Causal Estimation of Long-term Intervention Cost-effectiveness Using Genetic Instrumental Variables: An Application to Cancer.

BACKGROUND: This article demonstrates a means of assessing long-term intervention cost-effectiveness in the absence of data from randomized controlled trials and without recourse to Markov simulation or similar types of cohort simulation. METHODS: Using a Mendelian randomization study design, we developed causal estimates of the genetically predicted effect of bladder, breast, colorectal, lung, multiple myeloma, ovarian, prostate, and thyroid cancers on health care costs and quality-adjusted life-years (QALYs) using outcome data drawn from the UK Biobank cohort. We then used these estimates in a simulation model to estimate the cost-effectiveness of a hypothetical population-wide preventative intervention based on a repurposed class of antidiabetic drugs known as sodium-glucose cotransporter-2 (SGLT2) inhibitors very recently shown to reduce the odds of incident prostate cancer. RESULTS: Genetic liability to prostate cancer and breast cancer had material causal impacts on either or both health care costs and QALYs. Mendelian randomization results for the less common cancers were associated with considerable uncertainty. SGLT2 inhibition was unlikely to be a cost-effective preventative intervention for prostate cancer, although this conclusion depended on the price at which these drugs would be offered for a novel anticancer indication. IMPLICATIONS: Our new causal estimates of cancer exposures on health economic outcomes may be used as inputs into decision-analytic models of cancer interventions such as screening programs or simulations of longer-term outcomes associated with therapies investigated in randomized controlled trials with short follow-ups. Our method allowed us to rapidly and efficiently estimate the cost-effectiveness of a hypothetical population-scale anticancer intervention to inform and complement other means of assessing long-term intervention value. HIGHLIGHTS: The article demonstrates a novel method of assessing long-term intervention cost-effectiveness without relying on randomized controlled trials or cohort simulations.Mendelian randomization was used to estimate the causal effects of certain cancers on health care costs and quality-adjusted life-years (QALYs) using data from the UK Biobank cohort.Given causal data on the association of different cancer exposures on costs and QALYs, it was possible to simulate the cost-effectiveness of an anticancer intervention.Genetic liability to prostate cancer and breast cancer significantly affected health care costs and QALYs, but the hypothetical intervention using SGLT2 inhibitors for prostate cancer may not be cost-effective, depending on the drug's price for the new anticancer indication. The methods we propose and implement can be used to efficiently estimate intervention cost-effectiveness and to inform decision making in all manner of preventative and therapeutic contexts.

Impact of PSA testing on secondary care costs in England and Wales: estimates from the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).

BACKGROUND: Screening men for prostate cancer using prostate-specific antigen (PSA) testing remains controversial. We aimed to estimate the likely budgetary impact on secondary care in England and Wales to inform screening decision makers. METHODS: The Cluster randomised triAl of PSA testing for Prostate cancer study (CAP) compared a single invitation to men aged 50-69 for a PSA test with usual care (no screening). Routinely collected hospital care data were obtained for all men in CAP, and NHS reference costs were mapped to each event via Healthcare Resource Group (HRG) codes. Secondary-care costs per man per year were calculated, and cost differences (and population-level estimates) between arms were derived annually for the first five years following randomisation. RESULTS: In the first year post-randomisation, secondary-care costs averaged across all men (irrespective of a prostate cancer diagnosis) in the intervention arm (n = 189279) were £44.80 (95% confidence interval: £18.30-£71.30) higher than for men in the control arm (n = 219357). Extrapolated to a population level, the introduction of a single PSA screening invitation could lead to additional secondary care costs of £314 million. CONCLUSIONS: Introducing a single PSA screening test for men aged 50-69 across England and Wales could lead to very high initial secondary-care costs.

Progressing From Disparity to Equity: Untangling the Complexities of Timely Care and the Rural Cancer Experience.

Richard L. Martin III, MD, MPH, and Stephen Schleicher, MD, MBA, share a perspective on rural cancer care.

Intravascular imaging assessment of pharmacotherapies targeting atherosclerosis: advantages and limitations in predicting their prognostic implications.

