The problems with systematic reviews: a living systematic review.

OBJECTIVES: Systematic reviews and meta-analyses are proliferating as they are an important building block to inform evidence-based guidelines and decision-making. Enforcement of best practice in clinical trials is firmly on the research agenda of good clinical practice, but there is less clarity as to how evidence syntheses that combine these studies can be influenced by bad practice. Our aim was to conduct a living systematic review of articles that highlight flaws in published systematic reviews to formally document and understand these problems. STUDY DESIGN AND SETTING: We conducted a comprehensive assessment of all literature examining problems, which relate to published systematic reviews. RESULTS: The first iteration of our living systematic review (https://systematicreviewlution.com/) has found 485 articles documenting 67 discrete problems relating to the conduct and reporting of systematic reviews which can potentially jeopardize their reliability or validity. CONCLUSION: Many hundreds of articles highlight that there are many flaws in the conduct, methods, and reporting of published systematic reviews, despite the existence and frequent application of guidelines. Considering the pivotal role that systematic reviews have in medical decision-making due to having apparently transparent, objective, and replicable processes, a failure to appreciate and regulate problems with these highly cited research designs is a threat to credible science.

Living Health Technology Assessment: Issues, Challenges and Opportunities.

Health technology assessments (HTAs) are typically performed as one-off evaluations and can potentially become out-of-date due to the availability of new data, new comparators, or other factors. Recently, living approaches have been applied to systematic reviews and network meta-analyses to enable evidence syntheses to be updated more easily. In this paper, we provide a definition for 'Living HTA' where such a living approach could be applied to the entire HTA process. Living HTA could involve performing regular or scheduled updates using a traditional manual approach, or indeed in a semi-automated manner leveraging recent technological innovations that automate parts of the HTA process. The practical implementation of living HTA using both approaches (i.e., manual approach and using semi-automation) is described along with the likely issues and challenges with planning and implementing a living HTA process. The time, resources and additional considerations outlined may prohibit living HTA from becoming the norm for every evaluation; however, scenarios where living HTA would be particularly beneficial are discussed.

Housing With Care for Older People: A Scoping Review Using the CASP Assessment Tool to Inform Optimal Design.

OBJECTIVE: The purpose of this scoping review is to synthesize and map available evidence on the design of "housing with care" (HWC) schemes to inform design decisions built on objective data from previous research, which is key to ensuring such schemes are fit for purpose for older people. BACKGROUND: HWC is becoming increasingly recognized as a model for developing housing schemes for older people and balances independent living with elevated levels of care. However, as this scheme is still relatively novel, there are currently no established theoretical frameworks to inform design. METHODS: Scoping review, thematic analysis, and mapping methods were used to comprehensively search for and synthesize evidence that links design with assessments of quality-of-life data for HWC schemes. Study findings for each included paper were subject to data extraction for inductive analysis, and the quality of each study was assessed using a modified critical appaisal skills programme (CASP) checklist. RESULTS: Our searches yielded 821 unique references, of which 18 unique articles met the inclusion criteria. The outcomes of interest were the design considerations or features in HWC schemes and their impact on the residents. The main themes identified were related to design element, accessibility, maneuverability, views, design procedure, and quality of life (QOL). Further subthemes identified across papers were identified to create a comprehensive map of the key features to consider in designing HWC schemes. CONCLUSION: This review provides an initial framework for designers and architects to (1) understand the effect of each design element of HWC and (2) inform design to ultimately improve the QOL of aged people.

Clonality, Mutation and Kaposi Sarcoma: A Systematic Review.

BACKGROUND: It remains uncertain whether Kaposi sarcoma (KS) is a true neoplasm, in that it regresses after removal of the stimulus to growth (as HHV8) when immunosuppression is reduced. We aimed to summarize the available evidence on somatic mutations and clonality within KS to assess whether KS is a neoplasm or not. METHODS: Medline and Web of Science were searched until September 2020 for articles on clonality or mutation in KS. Search strings were supervised by expert librarians, and two researchers independently performed study selection and data extraction. An adapted version of the QUADAS2 tool was used for methodological quality appraisal. RESULTS: Of 3077 identified records, 20 publications reported on relevant outcomes and were eligible for qualitative synthesis. Five studies reported on clonality, 10 studies reported on various mutations, and 5 studies reported on chromosomal aberrations in KS. All studies were descriptive and were judged to have a high risk of bias. There was considerable heterogeneity of results with respect to clonality, mutation and cytogenetic abnormalities as well as in terms of types of lesions and patient characteristics. CONCLUSIONS: While KS certainly produces tumours, the knowledge is currently insufficient to determine whether KS is a clonal neoplasm (sarcoma), or simply an aggressive reactive virus-driven lesion.

