Methods to Include Environmental Impacts in Health Economic Evaluations and Health Technology Assessments: A Scoping Review.

OBJECTIVES: The environmental impacts of healthcare are important factors that should be considered during health technology assessments. This study aims to summarize the evidence that exists about methods to include environmental impacts in health economic evaluations and health technology assessments. METHODS: We identified records for screening using an existing scoping review and a systematic search of academic databases and gray literature up to September 2023. We screened the identified records for eligibility and extracted data using a narrative synthesis approach. The review was conducted following the JBI Manual for Evidence Synthesis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses Extension for Scoping Reviews checklist. RESULTS: We identified 2898 records and assessed the full text of 114, of which 54 were included in this review. Ten methods were identified to include environmental impacts in health economic evaluations and health technology assessments. Methods included converting environmental impacts to dollars or disability-adjusted life years and including them in a cost-effectiveness, cost-utility, or cost-benefit analysis, calculating an incremental carbon footprint effectiveness ratio or incremental carbon footprint cost ratio, incorporating impacts as one criteria of a multi-criteria decision analysis, and freely considering impacts during health technology assessment deliberation processes. CONCLUSIONS: Methods to include environmental impacts in health economic evaluations and health technology assessments exist but have not been tested for widespread use by health technology assessment agencies. Further research and implementation work is needed to determine which method can best aid decision makers to choose low environmental impact healthcare interventions.

Outcome-based analytical performance specifications: current status and future challenges.

Analytical performance specifications (APS) based on outcomes refer to how 'good' the analytical performance of a test needs to be to do more good than harm to the patient. Analytical performance of a measurand affects its clinical performance. Without first setting clinical performance requirements, it is difficult to define how good analytically the test needs to be to meet medical needs. As testing is indirectly linked to health outcomes through clinical decisions on patient management, often simulation-based studies are used to assess the impact of analytical performance on the probability of clinical outcomes which is then translated to Model 1b APS according to the Milan consensus. This paper discusses the related key definitions, concepts and considerations that should assist in finding the most appropriate methods for deriving Model 1b APS. We review the advantages and limitations of published methods and discuss the criteria for transferability of Model 1b APS to different settings. We consider that the definition of the clinically acceptable misclassification rate is central to Model 1b APS. We provide some examples and guidance on a more systematic approach for first defining the clinical performance requirements for tests and we also highlight a few ideas to tackle the future challenges associated with providing outcome-based APS for laboratory testing.

Applying the Milan models to setting analytical performance specifications - considering all the information.

Analytical performance specifications (APS) are used for decisions about the required analytical quality of pathology tests to meet clinical needs. The Milan models, based on clinical outcome, biological variation, or state of the art, were developed to provide a framework for setting APS. An approach has been proposed to assign each measurand to one of the models based on a defined clinical use, physiological control, or an absence of quality information about these factors. In this paper we propose that in addition to such assignment, available information from all models should be considered using a risk-based approach that considers the purpose and role of the actual test in a clinical pathway and its impact on medical decisions and clinical outcomes in addition to biological variation and the state-of-the-art. Consideration of APS already in use and the use of results in calculations may also need to be considered to determine the most appropriate APS for use in a specific setting.

Low-risk prostate lesions: An evidence review to inform discussion on losing the "cancer" label.

