Hierarchical network meta-analysis models for synthesis of evidence from randomised and non-randomised studies

BACKGROUND: With the increased interest in the inclusion of non-randomised data in network meta-analyses (NMAs) of randomised controlled trials (RCTs), analysts need to consider the implications of the differences in study designs as such data can be prone to increased bias due to the lack of randomisation and unmeasured confounding. This study aims to explore and extend a number of NMA models that account for the differences in the study designs, assessing their impact on the effect estimates and uncertainty. METHODS: Bayesian random-effects meta-analytic models, including naïve pooling and hierarchical models differentiating between the study designs, were extended to allow for the treatment class effect and accounting for bias, with further extensions allowing for bias terms to vary depending on the treatment class. Models were applied to an illustrative example in type 2 diabetes; using data from a systematic review of RCTs and non-randomised studies of two classes of glucose-lowering medications: sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. RESULTS: Across all methods, the estimated mean differences in glycated haemoglobin after 24 and 52 weeks remained similar with the inclusion of observational data. The uncertainty around these estimates reduced when conducting naïve pooling, compared to NMA of RCT data alone, and remained similar when applying hierarchical model allowing for class effect. However, the uncertainty around these effect estimates increased when fitting hierarchical models allowing for the differences in study design. The impact on uncertainty varied between treatments when applying the bias adjustment models. Hierarchical models and bias adjustment models all provided a better fit in comparison to the naïve-pooling method. CONCLUSIONS: Hierarchical and bias adjustment NMA models accounting for study design may be more appropriate when conducting a NMA of RCTs and observational studies. The degree of uncertainty around the effectiveness estimates varied depending on the method but use of hierarchical models accounting for the study design resulted in increased uncertainty. Inclusion of non-randomised data may, however, result in inferences that are more generalisable and the models accounting for the differences in the study design allow for more detailed and appropriate modelling of complex data, preventing overly optimistic conclusions

AD-8 for detection of dementia across a variety of healthcare settings

BACKGROUND: Dementia assessment often involves initial screening, using a brief tool, followed by more detailed assessment where required. The AD-8 is a short questionnaire, completed by a suitable 'informant' who knows the person well. AD-8 is designed to assess change in functional performance secondary to cognitive change. OBJECTIVES: To determine the diagnostic accuracy of the informant-based AD-8 questionnaire, in detection of all-cause (undifferentiated) dementia in adults. Where data were available, we described the following: the diagnostic accuracy of the AD-8 at various predefined threshold scores; the diagnostic accuracy of the AD-8 for each healthcare setting and the effects of heterogeneity on the reported diagnostic accuracy of the AD-8. SEARCH METHODS: We searched the following sources on 27 May 2014, with an update to 7 June 2018: ALOIS (Cochrane Dementia and Cognitive Improvement Group), MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection (includes Conference Proceedings Citation Index) (Thomson Reuters Web of Science), CINAHL (EBSCOhost) and LILACS (BIREME). We checked reference lists of relevant studies and reviews, used searches of known relevant studies in PubMed to track related articles, and contacted research groups conducting work on the AD-8 to try to find additional studies. We developed a sensitive search strategy and used standardised database subject headings as appropriate. Foreign language publications were translated. SELECTION CRITERIA: We selected those studies which included the AD-8 to assess for the presence of dementia and where dementia diagnosis was confirmed with clinical assessment. We only included those studies where the AD-8 was used as an informant assessment. We made no exclusions in relation to healthcare setting, language of AD-8 or the AD-8 score used to define a 'test positive' case. DATA COLLECTION AND ANALYSIS: We screened all titles generated by electronic database searches, and reviewed abstracts of potentially relevant studies. Two independent assessors checked full papers for eligibility and extracted data. We extracted data into two-by-two tables to allow calculation of accuracy metrics for individual studies. We then created summary estimates of sensitivity, specificity and likelihood ratios using the bivariate approach and plotting results in receiver operating characteristic (ROC) space. We determined quality assessment (risk of bias and applicability) using the QUADAS-2 tool. MAIN RESULTS: From 36 papers describing AD-8 test accuracy, we included 10 papers. We utilised data from nine papers with 4045 individuals, 1107 of whom (27%) had a clinical diagnosis of dementia. Pooled analysis of seven studies, using an