Intravascular imaging has been often used over the recent years to examine the efficacy of emerging therapies targeting plaque evolution. Serial intravascular ultrasound, optical coherence tomography, or near-infrared spectroscopy-intravascular ultrasound studies have allowed us to evaluate the effects of different therapies on plaque burden and morphology, providing unique mechanistic insights about the mode of action of these treatments. Plaque burden reduction, a decrease in necrotic core component or macrophage accumulation-which has been associated with inflammation-and an increase in fibrous cap thickness over fibroatheromas have been used as surrogate endpoints to assess the value of several drugs in inhibiting plaque evolution and improving clinical outcomes. However, some reports have demonstrated weak associations between the effects of novel treatments on coronary atheroma and composition and their prognostic implications. This review examines the value of invasive imaging in assessing pharmacotherapies targeting atherosclerosis. It summarizes the findings of serial intravascular imaging studies assessing the effects of different drugs on atheroma burden and morphology and compares them with the results of large-scale trials evaluating their impact on clinical outcome. Furthermore, it highlights the limited efficacy of established intravascular imaging surrogate endpoints in predicting the prognostic value of these pharmacotherapies and introduces alternative imaging endpoints based on multimodality/hybrid intravascular imaging that may enable more accurate assessment of the athero-protective and prognostic effects of emerging therapies.

Patient-Reported Outcomes 12 Years after Localized Prostate Cancer Treatment.

BACKGROUND: Long-term patient-reported outcomes are needed to inform treatment decisions for localized prostate cancer. METHODS: Patient-reported outcomes of 1643 randomly assigned participants in the ProtecT (Prostate Testing for Cancer and Treatment) trial were evaluated to assess the functional and quality-of-life impacts of prostatectomy, radiotherapy with neoadjuvant androgen deprivation, and active monitoring. This article focuses on the outcomes of the randomly assigned participants from 7 to 12 years using mixed effects linear and logistic models. RESULTS: Response rates exceeded 80% for most measures. Among the randomized groups over 7 to 12 years, generic quality-of-life scores were similar. Among those in the prostatectomy group, urinary leakage requiring pads occurred in 18 to 24% of patients over 7 to 12 years, compared with 9 to 11% in the active monitoring group and 3 to 8% in the radiotherapy group. In the prostatectomy group, 18% reported erections sufficient for intercourse at 7 years, compared with 30% in the active monitoring and 27% in the radiotherapy groups; all converged to low levels of potency by year 12. Nocturia (voiding at least twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and 47% in the active monitoring group at 12 years. Fecal leakage affected 12% in the radiotherapy group compared with 6% in the other groups by year 12. The active monitoring group experienced gradual age-related declines in sexual and urinary function, avoiding radical treatment effects unless they changed management. CONCLUSIONS: ProtecT provides robust evidence about continued impacts of treatments in the long term. These data allow patients newly diagnosed with localized prostate cancer and their clinicians to assess the trade-offs between treatment harms and benefits and enable better informed and prudent treatment decisions. (Funded by the UK National Institute for Health and Care Research Health Technology Assessment Programme projects 96/20/06 and 96/20/99; ISRCTN number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Cost-Effectiveness Analysis of Prostate Cancer Screening in the UK: A Decision Model Analysis Based on the CAP Trial.

BACKGROUND AND OBJECTIVE: Most guidelines in the UK, Europe and North America do not recommend organised population-wide screening for prostate cancer. Prostate-specific antigen-based screening can reduce prostate cancer-specific mortality, but there are concerns about overdiagnosis, overtreatment and economic value. The aim was therefore to assess the cost effectiveness of eight potential screening strategies in the UK. METHODS: We used a cost-utility analysis with an individual-based simulation model. The model was calibrated to data from the 10-year follow-up of the Cluster Randomised Trial of PSA Testing for Prostate Cancer (CAP). Treatment effects were modelled using data from the Prostate Testing for Cancer and Treatment (ProtecT) trial. The participants were a hypothetical population of 10 million men in the UK followed from age 30 years to death. The strategies were: no screening; five age-based screening strategies; adaptive screening, where men with an initial prostate-specific antigen level of < 1.5 ng/mL are screened every 6 years and those above this level are screened every 4 years; and two polygenic risk-stratified screening strategies. We assumed the use of pre-biopsy multi-parametric magnetic resonance imaging for men with prostate-specific antigen ≥ 3 ng/mL and combined transrectal ultrasound-guided and targeted biopsies. The main outcome measures were projected lifetime costs and quality-adjusted life-years from a National Health Service perspective. RESULTS: All screening strategies increased costs compared with no screening, with the majority also increasing quality-adjusted life-years. At willingness-to-pay thresholds of £20,000 or £30,000 per quality-adjusted life-year gained, a once-off screening at age 50 years was optimal, although this was sensitive to the utility estimates used. Although the polygenic risk-stratified screening strategies were not on the cost-effectiveness frontier, there was evidence to suggest that they were less cost ineffective than the alternative age-based strategies. CONCLUSIONS: Of the prostate-specific antigen-based strategies compared, only a once-off screening at age 50 years was potentially cost effective at current UK willingness-to-pay thresholds. An additional follow-up of CAP to 15 years may reduce uncertainty about the cost effectiveness of the screening strategies.