BACKGROUND: Active surveillance (AS) mitigates harms from overtreatment of low-risk prostate lesions. Recalibration of diagnostic thresholds to redefine which prostate lesions are considered "cancer" and/or adopting alternative diagnostic labels could increase AS uptake and continuation. METHODS: We searched PubMed and EMBASE to October 2021 for evidence on: (1) clinical outcomes of AS, (2) subclinical prostate cancer at autopsy, (3) reproducibility of histopathological diagnosis, and (4) diagnostic drift. Evidence is presented via narrative synthesis. RESULTS: AS: one systematic review (13 studies) of men undergoing AS found that prostate cancer-specific mortality was 0%-6% at 15 years. There was eventual termination of AS and conversion to treatment in 45%-66% of men. Four additional cohort studies reported very low rates of metastasis (0%-2.1%) and prostate cancer-specific mortality (0%-0.1%) over follow-up to 15 years. Overall, AS was terminated without medical indication in 1%-9% of men. Subclinical reservoir: 1 systematic review (29 studies) estimated that the subclinical cancer prevalence was 5% at <30 years, and increased nonlinearly to 59% by >79 years. Four additional autopsy studies (mean age: 54-72 years) reported prevalences of 12%-43%. Reproducibility: 1 recent well-conducted study found high reproducibility for low-risk prostate cancer diagnosis, but this was more variable in 7 other studies. Diagnostic drift: 4 studies provided consistent evidence of diagnostic drift, with the most recent (published 2020) reporting that 66% of cases were upgraded and 3% were downgraded when using contemporary diagnostic criteria compared to original diagnoses (1985-1995). CONCLUSIONS: Evidence collated may inform discussion of diagnostic changes for low-risk prostate lesions.

Should low-risk DCIS lose the cancer label? An evidence review.

BACKGROUND: Population mammographic screening for breast cancer has led to large increases in the diagnosis and treatment of ductal carcinoma in situ (DCIS). Active surveillance has been proposed as a management strategy for low-risk DCIS to mitigate against potential overdiagnosis and overtreatment. However, clinicians and patients remain reluctant to choose active surveillance, even within a trial setting. Re-calibration of the diagnostic threshold for low-risk DCIS and/or use of a label that does not include the word 'cancer' might encourage the uptake of active surveillance and other conservative treatment options. We aimed to identify and collate relevant epidemiological evidence to inform further discussion on these ideas. METHODS: We searched PubMed and EMBASE databases for low-risk DCIS studies in four categories: (1) natural history; (2) subclinical cancer found at autopsy; (3) diagnostic reproducibility (two or more pathologist interpretations at a single time point); and (4) diagnostic drift (two or more pathologist interpretations at different time points). Where we identified a pre-existing systematic review, the search was restricted to studies published after the inclusion period of the review. Two authors screened records, extracted data, and performed risk of bias assessment. We undertook a narrative synthesis of the included evidence within each category. RESULTS: Natural History (n = 11): one systematic review and nine primary studies were included, but only five provided evidence on the prognosis of women with low-risk DCIS. These studies reported that women with low-risk DCIS had comparable outcomes whether or not they had surgery. The risk of invasive breast cancer in patients with low-risk DCIS ranged from 6.5% (7.5 years) to 10.8% (10 years). The risk of dying from breast cancer in patients with low-risk DCIS ranged from 1.2 to 2.2% (10 years). Subclinical cancer at autopsy (n = 1): one systematic review of 13 studies estimated the mean prevalence of subclinical in situ breast cancer to be 8.9%. Diagnostic reproducibility (n = 13): two systematic reviews and 11 primary studies found at most moderate agreement in differentiating low-grade DCIS from other diagnoses. Diagnostic drift: no studies found. CONCLUSION: Epidemiological evidence supports consideration of relabelling and/or recalibrating diagnostic thresholds for low-risk DCIS. Such diagnostic changes would need agreement on the definition of low-risk DCIS and improved diagnostic reproducibility.

Regular high-frequency whole blood donation and risk of cardiovascular disease in middle-aged and older blood donors in Australia.

