Heterogeneity in the Association Between the Presence of Coronary Artery Calcium and Cardiovascular Events: A Machine Learning Approach in the MESA Study

Background: Coronary artery calcium (CAC) has been widely recognized as an important predictor of cardiovascular disease (CVD). Given the finite resources, it is important to identify individuals who would receive the most benefit from detecting positive CAC by screening. However, the evidence is limited as to whether the burden of positive CAC on CVD differs by multi-dimensional individual characteristics. We sought to investigate the heterogeneity in the association between positive coronary artery calcium (CAC) and incident cardiovascular disease (CVD). Methods: This cohort study included adults aged ≥45 years free of cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis. After propensity score matching in a 1:1 ratio, we applied a machine-learning causal forest model to (i) evaluate the heterogeneity in the association between positive CAC and incident CVD and (ii) predict the increase in CVD risk at 10-year when CAC>0 (vs. CAC=0) at the individual level. We then compared the estimated increase in CVD risk when CAC>0 to the absolute 10-year atherosclerotic CVD (ASCVD) risk calculated by the 2013 ACC/AHA pooled cohort equations. Results: Across 3, 328 adults in our propensity score-matched analysis, our causal forest model showed the heterogeneity in the association between CAC>0 and incident CVD. We found a dose-response relationship of the estimated increase in CVD risk when CAC>0 with higher 10-year ASCVD risk. Almost all individuals (2293/2428 [94.4%]) with borderline or higher ASCVD risk showed ≥2.5% increase in CVD risk when CAC>0. Even among 900 adults with low ASCVD risk, 689 (69.2%) showed ≥2.5% increase in CVD risk when CAC>0; these individuals were more likely to be male, Hispanic, and have unfavorable CVD risk factors than others. Conclusions: The expected increases in CVD risk when CAC>0 were heterogeneous across individuals. Moreover, nearly 70% of people with low ASCVD risk showed a large increase in CVD risk when CAC>0, highlighting the need for CAC screening among such low-risk individuals. Future studies are needed to assess whether targeting individuals for CAC measurements based on not only the absolute ASCVD risk but also the expected increase in CVD risk when CAC>0 improves cardiovascular outcomes

Second cancer risk and mortality in men treated with radiotherapy for stage I seminoma

BACKGROUND: Patients with stage I testicular seminoma are typically diagnosed at a young age and treatment is associated with low relapse and mortality rates. The long-term risks of adjuvant radiotherapy in this patient group are therefore particularly relevant. METHODS: We identified patients and obtained treatment details from 12 cancer centres (11 United Kingdom, 1 Norway) and ascertained second cancers and mortality through national registries. Data from 2629 seminoma patients treated with radiotherapy between 1960 and 1992 were available, contributing 51,151 person-years of follow-up. RESULTS: Four hundred and sixty-eight second cancers (excluding non-melanoma skin cancers) were identified. The standardised incidence ratio (SIR) was 1.61 (95% confidence interval (CI): 1.47-1.76, P<0.0001). The SIR was 1.53 (95% CI: 1.39-1.68, P<0.0001) when the 32 second testicular cancers were also excluded. This increase was largely due to an excess risk to organs in the radiation field; for pelvic-abdominal sites the SIR was 1.62 (95% CI: 1.43-1.83), with no significant elevated risk of cancers in organs elsewhere. There was no overall increase in mortality with a standardised mortality ratio (SMR) of 1.06 (95% CI: 0.98-1.14), despite an increase in the cancer-specific mortality (excluding testicular cancer deaths) SMR of 1.46 (95% CI: 1.30-1.65, P<0.0001). CONCLUSION: The prognosis of stage I seminoma is excellent and it is important to avoid conferring long-term increased risk of iatrogenic disease such as radiation-associated second cancers

Normative Alethic Pluralism

Some philosophers have argued that truth is a norm of judgement and have provided a variety of formulations of this general thesis. In this paper, I shall side with these philosophers and assume that truth is a norm of judgement. What I am primarily interested in here are two core questions concerning the judgement-truth norm: (i) what are the normative relationships between truth and judgement? And (ii) do these relationships vary or are they constant? I argue for a pluralist picture—what I call Normative Alethic Pluralism (NAP)—according to which (i) there is more than one correct judgement-truth norm and (ii) the normative relationships between truth and judgement vary in relation to the subject matter of the judgement. By means of a comparative analysis of disagreement in three areas of the evaluative domain—refined aesthetics, basic taste and morality—I show that there is an important variability in the normative significance of disagreement—I call this the variability conjecture. By presenting a variation of Lynch’s scope problem for alethic monism, I argue that a monistic approach to the normative function of truth is unable to vindicate the conjecture. I then argue that normative alethic pluralism provides us with a promising model to account for it

Association of Intensive Blood Pressure Control and Living Arrangement on Cardiovascular Outcomes by Race

Importance: Living alone, a key proxy of social isolation, is a risk factor for cardiovascular disease. In addition, Black race is associated with less optimal blood pressure (BP) control than in other racial or ethnic groups. However, it is not clear whether living arrangement status modifies the beneficial effects of intensive BP control on reduction in cardiovascular events among Black individuals. Objective: To examine whether the association of intensive BP control with cardiovascular events differs by living arrangement among Black individuals and non-Black individuals (eg, individuals who identified as Alaskan Native, American Indian, Asian, Native Hawaiian, Pacific Islander, White, or other) in the Systolic Blood Pressure Intervention Trial (SPRINT). Design, Setting, and Participants: This secondary analysis incorporated data from SPRINT, a multicenter study of individuals with increased risk for cardiovascular disease and free of diabetes, enrolled at 102 clinical sites in the United States between November 2010 and March 2013. Race and living arrangement (ie, living alone or living with others) were self-reported. Data were collected between November 2010 and March 2013 and analyzed from January 2021 to October 2021. Exposures: The SPRINT participants were randomized to a systolic BP target of either less than 120 mm Hg (intensive treatment group) or less than 140 mm Hg (standard treatment group). Antihypertensive medications were adjusted to achieve the targets in each group. Main Outcomes and Measures: Cox proportional hazards model was used to investigate the association of intensive treatment with the incident composite cardiovascular outcome (by August 20, 2015) according to living arrangement among Black individuals and other individuals. Transportability formula was applied to generalize the SPRINT findings to hypothetical external populations by varying the proportion of Black race and living arrangement status. Results: Among the 9342 total participants, the mean (SD) age was 67.9 (9.4) years; 2793 participants [30%] were Black, 2714 [29%] lived alone, and 3320 participants (35.5%) were female. Over a median (IQR) follow-up of 3.22 (2.74-3.76) years, the primary composite cardiovascular outcome was observed in 67 of 1001 Black individuals living alone (6.7%), 76 of 1792 Black individuals living with others (4.2%), 108 of 1713 non-Black individuals living alone (6.3%), and 311 of 4836 non-Black individuals living with others (6.4%). The intensive treatment group showed a significantly lower rate of the composite cardiovascular outcome than the standard treatment group among Black individuals living with others (hazard ratio [HR], 0.53 [95% CI, 0.33-0.85]) but not among those living alone (HR, 1.07 [95% CI, 0.66-1.73]; P for interaction = .04). The association was observed among individuals who were not Black regardless of living arrangement status. Using transportability, we found a smaller or null association between intensive control and cardiovascular outcomes among hypothetical populations of 60% Black individuals or more and 60% or more of individuals living alone. Conclusions and Relevance: Intensive BP control was associated with a lower rate of cardiovascular events among Black individuals living with others and individuals who were not Black but not among Black individuals living alone. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062