Can polygenic risk scores contribute to cost-effective cancer screening? A systematic review.

PURPOSE: Polygenic risk influences susceptibility to cancer. We assessed whether polygenic risk scores could be used in conjunction with other predictors of future disease status in cost-effective risk-stratified screening for cancer. METHODS: We undertook a systematic review of papers that evaluated the cost-effectiveness of screening interventions informed by polygenic risk scores compared with more conventional screening modalities. We included papers reporting cost-effectiveness outcomes with no restriction on type of cancer or form of polygenic risk modeled. We evaluated studies using the Quality of Health Economic Studies checklist. RESULTS: A total of 10 studies were included in the review, which investigated 3 cancers: prostate (n = 5), colorectal (n = 3), and breast (n = 2). Of the 10 papers, 9 scored highly (score >75 on a 0-100 scale) when assessed using the quality checklist. Of the 10 studies, 8 concluded that polygenic risk-informed cancer screening was likely to be more cost-effective than alternatives. CONCLUSION: Despite the positive conclusions of the included studies, it is unclear if polygenic risk stratification will contribute to cost-effective cancer screening given the absence of robust evidence on the costs of polygenic risk stratification, the effects of differential ancestry, potential downstream economic sequalae, and how large volumes of polygenic risk data would be collected and used.

Systematic Review of Cost-Effectiveness Models in Prostate Cancer: Exploring New Developments in Testing and Diagnosis.

OBJECTIVES: Recent innovations in prostate cancer diagnosis include new biomarkers and more accurate biopsy methods. This study assesses the evidence base on cost-effectiveness of these developments (eg, Prostate Health Index and magnetic resonance imaging [MRI]-guided biopsy) and identifies areas of improvement for future cost-effectiveness models. METHODS: A systematic review using the National Health Service Economic Evaluation Database, MEDLINE, Embase, Health Technology Assessment databases, National Institute for Health and Care Excellence guidelines, and United Kingdom National Screening Committee guidance was performed, between 2009 and 2021. Relevant data were extracted on study type, model inputs, modeling methods and cost-effectiveness conclusions, and results narratively synthesized. RESULTS: A total of 22 model-based economic evaluations were included. A total of 11 compared the cost-effectiveness of new biomarkers to prostate-specific antigen testing alone and all found biomarkers to be cost saving. A total of 8 compared MRI-guided biopsy methods to transrectal ultrasound-guided methods and found MRI-guided methods to be most cost-effective. Newer detection methods showed a reduction in unnecessary biopsies and overtreatment. The most cost-effective follow-up strategy in men with a negative initial biopsy was uncertain. Many studies did not model for stage or grade of cancer, cancer progression, or the entire testing and treatment pathway. Few fully accounted for uncertainty. CONCLUSIONS: This review brings together the cost-effectiveness literature for novel diagnostic methods in prostate cancer, showing that most studies have found new methods to be more cost-effective than standard of care. Several limitations of the models were identified, however, limiting the reliability of the results. Areas for further development include accurately modeling the impact of early diagnostic tests on long-term outcomes of prostate cancer and fully accounting for uncertainty.

Investigating the effect of sexual behaviour on oropharyngeal cancer risk: a methodological assessment of Mendelian randomization.

