emerging infectious agents.

ObjectivesTo compare paediatric healthcare practice variation among five European emergency departments (EDs) by analysing variability in decisions about diagnostic testing, treatment and admission.Design and populationConsecutive paediatric visits in five European EDs in four countries (Austria, Netherlands, Portugal, UK) were prospectively collected during a study period of 9–36 months (2012–2015).Primary outcome measuresPractice variation was studied for the following management measures: lab testing, imaging, administration of intravenous medication and patient disposition after assessment at the ED.AnalysisMultivariable logistic regression was used to adjust for general patient characteristics and markers of disease severity. To assess whether ED was significantly associated with management, the goodness-of-fit of regression models based on all variables with and without ED as explanatory variable was compared. Management measures were analysed across different categories of presenting complaints.ResultsData from 111 922 children were included, with a median age of 4 years (IQR 1.7–9.4). There were large differences in frequencies of Manchester Triage System (MTS) urgency and selected MTS presentational flow charts. ED was a significant covariate for management measures. The variability in management among EDs was fairly consistent across different presenting complaints after adjustment for confounders. Adjusted OR (aOR) for laboratory testing were consistently higher in one hospital while aOR for imaging were consistently higher in another hospital. Iv administration of medication and fluids and admission was significantly more likely in two other hospitals, compared with others, for most presenting complaints.ConclusionsDistinctive hospital-specific patterns in variability of management could be observed in these five paediatric EDs, which were consistent across different groups of clinical presentations. This could indicate fundamental differences in paediatric healthcare practice, influenced by differences in factors such as organisation of primary care, diagnostic facilities and available beds, professional culture and patient expectations.

BackgroundTimely diagnosis of heart failure (HF) is essential to optimize treatment opportunities that improve symptoms, quality of life, and survival. While most patients consult their general practitioner (GP) prior to HF, early stages of HF may be difficult to identify. An integrated clinical support tool may aid in identifying patients at high risk of HF. We therefore constructed a prediction model using routine health care data.MethodsOur study involved a dynamic cohort of patients (≥35 years) who consulted their GP with either dyspnea and/or peripheral edema within the Amsterdam metropolitan area in 2011-2020. The outcome of interest was incident HF, verified by an expert panel. We developed a regularized multivariable proportional hazards model (TARGET-HF). The model was evaluated with bootstrapping on an isolated validation set and compared to an existing model developed with hospital insurance data as well as patient age as a sole predictor.ResultsData from 31,905 patients were included (40% male, median age 60) of whom 1,301 (4.1%) were diagnosed with HF over 124,676 person-years of follow-up. Data were allocated to a development (n=25,524) and validation (n=6,381) set. TARGET-HF attained a C-statistic of 0.853 (95%-CI:0.834-0.872) on the validation set, which proved to provide a better discrimination than C=0.822 for age alone (95% CI:0.801-0.842, pConclusionThe TARGET-HF model illustrates that routine consultation codes can be used to build a performant model to identify patients at risk for HF at time of GP consultation.

Uvod: Preporučene smjernice za izvještavanje u sustavnim pregledima i metaanalizama (engl. Preferred Reporting Items for Systematic reviews and Meta-Analyses, PRISMA) prvi su puta objavljene 2009. godine kako bi autorima sustavnih pregleda omogućile transparentno izvještavanje o predmetu istraživanja, korištenim metodama i dobivenim rezultatima. Tijekom posljednjeg desetljeća postignut je značajan napredak u metodologiji i terminologiji sustavnih pregleda, što je rezultiralo potrebom za nadopunjavanjem i prilagođavanjem postojećih smjernica. Svrha rada: Predstaviti ažurirane smjernice PRISMA 2020. za izvještavanje u sustavnim pregledima. Metode: Pregledali smo 60 dokumenata sa smjernicama za izvještavanje u sustavnim pregledima s ciljem obuhvaćanja predloženih izmjena smjernica PRISMA iz 2009. godine. Tražili smo povratne informacije o predloženim izmjenama pomoću internetske ankete provedene među 110 urednika časopisa i metodologa sustavnih pregleda. O rezultatima anketa i pregleda raspravljalo se na sastanku na kojem je sudjelovao 21 član. Nakon sastanka, temeljem povratnih informacija koautora i prigodnog uzorka od 15 recenzenata sustavnih pregleda, generirali smo koncept za kontrolni popis PRISMA 2020., sažetak kontrolnog popisa, razradu i objašnjenje te dijagram toka. Rezultati: U ovom radu predstavljamo kontrolni popis za smjernice PRISMA 2020. sastavljene od 27 stavki, odnosno prošireni kontrolni popis s detaljnim preporukama za izvještavanje pojedine stavke, sažetak kontrolnog popisa PRISMA 2020. te revidirane dijagrame toka za izvorne i ažurirane preglede. Kontrolni popis uključuje nove smjernice za izvještavanje koje sadrže ažurirane metode identifikacije, odabira, procjene i sinteze istraživanja. Struktura i prikaz stavaka su izmijenjeni kako bi se olakšala njihova provedba. Smjernice PRISMA 2020. zamjenjuju smjernice iz 2009. godine. Zaključak: Svrha smjernica PRISMA 2020. je olakšati transparentnost, cjelovitost i točnost izvještavanja u sustavnim pregledima. Poboljšano izvještavanje koristiti će autorima sustavnih pregleda, autorima smjernica, kreatorima politike, zdravstvenim radnicima, pacijentima i drugim korisnicima. U svrhu postizanja navedenih ciljeva potičemo autore, urednike i recenzente da usvoje predstavljene smjernice.