BACKGROUND: Previous mixed findings on the associations between whole blood (WB) donation and risk of cardiovascular diseases (CVD) may in part reflect inadequate adjustment for the "healthy donor effect" (HDE). METHODS: We used the Sax Institute's 45 and Up Study linked with blood donation history and other health-related databases to examine the association between regular, high-frequency WB donation and the risk of CVD. To mitigate the impact of HDE, we used a "5-years qualification period," in which donors must donate at least 1 WB donation in the 1st and 5th year of "qualification period." We then compared the risk of CVD in the years following the "qualification period" between the regular high-frequency WB donors (≥2 WB donation in each qualification year) and others using Cox proportional-hazards models. Analyses were adjusted for potential confounders, such as sociodemographic, lifestyle, and health-related variables, and results are reported separately for male and female donors. RESULTS: A total of 2736 male and 2917 female donors were included in the analyses. The median years of follow-up per donor was 5.84 years (Q1-Q3, 5.47-6.23). The rate of CVD hospitalization was 11.20 and 4.50 per 1000 person-years for males and females, respectively. In fully adjusted models, the risk (hazard ratio) of CVD in regular high-frequency donors compared to other donors was 0.93 (95% Confidence Interval (CI), 0.68-1.29) for males and 0.79 (95% CI, 0.49-1.28) for females. CONCLUSIONS: We did not observe a statistically significant reduction of CVD risk in regular, high-frequency WB donors when adjusted for potential confounders.

What is the prevalence of fear of cancer recurrence in cancer survivors and patients? A systematic review and individual participant data meta-analysis.

OBJECTIVE: Care for fear of cancer recurrence (FCR) is considered the most common unmet need among cancer survivors. Yet the prevalence of FCR and predisposing factors remain inconclusive. To support targeted care, we provide a comprehensive overview of the prevalence and severity of FCR among cancer survivors and patients, as measured using the short form of the validated Fear of Cancer Recurrence Inventory (FCRI-SF). We also report on associations between FCR and clinical and demographic characteristics. METHODS: This is a systematic review and individual participant data (IPD) meta-analysis on the prevalence of FCR. In the review, we included all studies that used the FCRI-SF with adult (≥18 years) cancer survivors and patients. Date of search: 7 February 2020. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool. RESULTS: IPD were requested from 87 unique studies and provided for 46 studies comprising 11,226 participants from 13 countries. 9311 respondents were included for the main analyses. On the FCRI-SF (range 0-36), 58.8% of respondents scored ≥13, 45.1% scored ≥16 and 19.2% scored ≥22. FCR decreased with age and women reported more FCR than men. FCR was found across cancer types and continents and for all time periods since cancer diagnosis. CONCLUSIONS: FCR affects a considerable number of cancer survivors and patients. It is therefore important that healthcare providers discuss this issue with their patients and provide treatment when needed. Further research is needed to investigate how best to prevent and treat FCR and to identify other factors associated with FCR. The protocol was prospectively registered (PROSPERO CRD42020142185).

Clinician views and experiences of non-invasive prenatal genetic screening tests in Australia.

BACKGROUND: Non-invasive prenatal screening (NIPS) is being increasingly used by expectant parents. Much provision of this test in Australia is occurring in clinical settings where specialised genetic counselling is unavailable, such as general practice. Potential psychosocial consequences from this kind of prenatal genetic screening remain largely unexplored. AIMS: To explore clinicians' experiences with NIPS for aneuploidy, their perspectives of the benefits and harms of NIPS, clinicians' information needs, and their perceptions of the needs of expectant parents. MATERIALS AND METHODS: Qualitative, semi-structured interviews with 17 health professionals (clinical geneticists, obstetricians, genetic counsellors and general practitioners) who request and counsel for NIPS in Australian hospital and private practice settings, conducted between June 2019 and February 2020. RESULTS: Five themes were identified relating to clinicians' perceptions and experiences of NIPS in their practice: perceived benefits of NIPS, perceived harms of NIPS (with two subthemes: clinical harms and psychosocial harms), financial and equity-related concerns, counselling as a protective buffer against perceived harms, and clinicians' unmet education needs. While clinicians view NIPS as a useful and high-quality screening test, especially for detection of common trisomies, many participants had concerns about how NIPS has been implemented in practice, particularly the quality (and often absence) of pre-/post-test counselling and the routinisation of testing for sex chromosome aneuploidies, microdeletion and microduplication syndromes. CONCLUSION: These findings support the need for targeted clinician training around NIPS, and for a shared decision-making approach to support expectant parents' autonomous decisions about NIPS.

Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study.

BACKGROUND: The Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Lipid study found no evidence of a beneficial effect of statin-fibrate combined treatment, compared to statins alone, on cardiovascular outcomes and mortality in type 2 diabetes mellitus after 5 years of active treatment. However, a beneficial reduction in major CVD events was shown in a pre-specified sub-group of participants with dyslipidemia. The extended follow-up of this trial provides the opportunity to further investigate possible beneficial effects of fibrates in this group of patients. We aimed to evaluate possible "legacy effects" of fibrate add-on therapy on mortality and major cardiovascular outcomes in patients with dyslipidemia. METHODS: The ACCORD-lipid study was a randomized controlled trial of 5518 participants assigned to receive simvastatin plus fenofibrate vs simvastatin plus placebo. After randomized treatment allocation had finished at the end of the trial, all surviving participants were invited to attend an extended follow-up study (ACCORDION) to continue prospective collection of clinical outcomes. We undertook a secondary analysis of trial and post-trial data in patients who had dyslipidemia. The primary outcome was all-cause and cardiovascular mortality, and secondary outcomes were nonfatal myocardial infarction, stroke, congestive heart failure and major coronary heart disease. We used an intention-to-treat approach to analysis to make comparisons between the original randomized treatment groups. RESULTS: 853 participants with dyslipidemia had survived at the end of the trial. Most participants continued to use statins, but few used fibrates in either group during the post-trial period. The incidence rates in the fenofibrate group were lower with respect to all-cause mortality, CVD mortality, nonfatal myocardial infarction, congestive heart failure and major coronary heart disease than those in the placebo group over a post-trial follow-up. Allocation to the combined fibrate-statin treatment arm during the trial period had a beneficial legacy effect on all-cause mortality (adjusted HR = 0.65, 95% CI 0.45-0.94; P = 0.02). CONCLUSIONS: Fibrate treatment during the initial trial period was associated with a legacy benefit of improved survival over a post-trial follow-up. These findings support re-evaluation of fibrates as an add-on strategy to statins in order to reduce cardiovascular risk in diabetic patients with dyslipidemia. Trial registration clinicaltrials.gov, Identifier: NCT00000620.

Why clinicians overtest: development of a thematic framework.

BACKGROUND: Medical tests provide important information to guide clinical management. Overtesting, however, may cause harm to patients and the healthcare system, including through misdiagnosis, false positives, false negatives and overdiagnosis. Clinicians are ultimately responsible for test requests, and are therefore ideally positioned to prevent overtesting and its unintended consequences. Through this narrative literature review and workshop discussion with experts at the Preventing Overdiagnosis Conference (Sydney, 2019), we aimed to identify and establish a thematic framework of factors that influence clinicians to request non-recommended and unnecessary tests. METHODS: Articles exploring factors affecting clinician test ordering behaviour were identified through a systematic search of MedLine in April 2019, forward and backward citation searches and content experts. Two authors screened abstract titles and abstracts, and two authors screened full text for inclusion. Identified factors were categorised into a preliminary framework which was subsequently presented at the PODC for iterative development. RESULTS: The MedLine search yielded 542 articles; 55 were included. Another 10 articles identified by forward-backward citation and content experts were included, resulting in 65 articles in total. Following small group discussion with workshop participants, a revised thematic framework of factors was developed: "Intrapersonal" - fear of malpractice and litigation; clinician knowledge and understanding; intolerance of uncertainty and risk aversion; cognitive biases and experiences; sense of medical obligation "Interpersonal" - pressure from patients and doctor-patient relationship; pressure from colleagues and medical culture; "Environment/context" - guidelines, protocols and policies; financial incentives and ownership of tests; time constraints, physical vulnerabilities and language barriers; availability and ease of access to tests; pre-emptive testing to facilitate subsequent care; contemporary medical practice and new technology CONCLUSION: This thematic framework may raise awareness of overtesting and prompt clinicians to change their test request behaviour. The development of a scale to assess clinician knowledge, attitudes and practices is planned to allow evaluation of clinician-targeted interventions to reduce overtesting.