BACKGROUND: Human papilloma virus infection is known to influence oropharyngeal cancer (OPC) risk, likely via sexual transmission. However, sexual behaviour has been correlated with other risk factors including smoking and alcohol, meaning independent effects are difficult to establish. We aimed to evaluate the causal effect of sexual behaviour on the risk of OPC using Mendelian randomization (MR). METHODS: Genetic variants robustly associated with age at first sex (AFS) and the number of sexual partners (NSP) were used to perform both univariable and multivariable MR analyses with summary data on 2641 OPC cases and 6585 controls, obtained from the largest available genome-wide association studies (GWAS). Given the potential for genetic pleiotropy, we performed a number of sensitivity analyses: (i) MR methods to account for horizontal pleiotropy, (ii) MR of sexual behaviours on positive (cervical cancer and seropositivity for Chlamydia trachomatis) and negative control outcomes (lung and oral cancer), (iii) Causal Analysis Using Summary Effect estimates (CAUSE), to account for correlated and uncorrelated horizontal pleiotropic effects, (iv) multivariable MR analysis to account for the effects of smoking, alcohol, risk tolerance and educational attainment. RESULTS: In univariable MR, we found evidence supportive of an effect of both later AFS (IVW OR = 0.4, 95%CI (0.3, 0.7), per standard deviation (SD), p = < 0.001) and increasing NSP (IVW OR = 2.2, 95%CI (1.3, 3.8) per SD, p = < 0.001) on OPC risk. These effects were largely robust to sensitivity analyses accounting for horizontal pleiotropy. However, negative control analysis suggested potential violation of the core MR assumptions and subsequent CAUSE analysis implicated pleiotropy of the genetic instruments used to proxy sexual behaviours. Finally, there was some attenuation of the univariable MR results in the multivariable models (AFS IVW OR = 0.7, 95%CI (0.4, 1.2), p = 0.21; NSP IVW OR = 0.9, 95%CI (0.5 1.7), p = 0.76). CONCLUSIONS: Despite using genetic variants strongly related sexual behaviour traits in large-scale GWAS, we found evidence for correlated pleiotropy. This emphasizes a need for multivariable approaches and the triangulation of evidence when performing MR of complex behavioural traits.

Quantitative Bias Analysis of the Association between Occupational Radiation Exposure and Ischemic Heart Disease Mortality in UK Nuclear Workers.

The scientific question of whether protracted low-dose or low-dose-rate exposure to external radiation is causally related to the risk of circulatory disease continues to be an important issue for radiation protection. Previous analyses of a matched case-control dataset nested in a large cohort of UK nuclear fuel cycle workers indicated that there was little evidence that observed associations between external radiation dose and ischemic heart disease (IHD) mortality risk [OR = 1.35 (95% CI: 0.99-1.84) for 15-year-lagged exposure] could alternatively be explained by confounding from pre-employment tobacco smoking, BMI or blood pressure, or from socioeconomic status or occupational exposure to excessive noise or shiftwork. To improve causal inference about the observed external radiation dose and IHD mortality association, we estimated the potential magnitude and direction of non-random errors, incorporated sensitivity analyses and simulated bias effects under plausible scenarios. We conducted quantitative bias analyses of plausible scenarios based on 1,000 Monte Carlo samples to explore the impact of exposure measurement error, missing information on tobacco smoking, and unmeasured confounding, and assessed whether observed associations were reliant on the inclusion of specific matched pairs using bootstrapping with 10% of matched pairs randomly excluded in 1,000 samples. We further explored the plausibility that having been monitored for internal exposure, which was an important confounding factor in the case-control analysis for which models were adjusted, was indeed a confounding factor or whether it might have been the result of some form of selection bias. Consistent with the broader epidemiological evidence-base, these analyses provide further evidence that the dose-response association between cumulative external radiation exposure and IHD mortality is non-linear in that it has a linear shape plateauing at an excess risk of 43% (95% CI: 7-92%) on reaching 390 mSv. Analyses of plausible scenarios of patterns of missing data for tobacco smoking at start of employment indicated that this resulted in relatively little bias towards the null in the original analysis. An unmeasured confounder would have had to have been highly correlated (rp > 0.60) with cumulative external radiation dose to importantly bias observed associations. The confounding effect of "having been monitored for internal dose" was unlikely to have been a true confounder in a biological sense, but instead may have been some unknown factor related to differences over time and between sites in selection criteria for internal monitoring, possibly resulting in collider bias. Plausible patterns of exposure measurement error negatively biased associations regardless of the modeled scenario, but did not importantly change the shape of the observed dose-response associations. These analyses provide additional support for the hypothesis that the observed association between external radiation exposure and IHD mortality may be causal.