AD-8 informant cut-off score of two, indicated that sensitivity was 0.92 (95% confidence interval (CI) 0.86 to 0.96); specificity was 0.64 (95% CI 0.39 to 0.82); the positive likelihood ratio was 2.53 (95% CI 1.38 to 4.64); and the negative likelihood ratio was 0.12 (95% CI 0.07 to 0.21). Pooled analysis of five studies, using an AD-8 informant cut-off score of three, indicated that sensitivity was 0.91 (95% CI 0.80 to 0.96); specificity was 0.76 (95% CI 0.57 to 0.89); the positive likelihood ratio was 3.86 (95% CI 2.03 to 7.34); and the negative likelihood ratio was 0.12 (95% CI 0.06 to 0.24).Four studies were conducted in community settings; four were in secondary care (one in the acute hospital); and one study was in primary care. The AD-8 has a higher relative sensitivity (1.11, 95% CI 1.02 to 1.21), but lower relative specificity (0.51, 95% CI 0.23 to 1.09) in secondary care compared to community care settings.There was heterogeneity across the included studies. Dementia prevalence rate varied from 12% to 90% of included participants. The tool was also used in various different languages. Among all the included studies there was evidence of risk of bias. Issues included the selection of participants, conduct of index test, and flow of assessment procedures. AUTHORS' CONCLUSIONS: The high sensitivity of the AD-8 suggests it can be used to identify adults who may benefit from further specialist assessment and diagnosis, but is not a diagnostic test in itself. This pattern of high sensitivity and lower specificity is often suited to a screening test. Test accuracy varies by setting, however data in primary care and acute hospital settings are limited. This review identified significant heterogeneity and risk of bias, which may affect the validity of its summary findings

Altering the availability or proximity of food, alcohol, and tobacco products to change their selection and consumption.

BACKGROUND: Overconsumption of food, alcohol, and tobacco products increases the risk of non-communicable diseases. Interventions to change characteristics of physical micro-environments where people may select or consume these products - including shops, restaurants, workplaces, and schools - are of considerable public health policy and research interest. This review addresses two types of intervention within such environments: altering the availability (the range and/or amount of options) of these products, or their proximity (the distance at which they are positioned) to potential consumers. OBJECTIVES: 1. To assess the impact on selection and consumption of altering the availability or proximity of (a) food (including non-alcoholic beverages), (b) alcohol, and (c) tobacco products.2. To assess the extent to which the impact of these interventions is modified by characteristics of: i. studies, ii. interventions, and iii. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, and seven other published or grey literature databases, as well as trial registries and key websites, up to 23 July 2018, followed by citation searches. SELECTION CRITERIA: We included randomised controlled trials with between-participants (parallel group) or within-participants (cross-over) designs. Eligible studies compared effects of exposure to at least two different levels of availability of a product or its proximity, and included a measure of selection or consumption of the manipulated product. DATA COLLECTION AND ANALYSIS: We used a novel semi-automated screening workflow and applied standard Cochrane methods to select eligible studies, collect data, and assess risk of bias. In separate analyses for availability interventions and proximity interventions, we combined results using random-effects meta-analysis and meta-regression models to estimate summary effect sizes (as standardised mean differences (SMDs)) and to investigate associations between summary effect sizes and selected study, intervention, or participant characteristics. We rated the certainty of evidence for each outcome using GRADE. MAIN RESULTS: We included 24 studies, with the majority (20/24) giving concerns about risk of bias. All of the included studies investigated food products; none investigated alcohol or tobacco. The majority were conducted in laboratory settings (14/24), with adult participants (17/24), and used between-participants designs (19/24). All studies were conducted in high-income countries, predominantly in the USA (14/24).Six studies investigated availability interventions, of which two changed the absolute number of different options available, and four altered the relative proportion of less-healthy (to healthier) options. Most studies (4/6) manipulated snack foods or drinks. For selection outcomes, meta-analysis of three comparisons from three studies (n = 154) found that exposure to fewer options resulted in a large reduction in selection of the targeted food(s): SMD -1.13 (95% confidence interval (CI) -1.90 to -0.37) (low certainty evidence). For consumption outcomes, meta-analysis of three comparisons from two studies (n = 150) found that exposure to fewer options resulted in a moderate reduction in consumption of those foods, but with considerable uncertainty: SMD -0.55 (95% CI -1.27 to 0.18) (low certainty evidence).Eighteen studies investigated proximity interventions. Most (14/18) changed the distance at which a snack food or drink was placed from the participants, whilst four studies changed the order of meal components encountered along a line. For selection outcomes, only one study with one comparison (n = 41) was identified, which found that food placed farther away resulted in a moderate reduction in its selection: SMD -0.65 (95% CI -1.29 to -0.01) (very low certainty evidence). For consumption outcomes, meta-analysis of 15 comparisons from 12 studies (n = 1098) found that exposure to food placed farther away resulted in a moderate reduction in its consumption: SMD -0.60 (95% CI -0.84 to -0.36) (low certainty evidence). Meta-regression analyses indicated that this effect was greater: the farther away the product was placed; when only the targeted product(s) was available; when participants were of low deprivation status; and when the study was at high risk of bias. AUTHORS' CONCLUSIONS: The current evidence suggests that changing the number of available food options or altering the positioning of foods could contribute to meaningful changes in behaviour, justifying policy actions to promote such changes within food environments. However, the certainty of this evidence as assessed by GRADE is low or very low. To enable more certain and generalisable conclusions about these potentially important effects, further research is warranted in real-world settings, intervening across a wider range of foods - as well as alcohol and tobacco products - and over sustained time periods

School-based interventions to prevent anxiety, depression and conduct disorders in children and young people:a systematic review, network meta-analysis and economic evaluation

Background: Schools in the UK increasingly have to respond to anxiety, depression and conduct disorder as key causes of morbidity in children and young people. Objective: The objective was to assess the comparative effectiveness of educational setting-based interventions for the prevention of anxiety, depression and conduct disorder in children and young people. Design: This study comprised a systematic review, a network meta-analysis and an economic evaluation. Data sources: The databases MEDLINE, EMBASE™ (Elsevier, Amsterdam, the Netherlands), PsycInfo® (American Psychological Association, Washington, DC, USA) and Cochrane Central Register of Controlled Trials (CENTRAL) were searched to 4 April 2018, and the NHS Economic Evaluation Database (NHS EED) was searched on 22 May 2019 for economic evaluations. No language or date filters were applied. Main outcomes: The main outcomes were post-intervention self-reported anxiety, depression or conduct disorder symptoms. Review methods: Randomised/quasi-randomised trials of universal or targeted interventions for the prevention of anxiety, depression or conduct disorder in children and young people aged 4–18 years were included. Screening was conducted independently by two reviewers. Data extraction was conducted by one reviewer and checked by a second. Intervention- and component-level network meta-analyses were conducted in OpenBUGS. A review of the economic literature and a cost–consequence analysis were conducted. Results: A total of 142 studies were included in the review, and 109 contributed to the network meta-analysis. Of the 109 studies, 57 were rated as having an unclear risk of bias for random sequence generation and allocation concealment. Heterogeneity was moderate. In universal secondary school settings, mindfulness/relaxation interventions [standardised mean difference (SMD) –0.65, 95% credible interval (CrI) –1.14 to –0.19] and cognitive–behavioural interventions (SMD –0.15, 95% CrI –0.34 to 0.04) may be effective for anxiety. Cognitive–behavioural interventions incorporating a psychoeducation component may be effective (SMD –0.30, 95% CrI –0.59 to –0.01) at preventing anxiety immediately post intervention. There was evidence that exercise was effective in preventing anxiety in targeted secondary school settings (SMD –0.47, 95% CrI –0.86 to –0.09). There was weak evidence that cognitive–behavioural interventions may prevent anxiety in universal (SMD –0.07, 95% CrI –0.23 to 0.05) and targeted (SMD –0.38, 95% CrI –0.84 to 0.07) primary school settings. There was weak evidence that cognitive–behavioural (SMD –0.04, 95% CrI –0.16 to 0.07) and cognitive–behavioural + interpersonal therapy (SMD –0.18, 95% CrI –0.46 to 0.08) may be effective in preventing depression in universal secondary school settings. Third-wave (SMD –0.35, 95% CrI –0.70 to 0.00) and cognitive–behavioural interventions (SMD –0.11, 95% CrI –0.28 to 0.05) incorporating a psychoeducation component may be effective at preventing depression immediately post intervention. There was no evidence of intervention effectiveness in targeted secondary, targeted primary or universal primary school settings post intervention. The results for university settings were unreliable because of inconsistency in the network meta-analysis. A narrative summary was reported for five conduct disorder prevention studies, all in primary school settings. None reported the primary outcome at the primary post-intervention time point. The economic evidence review reported heterogeneous findings from six studies. Taking the perspective of a single school