Systematic reviews of diagnostic test accuracy (DTA) studies are fundamental to the decision-making process in evidence-based medicine. Although such studies are regarded as high-level evidence, these reviews are not always reported completely and transparently. Sub-optimal reporting of DTA systematic reviews compromises their validity and generalizability, and subsequently their value to key stakeholders. PRISMA-DTA, an extension of the PRISMA statement, was recently developed to improve the quality of reporting of DTA systematic reviews. The PRISMA-DTA statement consists of 27 items, of which 8 are unmodified from the original PRISMA statement. This document provides an explanation for the 19 new and modified items, along with their meaning and rationale. Examples of complete reporting are used for each item to illustrate best practices. The PRISMA-DTA statement, this explanation and elaboration document, and the associated web site (http://www.prisma-statement.org/Extensions/DTA) provide resources to support the complete and transparent reporting of DTA systematic reviews.

Objectives: To describe the grading of recommendations assessment, development and evaluation (GRADE) interactive evidence to decision (EtD) frameworks for tests and test strategies for clinical, public health, or coverage decisions. Study Design and Setting: As part of the GRADE Working Group's DECIDE project, we conducted workshops, user testing with systematic review authors, guideline developers and other decision makers, and piloted versions of the EtD framework. Results: EtD frameworks for tests share the structure, explicitness, and transparency of other EtD frameworks. They require specifying the purpose of the test, linked or related management, and the key outcomes of concern for different test results and subsequent management. The EtD criteria address test accuracy and assessments of the certainty of the additional evidence necessary for decision making. When there is no direct evidence of test effects on patient-important outcomes, formal or informal modeling is needed to estimate effects. We describe the EtD criteria based on examples developed with GRADEpro (www.gradepro.org), GRADE's software that also allows development and dissemination of interactive summary of findings tables. Conclusion: EtD frameworks for developing recommendations and making decisions about tests lay out the sequential steps in reviewing and assessing the different types of evidence that need to be linked. (C) 2016 Elsevier Inc. All rights reserved.