Morbidity following thyroid and parathyroid surgery: Results from key performance indicator assessment at a high-volume centre in New Zealand.

BACKGROUND: Complications following thyroid/parathyroid surgery include recurrent laryngeal nerve (RLN) injury, hypocalcaemia and return to theatre for haematoma evacuation. Rates of these form the basis of key performance indicators (KPI). An endocrine database, containing results from 1997, was established at the North Shore Hospital in Auckland, New Zealand. We aimed to measure complication rates by procedure (thyroid and parathyroid), explore a temporal change in our unit and compare our results against international literature. METHODS: A retrospective review of the database between July 1997 and February 2020 was performed. The results for each KPI were analysed in total and over consecutive time periods. A review of the literature was carried out to find international complication rates for comparison. A cumulative sum (CUSUM) analysis was performed to give visual feedback on performance. RESULTS: There were 1062 thyroidectomies and 336 parathyroidectomies from July 1997 to February 2020. Thyroid surgery results found rates of temporary/permanent RLN injury of 1.9%/0.3%, temporary/permanent hypocalcaemia of 22.3/2.5%, and return to theatre for haematoma evacuation of 1.1%. Parathyroid surgery results were, temporary RLN injury of 0.8% (no permanent injury), temporary/permanent hypocalcaemia of 1.7%/0.4%, and return to theatre for haematoma evacuation of 0.3%. CUSUM analysis found KPI results to be comparable with international literature. CONCLUSION: Our unit's KPI results are comparable to published results in the literature. The use of this clinical database will help in future monitoring of performance and help drive improvement in the service. Embedding prospective data collection as routine practice allows for continuous improvement for the unit.

Using a Modified Delphi Approach to Gain Consensus on Relevant Comparators in a Cost-Effectiveness Model: Application to Prostate Cancer Screening.

OBJECTIVE: Challenges can exist when framing the decision question in a cost-effectiveness analysis, particularly when there is disagreement among experts on relevant comparators. Using prostate cancer screening and recent developments in risk stratification, early-detection biomarkers, and diagnostic technologies as a case study, we report a modified Delphi approach to handle decision-question uncertainty. METHODS: The study involved two rounds of anonymous online questionnaires to identify the prostate cancer screening strategies that international researchers, clinicians and decision makers felt important to consider in a cost-effectiveness model. Both purposive and snowball sampling were used to recruit experts. The questionnaire was based on a review of the literature and was piloted for language, comprehension and ease of use prior to dissemination. In Round 1, respondents indicated their preferred screening strategy (including no screening) through a series of multiple-choice questions. The responses informed a set of 13 consensus statements, which respondents ranked their agreement with on a 9-point Likert scale (Round 2). Consensus was considered reached if > 70% of participants indicated agreement and < 15% indicated disagreement. RESULTS: Twenty participants completed Round 1 and 17 completed Round 2. Consensus was shown towards comparing no formal screening, age-based, and risk-based strategies. The risk-based approaches included screening only higher-risk men, using shorter screening intervals for higher-risk men, screening higher-risk men at an earlier age, and tailoring screening intervals based on prostate-specific antigen (PSA) level at a previous test. There was agreement that inclusion of MRI in the pathway should be considered, but disagreement on the inclusion of new biomarkers. CONCLUSION: In disease areas where technologies are rapidly evolving, a modified Delphi approach provides a useful tool to identify relevant comparators in an economic evaluation.

5-Axis CNC Micromilling for Rapid, Cheap, and Background-Free NMR Microcoils.