A review and analysis of the components of potentially effective perinatal mental health interventions for infant development and mother-infant relationship outcomes.

Children of mothers with serious mental health difficulties are at increased risk of developing mental health difficulties themselves in their own lifetime. Specialist interventions delivered in perinatal mental health services offer an opportunity to support the infant's development and long-term mental health. This review aimed to systematically evaluate the shared elements of successful perinatal mental health interventions that underpin improved outcomes for infants whose mothers experience perinatal mental health difficulties. Nine electronic databases were searched comprehensively for relevant controlled studies of perinatal mental health interventions, and a narrative synthesis undertaken to assess whether statistically significant benefits were noted. Sixteen studies, trialing 19 interventions, were analyzed using a narrative approach and grouped according to reported effectiveness. Eight interventions demonstrated significant improvements in infant outcomes and/or mother-infant relationship outcomes and were used to inform the analysis of the included interventions' components. While the interventions identified were diverse, there were common components which potentially underpin successful interventions for infants whose mothers are experiencing mental health difficulties, including: facilitation of positive Mother×Infant interactions; helping mothers to understand their infant's perspective or inner world; and the use of video feedback.

Interventions to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease: a cost-effective modelling review.

BACKGROUND: Creutzfeldt-Jakob disease is a fatal neurological disease caused by abnormal infectious proteins called prions. Prions that are present on surgical instruments cannot be completely deactivated; therefore, patients who are subsequently operated on using these instruments may become infected. This can result in surgically transmitted Creutzfeldt-Jakob disease. OBJECTIVE: To update literature reviews, consultation with experts and economic modelling published in 2006, and to provide the cost-effectiveness of strategies to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease. METHODS: Eight systematic reviews were undertaken for clinical parameters. One review of cost-effectiveness was undertaken. Electronic databases including MEDLINE and EMBASE were searched from 2005 to 2017. Expert elicitation sessions were undertaken. An advisory committee, convened by the National Institute for Health and Care Excellence to produce guidance, provided an additional source of information. A mathematical model was updated focusing on brain and posterior eye surgery and neuroendoscopy. The model simulated both patients and instrument sets. Assuming that there were potentially 15 cases of surgically transmitted Creutzfeldt-Jakob disease between 2005 and 2018, approximate Bayesian computation was used to obtain samples from the posterior distribution of the model parameters to generate results. Heuristics were used to improve computational efficiency. The modelling conformed to the National Institute for Health and Care Excellence reference case. The strategies evaluated included neither keeping instruments moist nor prohibiting set migration; ensuring that instruments were kept moist; prohibiting instrument migration between sets; and employing single-use instruments. Threshold analyses were undertaken to establish prices at which single-use sets or completely effective decontamination solutions would be cost-effective. RESULTS: A total of 169 papers were identified for the clinical review. The evidence from published literature was not deemed sufficiently strong to take precedence over the distributions obtained from expert elicitation. Forty-eight papers were identified in the review of cost-effectiveness. The previous modelling structure was revised to add the possibility of misclassifying surgically transmitted Creutzfeldt-Jakob disease as another neurodegenerative disease, and assuming that all patients were susceptible to infection. Keeping instruments moist was estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Based on probabilistic sensitivity analyses, keeping instruments moist was estimated to on average result in 2.36 (range 0-47) surgically transmitted Creutzfeldt-Jakob disease cases (across England) caused by infection occurring between 2019 and 2023. Prohibiting set migration or employing single-use instruments reduced the estimated risk of surgically transmitted Creutzfeldt-Jakob disease cases further, but at considerable cost. The estimated costs per quality-adjusted life-year gained of these strategies in addition to keeping instruments moist were in excess of £1M. It was estimated that single-use instrument sets (currently £350-500) or completely effective cleaning solutions would need to cost approximately £12 per patient to be cost-effective using a £30,000 per quality-adjusted life-year gained value. LIMITATIONS: As no direct published evidence to implicate surgery as a cause of Creutzfeldt-Jakob disease has been found since 2005, the estimations of potential cases from elicitation are still speculative. A particular source of uncertainty was in the number of potential surgically transmitted Creutzfeldt-Jakob disease cases that may have occurred between 2005 and 2018. CONCLUSIONS: Keeping instruments moist is estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Further surgical management strategies can reduce the risks of surgically transmitted Creutzfeldt-Jakob disease but have considerable associated costs. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017071807. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 11. See the NIHR Journals Library website for further project information.