Use of shared care and routine tests in follow-up after treatment for localised cutaneous melanoma.

BACKGROUND: Patients may decide to undertake shared care with a general practitioner (GP) during follow-up after treatment for localised melanoma. Routine imaging tests for surveillance may be commonly used despite no evidence of clinical utility. This study describes the frequency of shared care and routine tests during follow-up after treatment for localised melanoma. METHODS: We randomly sampled 351 people with localised melanoma [American Joint Cancer Committee (AJCC) substages 0 - II] who had not had recurrent or new primary melanoma diagnosed from a total of 902 people diagnosed and treated for localised melanoma at a specialist centre in 2014. We interviewed participants by telephone about their experience of follow-up in the past year, and documented the proportion of patients who were undertaking shared care follow-up with a GP. We also recorded the frequency and type of investigations during follow-up. We calculated weighted estimates that are representative of the full inception cohort. RESULTS: Of the 351 people who were invited to participate, 230 (66%) people consented to the telephone interview. The majority undertook shared care follow-up with a GP (61%). People who choose to have shared care follow-up with a GP are more likely to be male (p = 0.006), have lower AJCC stage (p for trend = 0.02), reside in more remote areas (p for trend< 0.001), and are less likely to have completed secondary school (p < 0.001). Few people saw a non-doctor health practitioner as part of their follow-up (9%). Many people report undergoing tests for melanoma, much of which may be routine tests for surveillance (37%). CONCLUSIONS: The majority of people treated for a first primary localised melanoma at a specialist centre, without recurrent or new melanoma, choose to undertake shared care follow-up with a GP. Many appear to have routine diagnostic imaging as part of their melanoma surveillance.

Prevalence of incidental breast cancer and precursor lesions in autopsy studies: a systematic review and meta-analysis.

BACKGROUND: Autopsy studies demonstrate the prevalence pool of incidental breast cancer in the population, but estimates are uncertain due to small numbers in any primary study. We aimed to conduct a systematic review of autopsy studies to estimate the prevalence of incidental breast cancer and precursors. METHODS: Relevant articles were identified through searching PubMed and Embase from inception up to April 2016, and backward and forward citations. We included autopsy studies of women with no history of breast pathology, which included systematic histological examination of at least one breast, and which allowed calculation of the prevalence of incidental breast cancer or precursor lesions. Data were pooled using logistic regression models with random intercepts (non-linear mixed models). RESULTS: We included 13 studies from 1948 to 2010, contributing 2363 autopsies with 99 cases of incidental cancer or precursor lesions. More thorough histological examination (≥20 histological sections) was a strong predictor of incidental in-situ cancer and atypical hyperplasia (OR = 126·8 and 21·3 respectively, p < 0·001), but not invasive cancer (OR = 1·1, p = 0·75). The estimated mean prevalence of incidental cancer or precursor lesion was 19·5% (0·85% invasive cancer + 8·9% in-situ cancer + 9·8% atypical hyperplasia). CONCLUSION: Our systematic review in ten countries over six decades found that incidental detection of cancer in situ and breast cancer precursors is common in women not known to have breast disease during life. The large prevalence pool of undetected cancer in-situ and atypical hyperplasia in these autopsy studies suggests screening programs should be cautious about introducing more sensitive tests that may increase detection of these lesions.

Fear of new or recurrent melanoma after treatment for localised melanoma.