The superior mass sensitivity of microcoil technology in nuclear magnetic resonance (NMR) spectroscopy provides potential for the analysis of extremely small-mass-limited samples such as eggs, cells, and tiny organisms. For optimal performance and efficiency, the size of the microcoil should be tailored to the size of the mass-limited sample of interest, which can be costly as mass-limited samples come in many shapes and sizes. Therefore, rapid and economic microcoil production methods are needed. One method with great potential is 5-axis computer numerical control (CNC) micromilling, commonly used in the jewelry industry. Most CNC milling machines are designed to process larger objects and commonly have a precision of >25 µm (making the machining of common spiral microcoils, for example, impossible). Here, a 5-axis MiRA6 CNC milling machine, specifically designed for the jewelry industry, with a 0.3 µm precision was used to produce working planar microcoils, microstrips, and novel microsensor designs, with some tested on the NMR in less than 24 h after the start of the design process. Sample wells could be built into the microsensor and could be machined at the same time as the sensors themselves, in some cases leaving a sheet of Teflon as thin as 10 µm between the sample and the sensor. This provides the freedom to produce a wide array of designs and demonstrates 5-axis CNC micromilling as a versatile tool for the rapid prototyping of NMR microsensors. This approach allowed the experimental optimization of a prototype microstrip for the analysis of two intact adult Daphnia magna organisms. In addition, a 3D volume slotted-tube resonator was produced that allowed for 2D 1H-13C NMR of D. magna neonates and exhibited 1H sensitivity (nLODω600 = 1.49 nmol s1/2) close to that of double strip lines, which themselves offer the best compromise between concentration and mass sensitivity published to date.

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT.

BACKGROUND: Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments. OBJECTIVES: To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years. DESIGN: A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up. SETTING: Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK. PARTICIPANTS: Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (n = 545), radical prostatectomy (n = 553) or radical radiotherapy (n = 545) and 997 chose a treatment. INTERVENTIONS: The interventions were active monitoring, radical prostatectomy and radical radiotherapy. TRIAL PRIMARY OUTCOME MEASURE: Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants. SECONDARY OUTCOME MEASURES: Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes. RESULTS: There were no statistically significant differences between the groups for 17 prostate cancer-specific (p = 0.48) and 169 all-cause (p = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy). LIMITATIONS: A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed. CONCLUSIONS: At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years. TRIAL REGISTRATION: Current Controlled Trials ISRCTN20141297. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.

Prostate cancer is the most common cancer in men and is often found through a blood test called a prostate-specific antigen test and through biopsies of the prostate. Over the years, these tests led to the detection of many small cancers that do not cause harm. Some prostate cancers are harmful, but it is difficult to recognise them early. When cancer is still inside the prostate, the conventional treatments are surgery or radiotherapy, which carry side effects including leaking urine and difficulty getting an erection, so another option is repeat investigations at regular intervals (active monitoring), with treatments given if the cancer progresses. These options needed to be compared in a study called a 'randomised trial' in which men agree to be allocated to one of the three treatments. In the Prostate testing for cancer and Treatment (ProtecT) study, 200,000 men aged 50­69 years were invited to have a prostate-specific antigen test. Of the 82,849 men who agreed to be tested, 1643 of whom had prostate cancer that was still contained in the prostate agreed to be allocated to one of the three treatments. After an average of 10 years of follow-up, 99% of men were alive in each of the treatment groups. However, when compared with active monitoring, surgery and radiotherapy reduced the risk of disease spreading outside the prostate by half. Patients reported that urinary leakage and sexual function were worst with surgery, and sexual and bowel functions were affected by radiotherapy. Men on active monitoring had a gradual decline in their urinary and sexual function, particularly as around half of them later had surgery or radiotherapy. Radiotherapy was the treatment that seemed to be the best value for money. The findings from the Prostate testing for cancer and Treatment (ProtecT) study can help men make decisions about being tested and which treatment to have if they are found to have cancer within the prostate. We now need to find out the longer-term effects of these treatments on how long men live and their quality of life.

The ProtecT randomised trial cost-effectiveness analysis comparing active monitoring, surgery, or radiotherapy for prostate cancer.

BACKGROUND: There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer. METHODS: The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years' median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk. RESULTS: Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups. CONCLUSIONS: Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man's lifetime. TRIAL REGISTRATION: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).

The financial implications of variability in decision to disposition times for patients placed in observation status.

INTRODUCTION: A host of variables beyond the control of the ED physician affect ED throughput. In-process time represents the period most directly affected by physician decision-making patterns. This study attempts to evaluate implications of variable decision-making for those patients placed in observation status for throughput and financial implications. METHODS: A retrospective review of all ED admissions to observation status over an 8-month period, for observation decision times (ODT) was performed. The average cost per patient bed hour in the ED, opportunity cost from patients not being seen during excessive ODTs, and the cost of an unfilled bed in an observation unit were estimated. RESULTS: Of 2693 observation cases reviewed, 114 (4.2%) had ODTs longer than two standard deviations above the median. These accumulated ODTs lead to an additional cost of $12,307, or $107 per admission. An additional 45 patients could have been treated during these excess ODTs, from which result an opportunity loss ranging from $32 to $1350 per hour. There is an additional cost of $8036 to maintain empty observation beds in the hospital. CONCLUSION: For those ODTs beyond two standard deviations above the median, there is a direct unreimbursed cost to the hospital, an opportunity cost for patients not seen in those occupied ED beds, and a cost of maintaining unfilled observation beds. Variability in the efficiency of decision-making suggests real consequences in terms of throughput and cost-to-treat.