BACKGROUND: About 10% of reproductive‐aged women suffer from endometriosis, a costly chronic disease causing pelvic pain and subfertility. Laparoscopy is the gold standard diagnostic test for endometriosis, but is expensive and carries surgical risks. Currently, there are no non‐invasive or minimally invasive tests available in clinical practice to accurately diagnose endometriosis. Although other reviews have assessed the ability of blood tests to diagnose endometriosis, this is the first review to use Cochrane methods, providing an update on the rapidly expanding literature in this field. OBJECTIVES: To evaluate blood biomarkers as replacement tests for diagnostic surgery and as triage tests to inform decisions on surgery for endometriosis. Specific objectives include: 1. To provide summary estimates of the diagnostic accuracy of blood biomarkers for the diagnosis of peritoneal, ovarian and deep infiltrating pelvic endometriosis, compared to surgical diagnosis as a reference standard. 2. To assess the diagnostic utility of biomarkers that could differentiate ovarian endometrioma from other ovarian masses. SEARCH METHODS: We did not restrict the searches to particular study designs, language or publication dates. We searched CENTRAL to July 2015, MEDLINE and EMBASE to May 2015, as well as these databases to 20 April 2015: CINAHL, PsycINFO, Web of Science, LILACS, OAIster, TRIP, ClinicalTrials.gov, DARE and PubMed. SELECTION CRITERIA: We considered published, peer‐reviewed, randomised controlled or cross‐sectional studies of any size, including prospectively collected samples from any population of reproductive‐aged women suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). We included studies comparing the diagnostic test accuracy of one or more blood biomarkers with the findings of surgical visualisation of endometriotic lesions. DATA COLLECTION AND ANALYSIS: Two authors independently collected and performed a quality assessment of data from each study. For each diagnostic test, we classified the data as positive or negative for the surgical detection of endometriosis, and we calculated sensitivity and specificity estimates. We used the bivariate model to obtain pooled estimates of sensitivity and specificity whenever sufficient datasets were available. The predetermined criteria for a clinically useful blood test to replace diagnostic surgery were a sensitivity of 0.94 and a specificity of 0.79 to detect endometriosis. We set the criteria for triage tests at a sensitivity of ≥ 0.95 and a specificity of ≥ 0.50, which 'rules out' the diagnosis with high accuracy if there is a negative test result (SnOUT test), or a sensitivity of ≥ 0.50 and a specificity of ≥ 0.95, which 'rules in' the diagnosis with high accuracy if there is a positive result (SpIN test). MAIN RESULTS: We included 141 studies that involved 15,141 participants and evaluated 122 blood biomarkers. All the studies were of poor methodological quality. Studies evaluated the blood biomarkers either in a specific phase of the menstrual cycle or irrespective of the cycle phase, and they tested for them in serum, plasma or whole blood. Included women were a selected population with a high frequency of endometriosis (10% to 85%), in which surgery was indicated for endometriosis, infertility work‐up or ovarian mass. Seventy studies evaluated the diagnostic performance of 47 blood biomarkers for endometriosis (44 single‐marker tests and 30 combined tests of two to six blood biomarkers). These were angiogenesis/growth factors, apoptosis markers, cell adhesion molecules, high‐throughput markers, hormonal markers, immune system/inflammatory markers, oxidative stress markers, microRNAs, tumour markers and other proteins. Most of these biomarkers were assessed in small individual studies, often using different cut‐off thresholds, and we could only perform meta‐analyses on the data sets for anti‐endometrial antibodies, interleukin‐6 (IL‐6), cancer antigen‐19.9 (CA‐19.9) and CA‐125. Diagnostic estimates varied significantly between studies for each of these biomarkers, and CA‐125 was the only marker with sufficient data to reliably assess sources of heterogeneity. The mean sensitivities and specificities of anti‐endometrial antibodies (4 studies, 759 women) were 0.81 (95% confidence interval (CI) 0.76 to 0.87) and 0.75 (95% CI 0.46 to 1.00). For IL‐6, with a cut‐off value of > 1.90 to 2.00 pg/ml (3 studies, 309 women), sensitivity was 0.63 (95% CI 0.52 to 0.75) and specificity was 0.69 (95% CI 0.57 to 0.82). For CA‐19.9, with a cut‐off value of > 37.0 IU/ml (3 studies, 330 women), sensitivity was 0.36 (95% CI 0.26 to 0.45) and specificity was 0.87 (95% CI 0.75 to 0.99). Studies assessed CA‐125 at different thresholds, demonstrating the following mean sensitivities and specificities: for cut‐off > 10.0 to 14.7 U/ml: 0.70 (95% CI 0.63 to 0.77) and 0.64 (95% CI 0.47 to 0.82); for cut‐off > 16.0 to 17.6 U/ml: 0.56 (95% CI 0.24, 0.88) and 0.91 (95% CI 0.75, 1.00); for cut‐off > 20.0 U/ml: 0.67 (95% CI 0.50 to 0.85) and 0.69 (95% CI 0.58 to 0.80); for cut‐off > 25.0 to 26.0 U/ml: 0.73 (95% CI 0.67 to 0.79) and 0.70 (95% CI 0.63 to 0.77); for cut‐off > 30.0 to 33.0 U/ml: 0.62 (95% CI 0.45 to 0.79) and 0.76 (95% CI 0.53 to 1.00); and for cut‐off > 35.0 to 36.0 U/ml: 0.40 (95% CI 0.32 to 0.49) and 0.91 (95% CI 0.88 to 0.94). We could not statistically evaluate other biomarkers meaningfully, including biomarkers that were assessed for their ability to differentiate endometrioma from other benign ovarian cysts. Eighty‐two studies evaluated 97 biomarkers that did not differentiate women with endometriosis from disease‐free controls. Of these, 22 biomarkers demonstrated conflicting results, with some studies showing differential expression and others no evidence of a difference between the endometriosis and control groups. AUTHORS' CONCLUSIONS: Of the biomarkers that were subjected to meta‐analysis, none consistently met the criteria for a replacement or triage diagnostic test. A subset of blood biomarkers could prove useful either for detecting pelvic endometriosis or for differentiating ovarian endometrioma from other benign ovarian masses, but there was insufficient evidence to draw meaningful conclusions. Overall, none of the biomarkers displayed enough accuracy to be used clinically outside a research setting. We also identified blood biomarkers that demonstrated no diagnostic value in endometriosis and recommend focusing research resources on evaluating other more clinically useful biomarkers.