budget and based on cognitive–behavioural therapy intervention costs in universal secondary school settings, the cost–consequence analysis estimated an intervention cost of £43 per student. Limitations: The emphasis on disorder-specific prevention excluded broader mental health interventions and restricted the number of eligible conduct disorder prevention studies. Restricting the study to interventions delivered in the educational setting may have limited the number of eligible university-level interventions. Conclusions: There was weak evidence of the effectiveness of school-based, disorder-specific prevention interventions, although effects were modest and the evidence not robust. Cognitive–behavioural therapy-based interventions may be more effective if they include a psychoeducation component. Future work: Future trials for prevention of anxiety and depression should evaluate cognitive–behavioural interventions with and without a psychoeducation component, and include mindfulness/relaxation or exercise comparators, with sufficient follow-up. Cost implications must be adequately measured. Study registration: This study is registered as PROSPERO CRD42016048184. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information

Clinical Presentations of Multiple Sclerosis at Royal Commission Hospital Yanbu Kingdom of Saudi Arabia

Introduction: Multiple sclerosis (MS) is an important cause of long standing disability especially in adult females. The incidence is more in Europe. In Europe specially in USA and UK the prevalence is about 120/ 100,000. The annual incidence is around 7 per 100,000, while the life time risk of developing MS is about 1in 400. The incidence of MS is higher in northern Europeans, and the disease is about twice as common in females. Objectives: To study various ways the patients of multiple sclerosis presented in the department of neurology atObjectives: To study various ways the patients of multiple sclerosis presented in the department of neurology at Royal commission hospital Yanbu, Kingdom of Saudi Arabia.Materials and Methods: This is new as well newly diagnosed patients who presented in the emergency as well as outpatient department of neurology at Royal Commission hospital Yanbu, Kingdom of Saudi Arabia. Yanbu is one of the biggest industrial city of Saudi Arabia. Duration of study was two years; from January 2011 to December 2012. The study included 50 patients. We diagnosed 45 patients ourselves and 5 patients were following in the neurology OPD.Results: The age range was 17 – 58; 38 patients were females and 2 were males. Most of the affected patients were in the age range of 17 – 36. Mean duration of illness was from 1 – 9 years. In most of the patients, the initial presentation was weakness and visual loss. Most of the patients were started on interferons and they has very good outcome.Conclusions: Multiple sclerosis involves both brain and spinal cord. Early diagnosis and treatment promises good outcome and rehabilitation. The new treatment modalities have played revolutionary role in modulating the disease. Abbreviations: MS = Multiple sclerosis

The effectiveness of ablative and non-surgical therapies for early hepatocellular carcinoma: systematic review and network meta-analysis of randomised controlled trials

Background & Aims Non-surgical therapies are frequently used for patients with early or very early hepatocellular carcinoma (HCC). The aim of this systematic review and network meta-analysis (NMA) was to evaluate and compare the effectiveness of ablative and non-surgical therapies for patients with small HCC. Methods Nine databases were searched (March 2021) along with clinical trial registries. Randomised controlled trials (RCTs) of any ablative or non-surgical therapy versus any comparator in patients with HCC ≤ 3cm were eligible. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. The effectiveness of therapies was compared using NMA. Threshold analysis was undertaken to identify which NMA results had less robust evidence. Results Thirty-seven eligible RCTs were included (including over 3700 patients). Most were from China (n=17) or Japan (n=7). Sample sizes ranged from 30 to 308 patients. The majority had a high RoB or some RoB concerns. No RCTs were identified for some therapies and no RCTs reported quality of life outcomes. The results of the NMA and treatment effectiveness rankings were very uncertain. However, the evidence demonstrated that percutaneous ethanol injection was worse than radiofrequency ablation for overall survival (hazard ratio [HR]: 1.45, 95% credible interval [CrI]: 1.16-1.82), progression-free survival (HR: 1.36, 95% CrI: 1.11-1.67), overall recurrence (relative risk [RR]: 1.19, 95% CrI: 1.02-1.39) and local recurrence (RR: 1.80, 95% CrI: 1.19-2.71). The threshold analysis suggested that robust evidence was lacking for some comparisons. Conclusions It is unclear which treatment is most effective for patients with small HCC because of limitations in the evidence base. It is also not known how these treatments would impact on quality of life. Further high quality RCTs are needed to provide robust evidence but may be difficult to undertake. Funding: National Institute for Health and Care Research (UK). Registration: PROSPERO CRD42020221357