The aims of this report were to summarise evidence relating to surgically transmitted Creutzfeldt­Jakob disease and to explore the value for money of strategies to reduce the chance of any future surgically transmitted Creutzfeldt­Jakob disease cases. Current recommendations include keeping sets of surgical instruments together for high-risk operations and using separate instruments for people born after 1996. The project involved reviewing published papers, speaking with experts and building a computer model. The literature reviews found that Creutzfeldt­Jakob disease occurs in around 1­2 per million people and that no definite cases of surgically transmitted Creutzfeldt­Jakob disease have been observed since the 1970s. The reviews also looked for information on the possibility of patients being infected with Creutzfeldt­Jakob disease after having surgery on high-risk tissues, such as the brain and the back of the eye. They found that there was a great deal of uncertainty regarding who might have Creutzfeldt­Jakob disease, but not yet have symptoms, as well as the risk of transmission and the ability of strategies to reduce this risk. The computer model aimed to estimate value for money of different strategies to reduce the risks of surgically transmitted Creutzfeldt­Jakob disease. However, the reviews found that some of the numbers needed for the model were not known, so experts were asked to estimate this information instead along with the range of possible values. This information included the effectiveness of different cleaning practices and the chances of infected tissue being transmitted between patients undergoing high-risk surgery. The model found that keeping surgical instruments moist prior to cleaning was likely to save money and reduce the chance of future surgically transmitted Creutzfeldt­Jakob disease cases. However, additional measures, such as using only sets of single-use instruments, ensuring that instruments were kept together in their sets or using separate instruments for those born after 1996, appeared to be poor value for money.

Creutzfeldt-Jakob disease: a systematic review of global incidence, prevalence, infectivity, and incubation.

Creutzfeldt-Jakob disease (CJD) is a fatal disease presenting with rapidly progressive dementia, and most patients die within a year of clinical onset. CJD poses a potential risk of iatrogenic transmission, as it can incubate asymptomatically in humans for decades before becoming clinically apparent. In this Review, we sought evidence to understand the current iatrogenic risk of CJD to public health by examining global evidence on all forms of CJD, including clinical incidence and prevalence of subclinical disease. We found that although CJD, particularly iatrogenic CJD, is rare, the incidence of sporadic CJD is increasing. Incubation periods as long as 40 years have been observed, and all genotypes have now been shown to be susceptible to CJD. Clinicians and surveillance programmes should maintain awareness of CJD to mitigate future incidences of its transmission. Awareness is particularly relevant for sporadic CJD, which occurs in older people in whom clinical presentation could resemble rapidly developing dementia.

Sex Categorization of Faces: The Effects of Age and Experience.

The face own-age bias effect refers to the better ability to recognize the face from one's own age compared with other age groups. Here we examined whether an own-age advantage occurs for faces sex categorization. We examined 7- and 9-year-olds' and adults' ability to correctly categorize the sex of 7- and 9-year-olds and adult faces without external cues, such as hair. Results indicated that all ages easily classify the sex of adult faces. They succeeded in classifying the sex of child faces, but their performance was poorer than for adult faces. In adults, processing time increased, and a response bias (male response) was elicited for child faces. In children, response times remained constant, and no bias was observed. Experience with specific category of faces seems to offer some advantage in speed of processing. Overall, sex categorization is more challenging for child than for adult faces due to their reduced sexual dimorphic facial characteristics.

A review of quality of life themes in Duchenne muscular dystrophy for patients and carers.