Quality assessment of a large primary GP skin cancer service in Auckland, New Zealand.

AIM: Waitemata District Health Board has implemented a new approach to the management of skin cancers by triaging lesions to specialist-trained general practitioners (GPSI) with the aim of reducing patient wait times and treatment costs. The primary outcome was to determine positive margin rates for the GP surgeons, with secondary outcome being infection rates. METHOD: A retrospective audit was conducted on all excisions (n=2,705) performed between 1 January 2016 and 31 December 2016 by the 13 WDHB GPSIs. Electronic patient records were accessed to review data. Each lesion was classified into benign, in-situ (pre-malignant) and malignant categories. Surgical margins were analysed for non-melanotic skin cancers (NMSC) and determined as positive, close or negative. Infection rates determined by microbiology results and prescribing information and time to treat analyses were conducted. RESULTS: WDHB GPSIs performed 2,705 excisions, 1,887 (69.8%) of which were malignant lesions. Among the 1,486 NMSC excised, a positive surgical margin was observed in 51 (3.4%). There were 294 (10.9%) cases of infection in 2,705 excisions. Median time to treat was 31 days across all lesions. New Zealand papers from the last two decades estimate the NMSC positive margin rate among primary care physicians varies between 16-31%; most recent papers have published rates 6.8-9.5%.European publications describe positive margin rates ranging between 13.9-33.5%. CONCLUSION: This study validates the use of surgically trained GP surgeons and shows their integral role in managing the high volume of skin cancer in New Zealand.

Varenicline versus nicotine replacement therapy for long-term smoking cessation: an observational study using the Clinical Practice Research Datalink.

BACKGROUND: Smoking is the leading avoidable cause of illness and premature mortality. The first-line treatments for smoking cessation are nicotine replacement therapy and varenicline. Meta-analyses of experimental studies have shown that participants allocated to the varenicline group were 1.57 times (95% confidence interval 1.29 to 1.91 times) as likely to be abstinent 6 months after treatment as those allocated to the nicotine replacement therapy group. However, there is limited evidence about the effectiveness of varenicline when prescribed in primary care. We investigated the effectiveness and rate of adverse events of these medicines in the general population. OBJECTIVE: To estimate the effect of prescribing varenicline on smoking cessation rates and health outcomes. DATA SOURCES: Clinical Practice Research Datalink. METHODS: We conducted an observational cohort study using electronic medical records from the Clinical Practice Research Datalink. We extracted data on all patients who were prescribed varenicline or nicotine replacement therapy after 1 September 2006 who were aged ≥ 18 years. We investigated the effects of varenicline on smoking cessation, all-cause mortality and cause-specific mortality and hospitalisation for: (1) chronic lung disease, (2) lung cancer, (3) coronary heart disease, (4) pneumonia, (5) cerebrovascular disease, (6) diabetes, and (7) external causes; primary care diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression, or prescription for anxiety; weight in kg; general practitioner and hospital attendance. Our primary outcome was smoking cessation 2 years after the first prescription. We investigated the baseline differences between patients prescribed varenicline and patients prescribed nicotine replacement therapy. We report results using multivariable-adjusted, propensity score and instrumental variable regression. Finally, we developed methods to assess the relative bias of the different statistical methods we used. RESULTS: People prescribed varenicline were healthier at baseline than those prescribed nicotine replacement therapy in almost all characteristics, which highlighted the potential for residual confounding. Our instrumental variable analysis results found little evidence that patients prescribed varenicline had lower mortality 2 years after their first prescription (risk difference 0.67, 95% confidence interval -0.11 to 1.46) than those prescribed nicotine replacement therapy. They had similar rates of all-cause hospitalisation, incident primary care diagnoses of myocardial infarction and chronic obstructive pulmonary disease. People prescribed varenicline subsequently attended primary care less frequently. Patients prescribed varenicline were more likely (odds ratio 1.46, 95% confidence interval 1.42 to 1.50) to be abstinent 6 months after treatment than those prescribed nicotine replacement therapy when estimated using multivariable-adjusted for baseline covariates. Patients from more deprived areas were less likely to be prescribed varenicline. However, varenicline had similar effectiveness for these groups. CONCLUSION: Patients prescribed varenicline in primary care were more likely to quit smoking than those prescribed nicotine replacement therapy, but there was little evidence that they had lower rates of mortality or morbidity in the 4 years following the first prescription. There was little evidence of heterogeneity in effectiveness across the population. FUTURE WORK: Future research should investigate the decline in prescribing of smoking cessation products; develop an optimal treatment algorithm for smoking cessation; use methods for using instruments with survival outcomes; and develop methods for comparing multivariable-adjusted and instrumental variable estimates. LIMITATIONS: Not all of our code lists were validated, body mass index and Index of Multiple Deprivation had missing values, our results may suffer from residual confounding, and we had no information on treatment adherence. TRIAL REGISTRATION: This trial is registered as NCT02681848. 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. 9. See the NIHR Journals Library website for further project information.