Ablative and non-surgical therapies for early and very early hepatocellular carcinoma: a systematic review and network meta-analysis

Background A wide range of ablative and non-surgical therapies are available for treating small hepatocellular carcinoma in patients with very early or early-stage disease and preserved liver function. Objective To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm). Design Systematic review and network meta-analysis. Data sources Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews. Review methods Eligible studies were randomised controlled trials of ablative and non-surgical therapies, versus any comparator, for small hepatocellular carcinoma. Randomised controlled trials were quality assessed using the Cochrane Risk of Bias 2 tool and mapped. The comparative effectiveness of therapies was assessed using network meta-analysis. A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence. Where comparisons based on randomised controlled trial evidence were not robust or no randomised controlled trials were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis. The feasibility of undertaking economic modelling was explored. A workshop with patients and clinicians was held to discuss the findings and identify key priorities for future research. Results Thirty-seven randomised controlled trials (with over 3700 relevant patients) were included in the review. The majority were conducted in China or Japan and most had a high risk of bias or some risk of bias concerns. The results of the network meta-analysis were uncertain for most comparisons. There was evidence that percutaneous ethanol injection is inferior to radiofrequency ablation for overall survival (hazard ratio 1.45, 95% credible interval 1.16 to 1.82), progression-free survival (hazard ratio 1.36, 95% credible interval 1.11 to 1.67), overall recurrence (relative risk 1.19, 95% credible interval 1.02 to 1.39) and local recurrence (relative risk 1.80, 95% credible interval 1.19 to 2.71). Percutaneous acid injection was also inferior to radiofrequency ablation for progression-free survival (hazard ratio 1.63, 95% credible interval 1.05 to 2.51). Threshold analysis showed that further evidence could plausibly change the result for some comparisons. Fourteen eligible non-randomised studies were identified (n ≥ 2316); twelve had a high risk of bias so were not included in updated network meta-analyses. Additional non-randomised data, made available by a clinical advisor, were also included (n = 303). There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated. However, the updated analyses suggested that microwave ablation and resection are superior to percutaneous ethanol injection and percutaneous acid injection for some outcomes. Further research on stereotactic ablative radiotherapy was recommended at the workshop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials. Limitations Many studies were small and of poor quality. No comparative studies were found for some therapies. Conclusions The existing evidence base has limitations; the uptake of specific ablative therapies in the United Kingdom appears to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness. However, there is evidence that percutaneous ethanol injection and percutaneous acid injection are inferior to radiofrequency ablation, microwave ablation and resection. Study registration PROSPERO CRD42020221357. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (NIHR award ref: NIHR131224) and is published in full in Health Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information. Plain language summary Hepatocellular carcinoma is the most common type of primary liver cancer. There are a range of different treatments available for patients with early hepatocellular carcinoma. We looked for clinical trials in patients with small tumours (up to 3 cm) that compared different treatments. We brought together and analysed the results of these trials to see which treatments were most effective in terms of survival, progression, side effects and quality of life. Overall, the evidence has limitations; many trials had few patients and were of poor quality. Most were from China or Japan, where the common causes of liver disease and treatments available differ from those in the United Kingdom. The results of our analyses were very uncertain so we cannot be sure which treatment is the best overall. We did find that three treatments – radiofrequency ablation, microwave ablation and surgery – were generally more effective than percutaneous ethanol injection and percutaneous acid injection. There was not enough evidence to be certain which treatment was better when radiofrequency ablation was compared with laser ablation, microwave ablation, proton beam therapy or surgery. We found only poor-quality, non-randomised trials on high-intensity focused ultrasound, cryoablation and irreversible electroporation. There was very little evidence on treatments that combined radiofrequency ablation with other therapies. We found no studies that compared electrochemotherapy, histotripsy, stereotactic ablative radiotherapy or wider radiotherapy techniques with other treatments. Only two studies reported data on quality of life or patient satisfaction. We discussed the findings with patients and clinical