SUMMARY The results are presented of a follow-up study of 155 Dutch children after the first febrile seizure. Of these initially untreated children 37 per cent had had at least one, 30 per cent at least two and 17 per cent at least three subsequent seizures. The vulnerable period for recurrent seizures after the first febrile seizure was between 12 and 24 months, whereafter the risk was four to five times lower; after any seizure the risk was highest within the first six months, declining steadily after six months without seizures. A first-degree family history of any type of seizure predicted multiple recurrences; an age of at least 30 months and a temperature of 40dC at initial seizure were associated with reduced risk. Factors in combination influenced the risk of recurrent seizures, sometimes in opposite ways. ReSUMe Rŕcidives de crises comitiales apres une premiere crise hyperthermique: une approche multivariŕe L'article rapporte les rŕsultats d'une ŕtude longitudinale de 155 enfants hollandais apres une premiere crise hyperthermique. Parmi ces enfants initialement non traitŕs, 37 pour cent avaient eu au moins une crise ultŕrieure, 30 pour cent au moins deux crises et 17 pour cent au moins trois crises. La pŕriode sensible pour le retour de crises ŕtait comprise entre 12 et 24 mois, le risque ultŕrieur ŕtant quatre ou cinq fois plus faible; apres n'importe quelle crise, le risque maximal se situait dans les six mois suivants, dŕclinant rapidement apres six mois sans crises. Une histoire familiale de n'importe quel type de crise dans les relations au premier degrŕ conduisait a prŕvoir de multiples rŕcidives; a un âge d'au moins 30 mois et a une tempŕrature ŕgale ou supŕrieure a 40dC lors de la crise initiale, le risque de rŕcidive ŕtait rŕduit. Les facteurs associŕs modifient le risque de rŕcidive, agissant parfois de facon opposŕe. ZUSAMMENFASSUNG Wiederauftreten von Anfallen nach dem ersten Fieberkrampf: eine Multivarianzanalyse Es werden die Ergebnisse einer Kontrollstudie bei 155 hollandischen Kindern nach ihrem ersten Fieberkrampf dargestellt. Von diesen zunachst unbehandelten Kindern hatten 37 Prozent mindestens einen, 30 Prozent zwei und 17 Prozent drei weitere Anfalle. Die vulnerable Phase fur Anfallsrezidive nach dem ersten Fieberkrampf war zwischen 12 und 24 Monaten, danach war das Risiko vier bis funf Mal geringer; nach jedem Anfall war das Risiko innerhalb der ersten sechs Monate am hochsten und fiel nach sechs anfallfreien Monaten stetig ab. Ein Anfallsleiden bei Familienangehorigen ersten Grades bedeutete multiple Rezidive. Ein Alter von mindestens 30 Monaten und eine Temperatur von ≥ 40° beim ersten Krampfanfall waren mit einem geringeren Risiko verbunden. Die Kombination von Faktoren beeinfluste das Risiko fur Anfallsrezidive, gelegentlich in kontrarer Wiese. RESUMEN Recurrencia de convulsiones despuŕs de una convulsion febril. Enfoque multivariado Se presenta los resultados de un estudio sobre el curso de 155 ninos holandeses despuŕs de una convulsion febril. De estos ninos, no tratados inicialmente, el 37 por ciento habian tenido por lo menos una, el 30 por ciento por lo menos dos y el 17 por ciento por lo menos tres convulsiones consecutivas. El periodo vulnerable para las convulsiones recurrentes despuŕs de la primera convulsion febril fue de 12 a 24 meses. Mas adelante el riesgo era de cuatro a cinco veces menor. Despuŕs de cualquier convulsion el riesgo era maximo dentro de los primeros seis meses, para disminuir despuŕs de forma constante despuŕs de seis meses sin convulsiones. Una historia familiar de primer grado de cualquier tipo de convulsion era predictiva de multiples recurrencias. Una edad de por lo menos 30 meses y una temperatura de ≥ 40° en la convulsion inicial iban asociados a un riesgo reducido. La combinacion de diversos factores influye sobre el riesgo de convulsiones recurrentes a veces en sentidos opuestos.

Deville WLJM, Bossuyt PMM. Beoordeling van de kwaliteit van rapportage van diagnostisch onderzoek. Huisarts Wet 2004;47(7):340-5.

Cost-effectiveness information can help health-system participants make decisions about diagnostic or therapeutic innovations that are more expensive but incrementally safe and effective. However, these analyses cannot help decide whether a less expensive approach is "sufficient" and funds ought to be allocated to other medical issues entirely. At present, formulary committees are commonly determining that medications are "mostly equivalent" in efficacy and safety and choosing individual medications or classes of medications based on cost. Clinicians may not agree with these decisions and will need to understand their rationale. For prophylaxis of venous thromboembolism after hip and knee replacement and hip fracture surgery, many preventive modalities are available with different safety and efficacy profiles and different costs. It is possible to list the important safety and efficacy outcomes of prophylaxis, estimate their incidences and costs, and "model" comparisons of one modality vs another, in order to help decide whether one is preferable.

Summary. Background: The selective antithrombotic fondaparinux is more effective than the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism (deep-vein thrombosis [DVT] or pulmonary embolism) in patients undergoing major orthopedic surgery, but its cost-effectiveness is undetermined. Objectives: To evaluate the cost-effectiveness of fondaparinux relative to enoxaparin as prophylaxis against venous thromboembolism (VTE) for patients undergoing total hip replacement, total knee replacement or hip fracture surgery in the UK. Patients/methods: A decision analysis model was created simulating the impact of fondaparinux and enoxaparin on patient outcomes and costs over various time points up to 5 years following surgery. The main outcome measures were treatment costs per patient and the incidence of clinical VTE and VTE-related deaths. A weighted (combined) cohort reflects the proportion of patients undergoing these procedures in 2000/2001. Results: In the combined cohort, compared with enoxaparin, fondaparinux is expected to produce 20 fewer clinical VTE events and 3.2 fewer VTE-related deaths per 1000 procedures at 5 years. Cost savings at 5 years are £27 per patient with fondaparinux (discounted at 6% per year). In each of the three surgical groups, fondaparinux leads to lower expected costs per patient and to a smaller number of VTE events and VTE-related deaths. Results are sensitive to the price difference between fondaparinux and enoxaparin and variation in the rate of late DVT. The analysis is robust to variations in all other key parameters. Conclusions: Compared with enoxaparin, fondaparinux is more effective and reduces costs to the healthcare system. At current prices, fondaparinux is the recommended strategy in the UK for prophylaxis following major orthopedic surgery.

