The standard two-stage approach for estimating non-linear dose-response curves based on aggregated data typically excludes those studies with less than three exposure groups. We develop the one-stage method as a linear mixed model and present the main aspects of the methodology, including model specification, estimation, testing, prediction, goodness-of-fit, model comparison, and quantification of between-studies heterogeneity. Using both fictitious and real data from a published meta-analysis, we illustrated the main features of the proposed methodology and compared it to a traditional two-stage analysis. In a one-stage approach, the pooled curve and estimates of the between-studies heterogeneity are based on the whole set of studies without any exclusion. Thus, even complex curves (splines, spike at zero exposure) defined by several parameters can be estimated. We showed how the one-stage method may facilitate several applications, in particular quantification of heterogeneity over the exposure range, prediction of marginal and conditional curves, and comparison of alternative models. The one-stage method for meta-analysis of non-linear curves is implemented in the dosresmeta R package. It is particularly suited for dose-response meta-analyses of aggregated where the complexity of the research question is better addressed by including all the studies.
TPS378 Background: Blood-based biomarkers and magnetic resonance imaging followed by targeted biopsies have been suggested to improve detection of prostate cancer by increasing sensitivity to detect significant disease, decrease over-detection of low-risk cancers and avoid benign biopsies. The STHLM3-MRI projects aims to assess the value of combining blood-based risk prediction with bi-parametric MRI (bpMRI) in the prostate cancer diagnostic chain. Methods: The STHLM3MRI Main Study is a randomized, diagnostic study recruiting ≈10,000 Swedish men aged 50-74 for prostate cancer testing in a screen-by-invitation setting. The study design includes a first paired step (blood-test) followed by a randomized step (biopsy technique). Participants with elevated blood-test levels (PSA≥3ng/ml or Stockholm3 test≥11% risk of GG≥2 cancer) are recommended further work-up and randomized 2:3 to 12-core systematic biopsies (standard arm) or to bpMRI followed by MRI-targeted biopsies and systematic biopsies in men with PI-RADSv2 ≥3 lesions (experimental arm). Endpoints include number of detected prostate cancers, number of performed biopsy procedures and number of performed MRIs. The study is centralized to three biopsy sites, one radiology department and one pathology department. A data safety and monitoring board monitors study progress and participant safety. There are two pre-planned main analyses. First, we will report the first large randomized evidence comparing MRI-targeted biopsies and systematic biopsies for prostate cancer detection in a screen-by-invitation setting. Second, we will report a comparison of a diagnostic strategy including the Stockholm3 blood-test and MRI-targeted biopsies with standard practice using PSA and systematic biopsies. A third analysis will compare the use of the bloodtests PSA and Stockholm3 for risk-stratification of men undergoing MRI-targeted biopsy. 9 Oct 2019 the study had included 47% of planned participants (n = 4,701), aiming to close inclusion by March 2020 with first report during 2020. The study is registered at ClinicalTrials.gov: NCT03377881 and has regional ethical approval (2017-1280/31). Clinical trial information: NCT03377881.
Abstract Objective Assess the cost-effectiveness of no screening and quadrennial magnetic resonance imaging (MRI)-based screening for prostate cancer using either Stockholm3 or prostate-specific antigen (PSA) test as a reflex test. Methods Test characteristics were estimated from the STHLM3-MR study ( NCT03377881 ). A cost-utility analysis was conducted from a lifetime societal perspective using a microsimulation model for men aged 55-69 in Sweden for no screening and three quadrennial screening strategies, including: PSA≥3ng/mL; and Stockholm3 with reflex test thresholds of PSA≥1.5 and 2ng/mL. Men with a positive test had an MRI, and those MRI positive had combined targeted and systematic biopsies. Predictions included the number of tests, cancer incidence and mortality, costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Uncertainties in key parameters were assessed using sensitivity analyses. Results Compared with no screening, the screening strategies were predicted to reduce prostate cancer deaths by 7-9% across a lifetime and were considered to be moderate costs per QALY gained in Sweden. Using Stockholm3 with a reflex threshold of PSA≥2ng/mL resulted in a 60% reduction in MRI compared with screening using PSA. This Stockholm3 strategy was cost-effective with a probability of 70% at a cost-effectiveness threshold of €47,218 (500,000 SEK). Conclusions All screening strategies were considered to be moderate costs per QALY gained compared with no screening. Screening with Stockholm3 test at a reflex threshold of PSA≥2ng/mL and MRI was predicted to be cost-effective in Sweden. Use of the Stockholm3 test may reduce screening-related harms and costs while maintaining the health benefits from early detection.