experts. Stereotactic ablative radiotherapy was highlighted as a treatment that requires further research; however, it is only appropriate for certain subgroups of patients. Feasibility studies could inform future clinical trials by exploring issues such as whether patients are willing to take part in a trial or find the treatments acceptable. Scientific summary Background Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Around one-third of people with cirrhosis go on to develop HCC. The prognosis of symptomatic HCC is poor, so the National Institute for Health and Care Excellence recommends that patients with cirrhosis are monitored for early HCC with six-monthly ultrasound scans. Patients with early HCC and good liver function can be offered surgical or non-surgical interventions with curative intent. However, liver resection is not always possible due to the location of the tumour, poor liver function or portal hypertension, and liver transplantation is limited by availability. Therefore, ablative or non-surgical therapies are frequently used for treating early HCC, including microwave ablation (MWA) and radiofrequency ablation (RFA). There has been no definitive assessment of these therapies. Objectives The aim of this project was to evaluate and compare the effectiveness of ablative and non-surgical therapies for patients with small HCC. The key objectives were to: systematically identify all randomised controlled trials (RCTs) of ablative and non-surgical therapies for HCC evaluate their quality and applicability to UK populations determine the comparative effectiveness of therapies using network meta-analysis (NMA) where the evidence base is insufficient, supplement the RCT evidence with high-quality, non-randomised, prospective comparative studies identify priority areas where additional high-quality evidence is required (in collaboration with patients and clinicians) assess whether future economic analysis would be feasible and worthwhile. Methods Systematic review of randomised controlled trials Nine databases (including MEDLINE, Embase, CENTRAL, Science Citation Index) were searched for RCTs and systematic reviews published from 2000 to March 2021. Two trial registries were searched in April 2021 to identify ongoing and unpublished RCTs. The reference lists of relevant systematic reviews were checked and clinical advisors were consulted. Randomised controlled trials of patients with HCC up to 3 cm in size (or data on a subgroup(s) of patients with tumours ≤ 3 cm) were eligible for inclusion. Any ablative or non-surgical therapy was eligible, including: RFA MWA laser ablation high-intensity focused ultrasound (HIFU) cryoablation percutaneous ethanol injection (PEI) percutaneous acetic acid injection (PAI) irreversible electroporation (IRE) transarterial chemoembolisation (TACE) transarterial embolisation selective internal radiation therapy electrochemotherapy (ECT) histotripsy stereotactic ablative radiotherapy [SABR; the term stereotactic body radiotherapy (SBRT) is also used for this technology] wider radiotherapy techniques. Any comparator was eligible, except a different method of undertaking the same intervention. Outcomes of interest were overall survival (OS), progression-free survival (PFS), time to progression (TTP), serious adverse events (AEs), intervention-specific AEs and quality of life. Titles and abstracts were screened by one reviewer, with 10% checked by another reviewer. Full texts were screened by two reviewers independently. Data extraction was checked by a second reviewer. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. When studies did not report hazard ratios (HRs) and their variances, Kaplan–Meier data were extracted. Network meta-analysis After mapping the identified RCTs, NMAs were conducted for four outcomes: OS, PFS, overall recurrence and local recurrence. They were conducted in a Bayesian framework using Markov chain Monte Carlo techniques. The NMAs were used to assess and rank interventions by comparative effectiveness. Threshold analysis Threshold analysis was conducted at the contrast level to examine the impact of potential changes to the evidence on each treatment contrast. Results of the analysis were used to identify treatment comparisons which lacked robust RCT evidence and where non-randomised evidence should be sought for further review. Systematic review of non-randomised evidence A second systematic review of non-randomised evidence was undertaken. This review included studies of comparisons where additional evidence could plausibly change the NMA conclusions, as identified by the threshold analysis. Four databases were searched in August 2021 for studies that compared the selected interventions (RFA, MWA and laser ablation), either with each other or with resection. The databases were also searched in July 2021 for interventions that the advisory group identified as being of particular interest and where there was no RCT evidence: HIFU, cryoablation, IRE, ECT, histotripsy, SABR and wider radiotherapy techniques. Prospective non-randomised comparative trials of patients with HCC up to 3 cm (or data on a subgroup(s) of such patients) were eligible. The outcomes of interest were OS, PFS, TTP and quality of life. Methods of screening and data extraction were the same as outlined