Smoking is the number one avoidable cause of ill health and death. Experiments suggest that more smokers will quit after being given the drug varenicline than with any other smoking cessation treatment. However, most of the experiments used to license varenicline had a relatively short follow-up (< 1 year) and did not necessarily recruit participants who were representative of smokers seen in a general practice in the UK, who tend to be older, are sicker and more likely to have neuropsychiatric illnesses. In this study, we investigated the outcomes of 287,079 patients prescribed varenicline or nicotine replacement therapy (e.g. nicotine patches and gum). We followed each patient for up to 4 years after they received their prescriptions and matched their data to information on deaths from the Office for National Statistics and hospital admissions. We investigated how often these patients subsequently attended their general practitioner, and how often they received a diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression or anxiety in primary care. We found that patients who were prescribed varenicline were much more likely to quit smoking up to 4 years after they received treatment and subsequently attended their general practitioner less frequently. These findings were robust across the three different analysis methods we used. We also found that patients prescribed varenicline were much less likely to be ill or to die than those prescribed nicotine replacement therapy. However, these results may be because the patients who were prescribed varenicline were much healthier before they received the prescription. Therefore, these differences in health are unlikely to be caused by taking varenicline or quitting smoking. In conclusion, varenicline helped patients quit smoking, but there was little causal evidence that prescribing patients varenicline causally reduced rates of mortality or morbidity compared with prescribing nicotine replacement therapy.

Assessment of eating attitudes and dieting behaviors in healthy children: Confirmatory factor analysis of the Children's Eating Attitudes Test.

OBJECTIVE: The Children's Eating Attitudes Test (ChEAT) is a self-report questionnaire that is conventionally summarized with a single score to identify "problematic" eating attitudes, masking informative variability in different eating attitude domains. This study evaluated the empirical support for single- versus multifactor models of the ChEAT. For validation, we compared how well the single- versus multifactor-based scores predicted body mass index (BMI). METHOD: Using data from 13,674 participants of the 11.5 year-follow-up of the Promotion of Breastfeeding Intervention Trial (PROBIT) in the Republic of Belarus, we conducted confirmatory factor analysis to evaluate the performance of 3- and 5-factor models, which were based on past studies, to a single-factor model representing the conventional summary of the ChEAT. We used cross-validated linear regression models and the reduction in mean squared error (MSE) to compare the prediction of BMI at 11.5 and 16 years by the conventional and confirmed factor-based ChEAT scores. RESULTS: The 5-factor model, based on 14 of the original 26 ChEAT items, had good fit to the data whereas the 3- and single-factor models did not. The MSE for concurrent (11.5 years) BMI regressed on the 5-factor ChEAT summary was 35% lower than that of the single-score models, which reduced the MSE from the null model by only 1%-5%. The MSE for BMI at 16 years was 20% lower. DISCUSSION: We found that a parsimonious 5-factor model of the ChEAT explained the data collected from healthy Belarusian children better than the conventional summary score and thus provides a more discriminating measure of eating attitudes.