Duchenne Muscular Dystrophy (DMD) is a severe, life-limiting and incurable condition. However, studies estimating quality of life and those measuring actual quality of life in people living with DMD vary considerably. This discrepancy indicates potential difficulties with assessing quality of life using common generic quality of life instruments in this rare and unique population. This study sought to document the range of themes relevant to quality of life for people with DMD by examining the published literature and additionally to investigate the themes that are relevant to quality of life for carers and the wider family. Eligible studies for the review were primary studies of any study design that reported outcomes or themes relevant to quality of life for either people with DMD, their families, or both. A review of studies identified from searching medical bibliographic sources between 2010 and 2016 found 45 relevant published studies. A thematic framework is proposed to categorise the themes identified into: i. physical; ii. psychological; iii. Social; iv. well-being domains. A final "other" domain was included to encompass themes identified from the literature that are not covered by commonly used quality of life instruments. The rich variety of themes identified from the review highlights that DMD has a complex quality of life profile which is not currently captured by standard quality of life tools that are commonly employed in the healthcare setting. The findings also highlight that the resulting impact on the quality of life of carers and wider family of people with DMD requires consideration.

Routine thyroglobulin, neck ultrasound and physical examination in the routine follow up of patients with differentiated thyroid cancer-Where is the evidence?

PURPOSE: Patients with differentiated thyroid cancer (DTC) typically have a favourable prognosis and recurrence as late as 45 years after diagnosis has been reported. International clinical guidelines for monitoring recommend routine thyroglobulin, ultrasound and physical examination for the detection of recurrence. The aim of this review was to systematically review whether routine monitoring using thyroglobulin (Tg), neck ultrasound and physical examination for recurrence in differentiated thyroid cancer patients is effective in improving patient survival and/or quality of life. METHODS: Primary studies were retrieved via a comprehensive search of three electronic bibliographic databases (PubMed, Web of Science Core Collection and Cochrane Library) without time restriction. Eligible studies must have reported on disease-free patients with DTC subject to long-term routine surveillance. The primary and secondary outcomes of interest were overall survival (or other survival parameters) and quality of life, respectively. RESULTS: Literature searches yielded 5529 citations, which were screened by two reviewers. 241 full texts were retrieved. No randomised controlled trials or two-arm cohort studies on the effectiveness of any of the three specified interventions were identified. However, three 'single-arm' studies reporting long-term follow-up outcomes in patients undergoing regular surveillance were identified and appraised. CONCLUSIONS: This review highlights a lack of empirical evidence to support current use of routine surveillance in DTC. Although early detection is possible, routine surveillance may lead to unnecessary intervention.

Tofacitinib for Treating Rheumatoid Arthritis After the Failure of Disease-Modifying Anti-rheumatic Drugs: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Pfizer) of tofacitinib (TOF; Xeljanz®) to submit evidence of the drug's clinical and cost-effectiveness in the treatment of rheumatoid arthritis (RA) after the failure of conventional disease-modifying antirheumatic drugs (cDMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost-effectiveness of the technology, based upon the company's submission to NICE. The clinical effectiveness evidence in the company's submission for TOF is based predominantly on four randomised controlled trials (RCTs) comparing the efficacy of TOF against placebo. Three RCTs investigated TOF in combination with methotrexate (MTX), and one RCT investigated TOF monotherapy. All four RCTs compared TOF with placebo plus cDMARDs, one RCT also included adalimumab as a comparator. The study population in the four RCTs comprised patients who were MTX inadequate responders or cDMARD inadequate responders (cDMARD-IR). The company performed network meta-analyses (NMA) to assess the relative efficacy of TOF compared with biologic DMARDs (bDMARDs) in patients who were cDMARD-IR or bDMARD-IR with moderate-to-severe RA for European League Against Rheumatism (EULAR) response and change in the Health Assessment Questionnaire Disability Index at 6 months. The company's NMA concluded that TOF had comparable efficacy to bDMARDs currently recommended by NICE. The company submitted a de novo model that assessed the cost-effectiveness of TOF versus its comparators in six different populations: (1) cDMARD-IR with severe RA; (2) cDMARD-IR with severe RA for whom MTX is contraindicated or not tolerated; (3) bDMARD-IR; (4) bDMARD-IR for whom rituximab (RTX) is contraindicated or not tolerated; (5) bDMARD-IR for whom MTX is contraindicated or not tolerated; and, (6) cDMARD-IR with moderate RA. According to the company's economic analyses, in cDMARD-IR with severe RA, TOF plus MTX dominates or extendedly dominates most comparators, whilst TOF monotherapy is slightly less effective and less expensive than its comparators, with the cost saved per quality-adjusted life year (QALY) lost always higher than £50,000. In bDMARD-IR with severe RA, RTX plus MTX dominated TOF plus MTX, but in patients for whom RTX was not an option, TOF plus MTX dominated all comparators included in the analysis (four comparators recommended by NICE were not included). In cDMARD-IR with moderate RA, the cost per QALY for TOF in combination with MTX or as monotherapy compared with a sequence of cDMARDs was estimated to be greater than £50,000/QALY. The ERG identified a number of limitations in the company's analyses, including use of a fixed-effects model in the NMA and the use of treatment sequences in the cost-effectiveness model which did not reflect NICE recommendations. These limitations were addressed partly by the company during the clarification round and partly by the ERG. The exploratory analyses undertaken by the ERG resulted in similar conclusions: (1) TOF plus MTX was dominated by RTX plus MTX; (2) TOF in combination with MTX or as monotherapy dominates or extendedly dominates some of its comparators in cDMARD-IR and bDMARD-IR with severe RA for whom RTX plus MTX was not an option; and (3) in cDMARD-IR with moderate RA, the cost per QALY of TOF in combination with MTX or as a monotherapy versus cDMARDs was in excess of £47,000. The NICE Appraisal Committee consequently recommended TOF plus MTX as an option for patients whose disease has responded inadequately to intensive therapy with a combination of cDMARDs only if (1) disease is severe [a Disease Activity Score (DAS28) of more than 5.1] and (2) the company provides TOF with the discount agreed in the Patient Access Scheme (PAS). TOF plus MTX is also recommended as an option for adults whose disease has responded inadequately to, or who cannot have, other DMARDs, including at least one bDMARD, only if (1) disease is severe, (2) they cannot have RTX, and (3) the company provides TOF with the discount agreed in the PAS. For patients who are intolerant of MTX, or where MTX is contraindicated, TOF monotherapy is recommended where TOF plus MTX would be recommended.