Risk scores and accelerated diagnostic protocols can identify chest pain patients with low risk of major adverse cardiac event who could be discharged early from the ED, saving time and costs. We aimed to derive and validate a chest pain score and accelerated diagnostic protocol (ADP) that could safely increase the proportion of patients suitable for early discharge. Logistic regression identified statistical predictors for major adverse cardiac events in a derivation cohort. Statistical coefficients were converted to whole numbers to create a score. Clinician feedback was used to improve the clinical plausibility and the usability of the final score (Emergency Department Assessment of Chest pain Score [EDACS]). EDACS was combined with electrocardiogram results and troponin results at 0 and 2 h to develop an ADP (EDACS-ADP). The score and EDACS-ADP were validated and tested for reproducibility in separate cohorts of patients. In the derivation (n = 1974) and validation (n = 608) cohorts, the EDACS-ADP classified 42.2% (sensitivity 99.0%, specificity 49.9%) and 51.3% (sensitivity 100.0%, specificity 59.0%) as low risk of major adverse cardiac events, respectively. The intra-class correlation coefficient for categorisation of patients as low risk was 0.87. The EDACS-ADP identified approximately half of the patients presenting to the ED with possible cardiac chest pain as having low risk of short-term major adverse cardiac events, with high sensitivity. This is a significant improvement on similar, previously reported protocols. The EDACS-ADP is reproducible and has the potential to make considerable cost reductions to health systems

Background: A variety of systems have been developed to grade evidence and develop recommendations based on the available evidence. However, development of guidelines for medical tests is especially challenging given the typical indirectness of the evidence; direct evidence of the effects of testing on patient important outcomes is usually absent. We compared grading systems for medical tests on how they use evidence in guideline development.Methods: We used a systematic strategy to look for grading systems specific to medical tests in PubMed, professional guideline websites, via personal correspondence, and handsearching back references of key articles. Using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument as a starting point, we defined two sets of characteristics to describe these systems: methodological and process ones. Methodological characteristics are features relating to how evidence is gathered, appraised, and used in recommendations. Process characteristics are those relating to the guideline development process. Data were extracted in duplicate and differences resolved through discussion.Results: Twelve grading systems could be included. All varied in the degree to which methodological and process characteristics were addressed. Having a clinical scenario, identifying the care pathway and/or developing an analytical framework, having explicit criteria for appraising and linking indirect evidence, and having explicit methodologies for translating evidence into recommendations were least frequently addressed. Five systems at most addressed these, to varying degrees of explicitness and completeness. Process wise, features most frequently addressed included involvement of relevant professional groups (8/12), external peer review of completed guidelines (9/12), and recommendations on methods for dissemination (8/12). Characteristics least often addressed were whether the system was piloted (3/12) and funder information (3/12).Conclusions: Five systems for grading evidence about medical tests in guideline development addressed to differing degrees of explicitness the need for and appraisal of different bodies of evidence, the linking of such evidence, and its translation into recommendations. At present, no one system addressed the full complexity of gathering, assessing and linking different bodies of evidence.

Because many ongoing clinical restenosis prevention trials are using quantitative angiography to assess whether a drug is capable of reducing the amount of intimal hyperplasia, quantitative angiographic risk factors for angiographic luminal narrowing after balloon angioplasty were determined, including stretch and elastic recoil at the dilatation site. Quantitative analysis was performed on 666 lesions in 575 patients during angioplasty and at 6-month follow-up. Stretch was defined as balloon diameter minus minimal luminal diameter (MLD) before angioplasty/reference diameter, and recoil as balloon diameter minus MLD after angioplasty/reference diameter. Multivariate analysis was used to yield independent risk factors for luminal narrowing at follow-up. Predictors of absolute change in MLD were (1) relative gain at angioplasty (gain in millimeters normalized for reference diameter) and (2) lesion length. To allow risk stratification, logistic regression analysis was applied using the decrease in MLD as a binary outcome variable. A decrease in MLD at follow-up of greater than or equal to 0.72 mm was considered significant. Variables retained in the model were: relative gain greater than 0.3 mm (rate ratio 2.9), relative gain 0.2 to 0.3 (rate ratio 2.1), stenosis length greater than or equal to 6.8 (rate ratio 1.7), and thrombus after angioplasty (rate ratio 2.6). Although stretch was significantly related to luminal narrowing at univariate analysis, it was not retained in the multivariate models. A large gain in lumen diameter at angioplasty, dilation of long lesions, and angiographically determined thrombus after angioplasty were found to be accompanied by more severe luminal narrowing at follow-up.