above. A validity assessment tool for non-randomised trials was developed. Updated network meta-analysis and threshold analysis Where the non-randomised trials were of sufficient quality, the NMAs were repeated after pooling (without any adjustments) the non-randomised evidence with the RCT evidence, to assess whether estimates were improved. A threshold analysis was conducted on the updated NMA results to explore robustness and sensitivity to bias of the new results. Results Systematic review of randomised controlled trial results Thirty-seven RCTs were included. Most were small, with sample sizes ranging from 30 to 308 patients. The majority of RCTs were conducted in China or Japan. The most frequently assessed therapy was RFA. The majority of RCTs assessed OS, PFS/disease-free survival and/or recurrence, along with response and AEs. One RCT assessed patient satisfaction. The RoB judgement was low for 9 RCTs, high for 12 RCTs and some concerns for 14 RCTs (two RCTs that reported no relevant outcomes were not assessed). For many comparisons, data were limited. Based on a narrative synthesis, RFA appears to be better than both PEI and PAI in terms of OS, PFS and recurrence, although AEs were more frequent after RFA. PAI appears to have similar effectiveness to PEI. For RFA versus resection, results were inconsistent, with some RCTs favouring RFA and some resection; AEs were more frequent after resection. Data from RCTs comparing RFA with MWA, laser ablation or proton beam therapy were limited. RCTs assessing RFA in combination with other treatments were also limited by small sample sizes. AEs were reported inconsistently. There was no RCT evidence for HIFU, cryoablation, IRE, ECT, histotripsy, SABR or wider radiotherapy techniques. Network meta-analysis and threshold analysis results The treatment rankings from the NMAs were very uncertain for all four outcomes (OS, PFS, overall and local recurrence). There was no meaningful difference in effectiveness for many of the treatment comparisons. There was evidence that PEI is worse than RFA for OS [HR 1.45, 95% credible interval (CrI) 1.16 to 1.82], PFS (HR 1.36, 95% CrI 1.11 to 1.67), overall recurrence [relative risk (RR) 1.19, 95% CrI 1.02 to 1.39] and local recurrence (RR 1.80, 95% CrI 1.19 to 2.71). PAI was worse than RFA for PFS (HR 1.63, 95% CrI 1.05 to 2.51). Resection was better than PEI for OS (HR 0.60, 95% CrI 0.39 to 0.92). RFA combined with PEI decreased the risk of local recurrence compared with PEI alone (RR 0.33, 95% CrI 0.12 to 0.94). Radiofrequency ablation + iodine-125 appears superior to RFA alone in terms of OS (HR 0.50, 95% CrI 0.31 to 0.80) and overall recurrence (RR 0.69, 95% CrI 0.48 to 0.99). There was also evidence to suggest that RFA + iodine-125 is better than PEI, PAI, TACE + PAI, RFA + TACE and laser ablation for OS, and better than PEI and TACE + PEI for overall recurrence. However, according to our clinical advisors RFA + iodine-125 is only used in selected centres in China. There was evidence to suggest an increased risk of overall recurrence with MWA + sorafenib, compared with both resection (RR 2.09, 95% CrI 1.12 to 3.89) and RFA + iodine-125 (RR 2.93, 95% CrI 1.31 to 6.56). Also, RFA + systemic chemotherapy decreased the risk of overall recurrence compared with MWA + sorafenib (RR 0.26, 95% CrI 0.08 to 0.92). The threshold analysis suggested that additional evidence could plausibly change the NMA result for comparisons including RFA, MWA, laser ablation, RFA + TACE, RFA + systemic chemotherapy or RFA + iodine-125. RFA, MWA and laser ablation were agreed to be interventions of interest by the advisory group. Systematic review of non-randomised evidence results Fourteen non-randomised studies were identified. The majority were conducted in China or Japan, with sample sizes ranging from 21 to 740 patients. No comparative studies were identified on ECT, histotripsy, SABR or wider radiotherapy techniques. The quality and reporting of the non-randomised studies were poor; 12 had a high RoB. Several studies allocated patients to treatments based on tumour characteristics, so there were potentially prognostic differences between groups at baseline. There was one study with a low RoB. It compared RFA with MWA and included 42 patients. Local tumour progression was similar between groups but new intrahepatic tumours were more frequent in the RFA group. One study of RFA compared with resection had an unclear RoB and included 346 patients. It reported significantly better health-related quality of life (HRQoL), fewer AEs and a shorter hospital stay in the RFA group. Updated network meta-analyses and threshold analysis results Due to the significant limitations of the non-randomised studies identified, only the two studies that were not at a high RoB were included in the updated NMAs. Additional non-randomised comparative data (RFA vs. MWA vs. IRE) made available prior to publication by a clinical advisor were also included. Updated NMAs using RCT and non-RCT evidence were undertaken for OS, PFS and local recurrence. Most results of the updated NMAs were consistent with the original results. There remained a high level of uncertainty in treatment rankings. However, the updated NMAs suggested that MWA improves OS and PFS compared with PEI (OS: HR 0.60, 95% CrI 