The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review.

BACKGROUND: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. METHODS: The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. RESULTS: The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). CONCLUSION: We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection.

The influence of the team in conducting a systematic review.

There is an increasing body of research documenting flaws in many published systematic reviews' methodological and reporting conduct. When good systematic review practice is questioned, attention is rarely turned to the composition of the team that conducted the systematic review. This commentary highlights a number of relevant articles indicating how the composition of the review team could jeopardise the integrity of the systematic review study and its conclusions. Key biases require closer attention such as sponsorship bias and researcher allegiance, but there may also be less obvious affiliations in teams conducting secondary evidence-syntheses. The importance of transparency and disclosure are now firmly on the agenda for clinical trials and primary research, but the meta-biases that systematic reviews may be at risk from now require further scrutiny.

A qualitative systematic review of service user and service provider perspectives on the acceptability, relative benefits, and potential harms of art therapy for people with non-psychotic mental health disorders.

PURPOSE: This systematic review aimed to synthesize qualitative evidence relating to user and service provider perspective on the acceptability and relative benefits and potential harms of art therapy for people with non-psychotic mental disorders. METHODS: A comprehensive literature search was conducted in 13 major bibliographic databases from May to July 2013. A qualitative evidence synthesis was conducted using thematic framework synthesis. RESULTS: The searches identified 10,270 citations from which 12 studies were included. Ten studies included data from 183 service users, and two studies included data from 16 service providers. The evidence demonstrated that art therapy was an acceptable treatment. The benefits associated with art therapy included the following: the development of relationships with the therapist and other group members; understanding the self/own illness/the future; gaining perspective; distraction; personal achievement; expression; relaxation; and empowerment. Small numbers of patients reported varying reasons for not wanting to take part, and some highlighted potentially negative effects of art therapy which included the evoking of feelings which could not be resolved. CONCLUSIONS: The findings suggest that for the majority of respondents art therapy was an acceptable intervention, although this was not the case for all respondents. Therefore, attention should be focussed on both identifying those who are most likely to benefit from art therapy and ensuring any potential harms are minimized. The findings provide evidence to commissioners and providers of mental health services about the value of future art therapy services. PRACTITIONER POINTS: Art therapy was reported to be an acceptable treatment for the majority of respondents. Art therapy may not be a preferred treatment option for a small number of patients, emphasizing the importance of considering patient preference in choice of treatment, and selection of the most suitable patients for art therapy. Consideration should be made of adjustments to make art therapy inclusive, particularly for those with physical illnesses. Ensuring the competence of the deliverer, providing patients with additional support, such as other therapies if required, and ensuring continuity of care should be key considerations in service provision.