Background A quality assessment tool for diagnostic accuracy studies, named QUADAS, has recently been developed. Although QUADAS has been used in several systematic reviews, it has not been formally validated. The objective was to evaluate the validity and usefulness of QUADAS. Methods Three reviewers independently rated the quality of 30 studies using QUADAS. We assessed the proportion of agreements between each reviewer and the final consensus rating. This was done for all QUADAS items combined and for each individual item. Twenty reviewers who had used QUADAS in their reviews completed a short structured questionnaire on their experience of QUADAS. Results Over all items, the agreements between each reviewer and the final consensus rating were 91%, 90% and 85%. The results for individual QUADAS items varied between 50% and 100% with a median value of 90%. Items related to uninterpretable test results and withdrawals led to the most disagreements. The feedback on the content of the tool was generally positive with only small numbers of reviewers reporting problems with coverage, ease of use, clarity of instructions and validity. Conclusion Major modifications to the content of QUADAS itself are not necessary. The evaluation highlighted particular difficulties in scoring the items on uninterpretable results and withdrawals. Revised guidelines for scoring these items are proposed. It is essential that reviewers tailor guidelines for scoring items to their review, and ensure that all reviewers are clear on how to score studies. Reviewers should consider whether all QUADAS items are relevant to their review, and whether additional quality items should be assessed as part of their review.

Cost-effectiveness information can help health-system participants make decisions about diagnostic or therapeutic innovations that are more expensive but incrementally safe and effective. However, these analyses cannot help decide whether a less expensive approach is "sufficient" and funds ought to be allocated to other medical issues entirely. At present, formulary committees are commonly determining that medications are "mostly equivalent" in efficacy and safety and choosing individual medications or classes of medications based on cost. Clinicians may not agree with these decisions and will need to understand their rationale. For prophylaxis of venous thromboembolism after hip and knee replacement and hip fracture surgery, many preventive modalities are available with different safety and efficacy profiles and different costs. It is possible to list the important safety and efficacy outcomes of prophylaxis, estimate their incidences and costs, and "model" comparisons of one modality vs another, in order to help decide whether one is preferable.

Patients who have undergone orthopaedic surgery represent a high-risk group for venous thromboembolism (VTE). Despite the routine prophylactic use of antithrombotic agents, patients still experience thrombotic events that can result in mortality and acute morbidity and, in significant numbers of patients, may lead to long-term consequences such as the post-thrombotic syndrome. Increasingly, initial VTE events occur after hospital discharge since the length of stay in hospital after major orthopaedic surgery has decreased in many countries. There is a need for further improvement in the prevention of VTE. As well as undergoing extensive safety and efficacy studies for registration purposes, new prophylactic strategies need to be evaluated from a pharmacoeconomic perspective to help guide their introduction into routine clinical practice. Over the past 15 years a number of pharmacoeconomic evaluation studies of VTE prophylaxis have been carried out in orthopaedic patients, most of which evaluated short-term clinical endpoints. During the same period, improvements in our understanding of the natural history of VTE as well as the emergence of new treatments have led to changes in the management of patients with, or at risk of, VTE. The aim of this paper was to address how best to conduct pharmacoeconomic analyses of new antithrombotic agents in light of changes in practice patterns for orthopaedic patients and greater understanding of the disease process. We put forward recommendations for relevant outcome measures, timeframes, endpoints and epidemiologic data sources. We also suggest a structure for a pharmacoeconomic model. In this model, the outcomes and costs of VTE-related care during both the acute and chronic phases of the disease are incorporated. Symptomatic deep vein thrombosis and pulmonary embolism, recurrent VTE, post-thrombotic syndrome, major hemorrhage and all-cause death are included. We also recommend that the relevance of quality-adjusted survival is investigated, and that economic appraisals are presented in both cost-consequence and budget-impact approaches. These recommendations are based on extensive examination of recent advances in the management of VTE combined with a greater understanding of its natural history.

Background Development of guidelines for medical tests are challenging given the indirectness of evidence on patient outcomes. We compared grading systems for medical tests in terms of basic guideline quality requirements and on how they use indirect evidence. Methods We used a systematic search to identify grading systems specific to medical tests in PubMed, professional guideline websites and handsearching back references of key articles. Using the AGREE instrument as a starting point, we defined two sets of characteristics to describe these systems: process and methodological ones. Process characteristics were features related to the guideline development process. Methodological characteristics were defined as features relating to how evidence is gathered, appraised and recommendations development. Data was extracted in duplicate and differences resolved through discussion. Results Twelve grading systems were included. Process characteristics least often addressed were whether the system was piloted (3/12) and funder information (3/12). Methodologically, developing a clinical scenario, care pathway and/or analytical framework, having explicit criteria for appraising and linking indirect evidence, and having explicit methodologies for translating evidence into recommendations were least frequently addressed. Five systems at most addressed these to varying degrees of completeness. Implications for Guideline Developers There is a need for standardisation of basic guideline features a grading system should address. No one system adequately addressed the complexity of gathering, assessing and linking different bodies of evidence. There is a need for critical appraisal of these features in each system and for targeted user testing among guideline developers.