0.40 to 0.90; PFS: HR 0.66, 95% CrI 0.46 to 0.95) and PAI (OS: HR 0.48, 95% CrI 0.24 to 0.99; PFS: HR 0.55, 95% CrI 0.33 to 0.94). Resection also improves PFS compared with PEI (HR 0.72, 95% CrI 0.54 to 0.96) and PAI (HR 0.61, 95% CrI 0.38 to 0.98). The NMA showed IRE to be worse than RFA (RR 2.97, 95% CrI 1.45 to 6.09) and RFA + PEI (RR 4.96, 95% CrI 1.50 to 16.36) for local recurrence, although the CrIs were very wide for both comparisons. There was also evidence that RFA + iodine-125 is better than resection in terms of OS (HR 0.53, 95% CrI 0.30 to 0.94). The threshold analysis suggested that additional evidence could plausibly change the NMA result for comparisons including MWA, RFA, IRE, RFA + TACE and laser. Feasibility of economic modelling Limitations in available clinical data may impact the feasibility of undertaking robust economic analysis. However, a value of information (VOI) analysis may be helpful as there are currently several treatments with limited evidence on effectiveness. VOI analysis quantifies the value of reducing decision uncertainty in monetary terms. This can then be compared with the costs of conducting further studies. This could help prioritise which treatments should (or should not) be assessed in future trials. This may be of particular relevance in considering treatments that are currently rarely used in NHS practice but may be effective. Patient and public involvement The project team included a patient collaborator, who was involved throughout the project. Four additional patients were recruited to the project advisory group, attending meetings at key stages of the project. Patients provided helpful information about the outcomes most important to them, which informed the development of the data extraction tool. Patients were surprised by the lack of data on patient preference and quality-of-life outcomes. Patient and public involvement added context to the review findings and informed the conclusions of the report and recommendations for further research. Workshop Two workshops were held with clinicians and patients to discuss the project findings and identify key priorities for future research. It was agreed that MWA would be the most appropriate comparator in future trials as it is widely used as the standard of care in the UK, and therapies that are more complex to deliver were considered unlikely to replace it. MWA is preferred over RFA due to technological advances and ease of use, rather than data on improved clinical effectiveness. However, future research may be most useful if focused on the subgroup of patients with tumours in challenging locations, less fit patients and those with incomplete response to primary therapy. SABR and proton beam therapy were considered to be of particular interest. They are not suitable for patients with advanced or moderately advanced liver disease and, unlike ablation, can usually only be delivered once, but may be appropriate for a subgroup of patients. Histotripsy is at an early stage of regulatory approval, so should not be assessed until efficacy has been demonstrated. It may be most feasible to undertake an international multicentre RCT as the marginal benefit of novel treatments compared with the existing standard of care is likely to be small, so future studies would need to be large to demonstrate a significant difference in outcomes, and the number of early HCC patients in the UK eligible for all treatments is limited. Outcomes that should be assessed in future trials include local recurrence, overall recurrence, OS, PFS, HRQoL and patient acceptability. Conclusions Implications for health care There are considerable limitations to the evidence on ablative and non-surgical therapies for early and very early HCC. There is insufficient evidence to draw any conclusions on quality-of-life outcomes. The only firm conclusions that can be drawn from the available data are that PEI and PAI are inferior to RFA, and also appear to be inferior to MWA and resection for certain survival outcomes. MWA and resection are the first-line standard of care for single HCC ≤ 3 cm in the UK. The uptake of specific ablative therapies in the UK appears to be based more on technological advancements and ease or speed of use than on high-quality evidence demonstrating superior clinical effectiveness. Recommendations for research It is difficult to make firm recommendations for research based on our findings. There are currently no comparative data on several ablative and non-surgical therapies, particularly those treatments reserved for the subgroup of patients with more challenging tumours. However, owing to the small number of such patients who would be eligible for both treatment arms within a trial, along with the marginal benefit of novel treatments compared with the existing standard of care, it is likely to be difficult to recruit sufficient numbers of patients. Future studies should assess local recurrence, overall recurrence, OS, PFS, HRQoL and patient acceptability, using clear and consistent definitions, in order to allow results to be compared across studies. Further research on SABR, and possibly other technologies, such as IRE, is required to identify where they should sit in the treatment pathway. Feasibility studies could address potential issues and c