Degarelix for Treating Advanced Hormone-Dependent Prostate Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal Process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of degarelix (Ferring Pharmaceuticals) to submit evidence for the clinical and cost effectiveness of degarelix for the treatment of advanced hormone-dependent prostate cancer. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company's submission to NICE. The evidence, which included a randomised controlled trial (RCT) of degarelix versus leuprorelin, found that degarelix was non-inferior to leuprorelin for reduction of testosterone levels and that degarelix achieved a more rapid suppression of prostate-specific antigen levels and subsequently decreased incidences of testosterone flare associated with luteinising hormone releasing-hormone (LHRH) agonists. However, protection against testosterone flare for the comparators in the clinical trials was not employed in line with UK clinical practice. Further claims surrounding overall survival, cardiovascular adverse events and clinical equivalence of the comparator drugs from six RCTs of degarelix should be regarded with caution because of flaws and inconsistencies in the pooling of trial data to draw conclusions. The cost-effectiveness evidence included a de novo economic model. Based on the ERG's preferred base case, the deterministic incremental cost-effectiveness analysis (ICER) for degarelix versus 3-monthly triptorelin was £14,798 per quality-adjusted life-year (QALY) gained. Additional scenario analyses undertaken by the ERG resulted in ICERs for degarelix versus 3-monthly triptorelin ranging from £17,067 to £35,589 per QALY gained. Subgroup analyses undertaken using the Appraisal Committee's preferred assumptions suggested that degarelix was not cost effective for the subgroup with metastatic disease but could be cost effective for the subgroup with spinal metastases. The company submitted further evidence to NICE following an initial negative Appraisal Committee decision. Further analyses from the Decision Support Unit found that that, whilst some evidence indicated that degarelix could be cost effective for a small subgroup of people with spinal cord compression (SCC), data on the potential size of this subgroup and the rate of SCC were insufficient to estimate an ICER based on the evidence submitted by the company and a separately commissioned systematic review. NICE recommended degarelix as an option for treating advanced hormone-dependent prostate cancer in people with spinal metastases, only if the commissioner can achieve at least the same discounted drug cost as that available to the UK NHS in June 2016.

Systematic Review of Trends in the Incidence Rates of Thyroid Cancer.

BACKGROUND: A large proportion of global increase in thyroid cancer (TC) incidence has been attributed to increased detection of papillary thyroid cancer (PTC). Nonetheless, some reports support a real increase in incidence. This study aimed to perform a systematic review to evaluate the changing trends in TC incidence and summarize potential risk factors predisposing to this trend. METHODS: Literature published in the English language between 1980 and August 2014 was searched via PubMed (MEDLINE) and OvidSP (EMBASE). Original studies on changes in TC incidence in defined geographic areas that described clear methods of case selection and population estimates were included. Data on incidence rates and risk factors were collected. RESULTS: Of 4719 manuscripts, 60 studies were included, of which 31 were from Europe, 13 from North America, and the rest from Asia (n = 9), Oceania (n = 4), and South America (n = 3). Fifty-three articles reported a significant increase in incidence (highest was a 10-fold increase in South Korea), six reported stable rates, and one noted a decrease. PTC was the commonest type reported to have increased in incidence (in 10 studies with relevant data). Follicular TC increased in incidence (in four studies), albeit at a lower rate compared with PTC. Data on risk factors were sparse; factors discussed included ionizing radiation, iodine deficiency, and supplementation. CONCLUSION: This systematic review strongly supports a widespread and persistent increase in TC incidence. Evidence for over-detection of PTC as the predominant influence includes increased numbers of smaller size tumors and improved or unchanged survival.

Building the Evidence Base of Blood-Based Biomarkers for Early Detection of Cancer: A Rapid Systematic Mapping Review.