In this section we will deal with the problem of how probabilistic unfolding theories can be evaluated. The approach that will be advocated has been hinted at in Chapter 2, in which properties of probabilistic choice behavior were explored. An examination of the properties of probabilistic choice behavior that are necessarily implied by a probabilistic choice theory resulted in a second classification of existing probabilistic unfolding theories. Looking at it from a different angle, one can consider the assumption that a particular property is satisfied in probabilities of choosing alternatives as axioms of alternative theories on probabilistic choice (Type I). Contrary to the theories presented in the Chapter 1 (Type II), these Type I theories are built then on assumed regularities in probabilistic choice behavior, instead of on some cognitive structure of a presupposed form, though the latter may (indirectly) lead to the same sort of regularities.

In this chapter we report on two experiments that were designed for a comparative evaluation of the applicability of existing theories on probabilistic unfolding, and in which the evaluation strategy unfolded in Chapter 3 and Chapter 4 was used. Each experiment consisted of a collection of paired comparisons tasks.

The method of paired comparisons is a technique for the collection of data used in a variety of fields such as acoustics, animal ecology, choice behavior, dentistry, economics, epidemiology, food science, marketing, optics, personnel testing, preference testing, psychometrics, sensory testing, sports, taste testing and others (David, 1988). Alternatives are presented in pairs to one or more subjects, who are asked to pick one of them. Making such a binary choice is probably the simplest of all choice tasks. For this reason, this method is primarily used in cases where judgements are necessarily subjective. The method is essentially due to Fechner, and several parametric and nonparametric methods for analyzing such data have been proposed ever since. Bradley (1976) and David (1988) have summarized most of these methodological approaches.

The customary approach to assess the applicability of a probabilistic choice theory is based on an appraisal of an index of the goodness-of-fit between a model of the theory and a model of data, such as the likelihood of the data as a function of the model. To compare (models of) two theories, one can turn to a statistical test — a likelihood ratio test, for example — if the model of one theory can be considered as a submodel of the model of a second theory. The latter applies if the first model’s parameters are a subset of the second’s. A second approach in comparing models is based on the goodness-of-fit index taking into account the number of parameters needed to achieve it. In probabilistic choice modeling, this comes down to a penalized likelihood function, as in Akaike’s information criterion aic (Akaike, 1973, 1974).

In Chapter 1 we offered a reintroduction of all proposals for a probabilistic unfolding theory for paired comparisons data that have appeared in the literature during the past thirty years. The classification we used in that review was based on the conceptual equivalencies between theories. We distinguished between random configuration theories, random distance theories, strong unfolding theories, and the midpoint unfolding theory.

Of all children with febrile seizures (FS) 15 to 80% are reported to have recurrent FS. Children at increased risk of frequent recurrences might be candidates for some form of prophylactic treatment. Accurate assessment of the individual child's recurrence risk is therefore essential. To determine the risk of subsequent seizures after a 1st, 2nd or 3rd episode of FS we used the findings of our large collaborative cohort study (J Pediatr 1994, April issue). Data on 2496 children with a total number of 3459 episodes at risk for a subsequent FS until the age of 5 years were examined. The overall recurrence rate after a 1st, a 2nd or 3rd FS was 32%, 47% and 49% respectively. A child's attained age was the most important determinant of seizure recurrence. Other significant factors were a first degree family history of febrile or unprovoked seizures and a temperature < 40.0°C at the first FS; the number and recency of previous experienced FS provided additional information. These risk factors were examined multivariate and combined into a prognostic index for each single child. Estimated recurrence risk and observed number of recurrences were compared in various risk strata, the predictive validity of the model was assessed using the individual data on 347 children from a recently published follow up study (N Engl J Med 1992:327:1122-7). For a child with a first FS recurrence at 18 months and no risk factors, the estimated probability of further seizures up to the age of 5 years is 47%, if a second recurrence occurs at 30 months, this risk becomes 26%. Patients allocated by the prognostic index into the highest of five risk groups had an observed recurrence risk of 89% at 5 years, with a predicted value of 85%. Corresponding results for low risk were 9% observed) and 7% (predicted), for medium risk 31% and 31%, respectively. We conclude that this prognostic index identifies children at high and low risk for requent recurrences and can be a useful tool for clinical practice.

[Background and Aims] Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH)., [Methods] PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model., [Results] We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs., [Conclusions] When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking., [Lay summary] Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring., This work has been undertaken as part of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) project. The LITMUS project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777377. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and Europen Federation of Pharmaceutical Industries and Associations (efpia.eu).

A framework for the concepts “model”, “theory” and “data” within the context of probabilistic choice models is presented. What is commonly called a test of a model comes down to an assessment of the goodness-of-fit relation between a model of a theory and a model of data. A distinction is made between theories that lead to ordinal restrictions on choice probabilities (Type I), and theories that specify a functional relation between utilities and choice probabilities (Type II). The study of probabilistic choice behavior could benefit from an assessment of the goodness-of-fit of Type I theories with statistical methods usually reserved for Type II theories.