OBJECTIVE: To estimate the amount of fear of new or recurrent melanoma among people treated for localised melanoma in an Australian specialist centre. METHODS: We randomly selected 400 potential participants from all those treated for localised melanoma at the Melanoma Institute Australia during 2014 (n = 902). They were asked to complete an adapted version of the Fear of Cancer Recurrence Inventory (FCRI). We calculated summary statistics for demographics, clinical variables and total FCRI and subscale scores. RESULTS: Two hundred fifteen people (54%) completed the FCRI questionnaire. The overall mean severity subscale score was 15.0 (95% CI 14.0-16.1). A high proportion of participants had scores above a proposed threshold to screen for clinical fear of cancer recurrence (77% and 63% of participants with and without new or recurrent melanoma had severity subscale scores ≥13). Most participants also had scores above a threshold found to have high specificity for clinical fear of cancer recurrence (65% and 48% of participants with and without new or recurrent melanoma had severity subscale scores ≥16). The severity subscale appeared to discriminate well between groups with differing levels of risk of new or recurrent melanoma. CONCLUSIONS: There is a substantial amount of fear of new or recurrent melanoma among this population, despite most having a very good prognosis.

What's the uptake? Pragmatic RCTs may be used to estimate uptake, and thereby population impact of interventions, but better reporting of trial recruitment processes is needed.

BACKGROUND: Effectiveness of interventions in pragmatic trials may not translate directly into population impact, because of limited uptake by clinicians and/or the public. Uptake of an intervention is influenced by a number of factors. METHODS: We propose a method for calculating population impact of clinical interventions that accounts for the intervention uptake. We suggest that population impact may be estimated by multiplying the two key components: (1) the effectiveness of the intervention in pragmatic trials (trial effect); and, (2) its uptake in clinical practice. We argue that participation rates in trials may be a valid proxy for uptake in clinical practice and, in combination with trial effectiveness estimates, be used to rank interventions by their likely population impact. We illustrate the method using the example of four interventions to decrease antibiotic prescription for acute respiratory infections in primary care: delayed prescribing, procalcitonin test, C-Reactive Protein, shared decision making. RESULTS: In order to estimate uptake of interventions from trial data we need detailed reporting on the recruitment processes used for clinician participation in the trials. In the antibiotic prescribing example, between 75 and 91% of the population would still be prescribed or consume antibiotics because effective interventions were not taken up. Of the four interventions considered, we found that delayed prescribing would have the highest population impact and shared decision making the lowest. CONCLUSION: Estimates of uptake and population impact of an intervention may be possible from pragmatic RCTs, provided the recruitment processes for these trials are adequately reported (which currently few of them are). Further validation of this method using empirical data on intervention uptake in the real world would support use of this method to decide on public funding of interventions.

EARLY CRT MONITORING USING TIME-DOMAIN OPTICAL COHERENCE TOMOGRAPHY DOES NOT ADD TO VISUAL ACUITY FOR PREDICTING VISUAL LOSS IN PATIENTS WITH CENTRAL RETINAL VEIN OCCLUSION TREATED WITH INTRAVITREAL RANIBIZUMAB: A Secondary Analysis of Trial Data.

PURPOSE: Our primary purpose was to assess the clinical (predictive) validity of central retinal thickness (CRT) and best corrected visual acuity (BCVA) at 1 week and 1 month after starting treatment with ranibizumab for central retinal vein occlusion. The authors also assessed detectability of response to treatment. METHODS: The authors used data from 325 participants in the CRUISE study, which included measurement of time-domain CRT and BCVA at baseline, 1 week, 1 month, and 6 months postrandomization. Analysis of covariance models were fitted to assess clinical validity, and distributions of change were constructed to assess detectability of response. RESULTS: There was no evidence that 1-week CRT, and very strong evidence that 1-week BCVA were associated with baseline-adjusted BCVA at 6 months (P = 0.17 and P < 0.001, respectively). There was strong evidence that both 1-month CRT and 1-month BCVA were associated with baseline-adjusted 6-month BCVA (P = 0.005 and P < 0.001, respectively), but simultaneous adjustment found evidence of independent association only for BCVA (P = 0.71 and P < 0.001 for CRT and BCVA, respectively). Detectability of response tended to be higher for CRT than BCVA at 1 week and 1 month but by 6 months these were equivalent for CRT and BCVA. CONCLUSION: In this study, BCVA monitoring of treated central retinal vein occlusion patients seemed more informative than time-domain optical coherence tomography monitoring.