BACKGROUND: The Early Cancer Detection Consortium is developing a blood-test to screen the general population for early identification of cancer, and has therefore conducted a systematic mapping review to identify blood-based biomarkers that could be used for early identification of cancer. METHODS: A mapping review with a systematic approach was performed to identify biomarkers and establish their state of development. Comprehensive searches of electronic databases Medline, Embase, CINAHL, the Cochrane library and Biosis were conducted in May 2014 to obtain relevant literature on blood-based biomarkers for cancer detection in humans. Screening of retrieved titles and abstracts was performed using an iterative sifting process known as "data mining". All blood based biomarkers, their relevant properties and characteristics, and their corresponding references were entered into an inclusive database for further scrutiny by the Consortium, and subsequent selection of biomarkers for rapid review. This systematic review is registered with PROSPERO (no. CRD42014010827). FINDINGS: The searches retrieved 19,724 records after duplicate removal. The data mining approach retrieved 3990 records (i.e. 20% of the original 19,724), which were considered for inclusion. A list of 814 potential blood-based biomarkers was generated from included studies. Clinical experts scrutinised the list to identify miss-classified and duplicate markers, also volunteering the names of biomarkers that may have been missed: no new markers were identified as a result. This resulted in a final list of 788 biomarkers. INTERPRETATION: This study is the first to systematically and comprehensively map blood biomarkers for early detection of cancer. Use of this rapid systematic mapping approach found a broad range of relevant biomarkers allowing an evidence-based approach to identification of promising biomarkers for development of a blood-based cancer screening test in the general population.

Sepsis: the LightCycler SeptiFast Test MGRADE®, SepsiTest™ and IRIDICA BAC BSI assay for rapidly identifying bloodstream bacteria and fungi - a systematic review and economic evaluation.

BACKGROUND: Sepsis can lead to multiple organ failure and death. Timely and appropriate treatment can reduce in-hospital mortality and morbidity. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of three tests [LightCycler SeptiFast Test MGRADE(®) (Roche Diagnostics, Risch-Rotkreuz, Switzerland); SepsiTest(TM) (Molzym Molecular Diagnostics, Bremen, Germany); and the IRIDICA BAC BSI assay (Abbott Diagnostics, Lake Forest, IL, USA)] for the rapid identification of bloodstream bacteria and fungi in patients with suspected sepsis compared with standard practice (blood culture with or without matrix-absorbed laser desorption/ionisation time-of-flight mass spectrometry). DATA SOURCES: Thirteen electronic databases (including MEDLINE, EMBASE and The Cochrane Library) were searched from January 2006 to May 2015 and supplemented by hand-searching relevant articles. REVIEW METHODS: A systematic review and meta-analysis of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. A decision tree was used to estimate the costs and quality-adjusted life-years (QALYs) associated with each test; all other parameters were estimated from published sources. The model was populated with evidence from the systematic review or individual studies, if this was considered more appropriate (base case 1). In a secondary analysis, estimates (based on experience and opinion) from seven clinicians regarding the benefits of earlier test results were sought (base case 2). A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Scenario analyses were used to assess uncertainty. RESULTS: For the review of diagnostic test accuracy, 62 studies of varying methodological quality were included. A meta-analysis of 54 studies comparing SeptiFast with blood culture found that SeptiFast had an estimated summary specificity of 0.86 [95% credible interval (CrI) 0.84 to 0.89] and sensitivity of 0.65 (95% CrI 0.60 to 0.71). Four studies comparing SepsiTest with blood culture found that SepsiTest had an estimated summary specificity of 0.86 (95% CrI 0.78 to 0.92) and sensitivity of 0.48 (95% CrI 0.21 to 0.74), and four studies comparing IRIDICA with blood culture found that IRIDICA had an estimated summary specificity of 0.84 (95% CrI 0.71 to 0.92) and sensitivity of 0.81 (95% CrI 0.69 to 0.90). Owing to the deficiencies in study quality for all interventions, diagnostic accuracy data should be treated with caution. No randomised clinical trial evidence was identified that indicated that any of the tests significantly improved key patient outcomes, such as mortality or duration in an intensive care unit or hospital. Base case 1 estimated that none of the three tests provided a benefit to patients compared with standard practice and thus all tests were dominated. In contrast, in base case 2 it was estimated that all cost per QALY-gained values were below £20,000; the IRIDICA BAC BSI assay had the highest estimated incremental net benefit, but results from base case 2 should be treated with caution as these are not evidence based. LIMITATIONS: Robust data to accurately assess the clinical effectiveness and cost-effectiveness of the interventions are currently unavailable. CONCLUSIONS: The clinical effectiveness and cost-effectiveness of the interventions cannot be reliably determined with the current evidence base. Appropriate studies, which allow information from the tests to be implemented in clinical practice, are required. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015016724. FUNDING: The National Institute for Health Research Health Technology Assessment programme.