This paper presents a new probabilistic unidimensional unfolding procedure for paired comparisons data. This procedure is related to a probabilistic unfolding theory in which a nonparametric random ideal coordinate assumption is added to the familiar unidimensional unfolding assumptions. The procedure can be used to find a maximum likelihood sequencing of alternatives or their midpoints, based on choices of a single subject or a group of subjects. It requires a sedation strategy and the calculation of maximum likelihood binomial probability estimates under order restrictions. Algorithms are presented for both purposes. The unfolding procedure can easily be modified to suit related probabilistic unfolding theories.

Last year BJOG set up facilities for clinical researchers to register their randomised controlled trial protocols for electronic publication early in the research process. The idea was to encourage good research practice and to make it more likely that the published results reflected the truth. We are now offering the same facility for studies of test accuracy. We believe that we are the first journal to offer this facility for primary research into test accuracy. Studies of test accuracy can go wrong in all sorts of ways. Authors may fail to define the population under investigation, the test, the cutoff values or their reference standard before they start data collection. Some patients may miss some tests, undergo different ones or not get the reference standard. Finally, the results may not be analysed and presented in ways that clinicians can understand and act on. If any of these things go wrong, or get changed halfway through, it makes it almost impossible to interpret the results. The requirements for reporting test accuracy studies are widely agreed but they are more likely to be met if they are considered and published before starting. Protocol registration makes the whole research process more transparent. If sample sizes, cutoff values or reference standard definitions are altered at any stage, referees can see what has happened and judge whether it may have affected the results. If protocols never get published because editors are biased towards selecting papers with positive results, this will also be clear. To register a test accuracy protocol (PT), visit our Web site at http://bjog.allentrack.net and follow instructions. On pages 847–848, and on the Web site, we publish suggested headings for such protocols which authors are free to follow, although we do not insist on this. Protocols will be sent to referees who will use these headings for evaluation. Accepted protocols will be published electronically on BJOG online and a summary printed in the journal. We hope that the main study publication would be submitted first to BJOG and we promise to send it to referees. If their reports are satisfactory, we would normally agree to publish the study, although we cannot guarantee this at the registration stage.

Recent advances in artificial intelligence have seen limited adoption in systematic reviews,and much of the systematic review process remains manual, time-consuming, and expensive. Authors conducting systematic reviews face issues throughout the systematic review process. It is difficult and time-consuming to search and retrieve,collect data, write manuscripts, and perform statistical analyses. Screening automation has been suggested as a way to reduce the workload, but uptake has been limited due to a number of issues,including licensing, steep learning curves, lack of support, and mismatches to workflow. There is a need to better a lign current methods to the need of the systematic review community.Diagnostic test accuracy studies are seldom indexed in an easily retrievable way, and suffer from variable terminology and missing or inconsistently applied database labels. Methodological search queries to identify diagnostic studies therefore tend to have low accuracy, and are discouraged for use in systematic reviews. Consequently, there is a particular need for alternative methods to reduce the workload in systematic reviews of diagnostic test accuracy.In this thesis we have explored the hypothesis that automation methods can offer an efficient way tomake the systematic review process quicker and less expensive, provided we can identify and overcomebarriers to their adoption. Automated methods have the opportunity to make the process cheaper as well as more transparent, accountable, and reproducible., Les récentes avancées en matière d'intelligence artificielle ont vu une adoption limitée dans la communauté des auteurs de revues systématiques, et une grande partie du processus d'élaboration des revues systématiques est toujours manuelle, longue et coûteuse. Les auteurs de revues systématiques rencontrent des défis tout au long du processus d'élaboration d'une revue. Il est long et difficile de chercher, d'extraire, de collecter des données, de rédiger des manuscrits et d'effectuer des analyses statistiques. L'automatisation de la sélection d'articles a été proposé comme un moyen de réduire la charge de travail, mais son adoption a été limitée en raison de différents facteurs,notamment l'investissement important de prise en main, le manque d'accompagnement et les décalages par rapport au flux de travail. Il est nécessaire de mieux harmoniser les méthodes actuelles avec les besoins de la communauté des revues systématiques.Les études sur l'exactitude des tests diagnostiques sont rarement indexées de façon à pouvoir être facilement retrouvées dans les bases de données bibliographiques. La variabilité terminologique et l'indexation lacunaire ou incohérente des ces études sont autant de facteurs augmentant le niveau de difficulté de réalisation des revues systématiques qui s'y intéressent. Les requêtes de recherche méthodologique visant à repérer les études diagnostiques ont donc tendance à être peu précises, et leur utilisation dans les études méthodiques est déconseillée. Par conséquent, il est particulièrement nécessaire d'avoir recours à d'autres méthodes pour réduire la charge de travail dans les études méthodiques sur l'exactitude des tests diagnostiques.Dans la présente thèse, nous avons examiné l'hypothèse selon laquelle les méthodes d'automatisation peuvent offrir un moyen efficace de rendre le processus d'élaboration des revues systématique plus rapide et moins coûteux, à condition de pouvoir cerner et surmonter les obstacles à leur adoption. Les travaux réalisés montrent que les méthodes automatisées offrent un potentiel de diminution des coûts tout en améliorant la transparence et la reproductibilité du processus.