Abstract Introduction Randomized clinical trials (RCT) produce the highest level of evidence and therefore form the basis for many guidelines. Their Achilles heel is external validity which is still poorly studied. Participants in clinical trials may partly be selected on unknown mechanisms in particular regarding socioeconomic status. To what extent participants in clinical trials after myocardial infarction (MI) are representative for the overall MI population is unknown. Purpose To investigate whether participants in clinical trials after myocardial infarction differ regarding socioeconomic status (SES), risk factor profile, prior and recurrent cardiovascular disease (CVD) events. Methods A total of 34,084 patients attending follow up after myocardial infarction between 2007 and 2014 were identified in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) out of which 3,037 had participated in a clinical trial. Information on disposable income, education level, marital status, prior CVD, risk factors and treatment were retrieved from national registers and patients were followed regarding recurrent CVD. Participants in clinical trials were compared to non-participants using logistic and Cox regression analyses. In a multivariable Cox-regression analysis adjustments were made for gender, age, inclusion-year, diabetes, LVEF, previous MI, previous stroke, prior cardiac surgery, ECG rhythm, eGFR, lipid levels, smoking status, use of ASA, use of ACE-I, use of beta-blockers, use of statins, level of education, disposable income and family status. Results Trial participants were more likely to be men (odds ratio (OR): 1.42; 95% CI: 1.29–1.55)), to be married (1.17; 1.09–1.27), to have a high income (1.58; 1.45–1.72), have a post-secondary education (>12 years) (1.33; 1.22–1.46) and less likely to be smokers (0.81; 0.72–0.90), have a reduced EF <30% (0.61; 0.46–0.80), history of previous stroke (0.79; 0.65–0.97) or MI (0.86; 0.77–0.97) compared to non-participants. The risk for recurrent CVD was lower among the participants compared to the non-participants (HR: 0.77; 95% CI: 0.67–0.88) and is illustrated in figure 1. In a fully adjusted model the lower risk remained after adjusting for age, gender, risk factors, prior disease including EF, evidence based treatments and SES (HR: 0.85; 95% CI: 0.74–0.97). Trial participation and recurrent CVD Conclusion Participants in clinical trials after MI constitute a highly selected group with higher SES, a more favourable risk profile and a better overall prognosis. The lower risk after full adjustments imply that additional selection bias exists. The external validity of post MI- trials in general can thus be questioned. To what extent results from clinical trials apply to the overall post MI population should be carefully scrutinized. Real world registry data are important. Acknowledgement/Funding Familjen Janne Elgqvists Stiftelse
The aim of focal treatments (FTs) in prostate cancer (PCa) is to treat lesions while preserving surrounding benign tissue and anatomic structures. Irreversible electroporation (IRE) is a nonthermal technique that uses high-voltage electric pulses to increase membrane permeability and induce membrane disruption in cells, which potentially causes less damage to the surrounding tissue in comparison to other ablative techniques. We summarize the study protocol for the Prostate Cancer IRE Study (PRIS), which involves two parallel randomized controlled trials comparing IRE with (1) robot-assisted radical prostatectomy (RARP) or (2) radiotherapy in men with newly diagnosed intermediate-risk PCa (NCT05513443). To reduce the number of patients for inclusion and the study duration, the primary outcomes are functional outcomes: urinary incontinence in study 1 and irritative urinary symptoms in study 2. Providing evidence of the lower impact of IRE on functional outcomes will lay a foundation for the design of future multicenter studies with an oncological outcome as the primary endpoint. Erectile function, quality of life, treatment failure, adverse events, and cost effectiveness will be evaluated as secondary objectives. Patients diagnosed with Gleason score 3 + 4 or 4 + 3 PCa from a single lesion visible on magnetic resonance imaging (MRI) without any Gleason grade 4 or higher in systematic biopsies outside of the target (unifocal significant disease), aged ≥40 yr, with no established extraprostatic extension on multiparametric MRI, a lesion volume of <1.5 cm3, prostate-specific antigen <20 ng/ml, and stage ≤T2b are eligible for inclusion. The study plan is to recruit 184 men.
In developed countries, the relationship between education level, wealth, and healthy aging have been found to be mediated by modifiable risk factors, such as obesity, physical activities, and smoking status. The present study was to investigate the association between education level, monthly per-capita expenditure (PCE), and healthy aging in the older Indonesian population, and to clarify modifiable risk factors that mediate this association. A 7-year prospective longitudinal study (2007-2014) was conducted on 696 older Indonesian individuals (≥ 50 years) living in 13 different provinces in Indonesia during the survey periods. Data on educational level, PCE, and modifiable risk factors were collected in 2007. Information on healthy aging was obtained in both 2007 and 2014. A multivariate-adjusted logistic regression model was used to estimate the odds ratio (ORs) and 95% confidence intervals (CIs) for healthy aging by education level and PCE. The mediating effects were estimated using a four-way effect decomposition. Out of 696 eligible subjects, 206 (29.6%) were judged as healthy aging in 2014. The OR (95% CI) for healthy aging for participants with a higher education level was 1.81 (1.23-2.65) compared with those with a lower education level, and no significant association was observed between PCE and healthy aging. An association was thus observed between education level and healthy aging, but not PCE. Importantly, the association between education level, PCE, and healthy aging does not appear to be mediated by the modifiable risk factors. Priorities in making health policy would be different between developed countries and developing countries.
BACKGROUND: Acute pancreatitis is linked to pancreatic cancer, but the direction of this association is not fully elaborated. METHODS: This was a population-based cohort study including all Swedish residents diagnosed with a first-time episode of acute pancreatitis between 1997 and 2013 and corresponding matched pancreatitis-free individuals from the general population. Hazard ratios for the association between acute pancreatitis and pancreatic cancer were estimated using multivariable Cox regression models. RESULTS: Overall, 49,749 individuals with acute pancreatitis and 138,750 matched individuals without acute pancreatitis were followed up for 1,192,134 person-years (median 5.3 years). A total of 769 individuals developed pancreatic cancer, of whom 536 (69.7%) had a history of acute pancreatitis. The risk of pancreatic cancer was substantially increased during the first few years after a diagnosis of acute pancreatitis but declined gradually over time, reaching a level comparable to the pancreatitis-free population after >10 years of follow-up. In those with non-gallstone-related acute pancreatitis, the risk of pancreatic cancer declined to a level comparable to the pancreatitis-free population only when follow-up time was censored for a second episode of acute pancreatitis or a diagnosis of chronic pancreatitis. Increasing number of recurrent episodes of acute pancreatitis was associated with increased risk of pancreatic cancer. CONCLUSION: These findings imply a delay in the diagnosis of pre-existing pancreatic cancer, if clinically presented as acute pancreatitis. Any association between non-gallstone-related acute pancreatitis and pancreatic cancer in the long-term (>10 years) could be mediated through recurrent acute pancreatitis or chronic pancreatitis.
