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Randomized controlled trials (RCTs) have traditionally been considered the gold standard for medical evidence. However, in light of emerging methodologies in data science, many experts question the role of RCTs. Within this context, experts in the USA and Canada came together to debate whether the primacy of RCTs as the gold standard for medical evidence, still holds in light of recent methodological advances in data science and in the era of big data. The purpose of this manuscript, aims to raise awareness of the pros and cons of RCTs and observational studies in order to help guide clinicians, researchers, students, and decision-makers in making informed decisions on the quality of medical evidence to support their work. In particular, new and underappreciated advantages and disadvantages of both designs are contrasted. Innovations taking place in both of these research methodologies, which can blur the lines between the two, are also discussed. Finally, practical guidance for clinicians and future directions in assessing the quality of evidence is offered., (© 2023. The Author(s).)

Background: Little is known about how normal variation in dietary patterns in humans affects the ageing process. To date, most analyses of the problem have used a unidimensional paradigm, being concerned with the effects of a single nutrient on a single outcome. Perhaps then, our ability to understand the problem has been complicated by the fact that both nutrition and the physiology of ageing are highly complex and multidimensional, involving a high number of functional interactions. Here we apply the multidimensional geometric framework for nutrition to data on biological ageing from 1560 older adults followed over four years to assess on a large-scale how nutrient intake associates with the ageing process., Results: Ageing and age-related loss of homeostasis (physiological dysregulation) were quantified via the integration of blood biomarkers. The effects of diet were modelled using the geometric framework for nutrition, applied to macronutrients and 19 micronutrients/nutrient subclasses. We observed four broad patterns: (1) The optimal level of nutrient intake was dependent on the ageing metric used. Elevated protein intake improved/depressed some ageing parameters, whereas elevated carbohydrate levels improved/depressed others; (2) There were non-linearities where intermediate levels of nutrients performed well for many outcomes (i.e. arguing against a simple more/less is better perspective); (3) There is broad tolerance for nutrient intake patterns that don't deviate too much from norms ('homeostatic plateaus'). (4) Optimal levels of one nutrient often depend on levels of another (e.g. vitamin E and vitamin C). Simpler linear/univariate analytical approaches are insufficient to capture such associations. We present an interactive tool to explore the results in the high-dimensional nutritional space., Conclusion: Using multidimensional modelling techniques to test the effects of nutrient intake on physiological dysregulation in an aged population, we identified key patterns of specific nutrients associated with minimal biological ageing. Our approach presents a roadmap for future studies to explore the full complexity of the nutrition-ageing landscape., (© 2022. The Author(s).)

Traditionally, the immune system is understood to be divided into discrete cell types that are identified via surface markers. While some cell type distinctions are no doubt discrete, others may in fact vary on a continum, and even within discrete types, differences in surface marker abundance could have functional implications. Here we propose a new way of looking at immune data, which is by looking directly at the values of the surface markers without dividing the cells into different subtypes. To assess the merit of this approach, we compared it with manual gating using cytometry data from the Singapore Longitudinal Aging Study (SLAS) database. We used two different neural networks (one for each method) to predict the presence of several health conditions. We found that the model built using raw surface marker abundance outperformed the manual gating one and we were able to identify some markers that contributed more to the predictions. This study is intended as a brief proof-of-concept and was not designed to predict health outcomes in an applied setting; nonetheless, it demonstrates that alternative methods to understand the structure of immune variation hold substantial progress., (© 2022. The Author(s).)

Background: We have previously developed and validated a biomarker-based metric of overall health status using Mahalanobis distance (DM) to measure how far from the norm of a reference population (RP) an individual's biomarker profile is. DM is not particularly sensitive to the choice of biomarkers; however, this makes comparison across studies difficult. Here we aimed to identify and validate a standard, optimized version of DM that would be highly stable across populations, while using fewer and more commonly measured biomarkers., Methods: Using three datasets (the Baltimore Longitudinal Study of Aging, Invecchiare in Chianti and the National Health and Nutrition Examination Survey), we selected the most stable sets of biomarkers in all three populations, notably when interchanging RPs across populations. We performed regression models, using a fourth dataset (the Women's Health and Aging Study), to compare the new DM sets to other well-known metrics [allostatic load (AL) and self-assessed health (SAH)] in their association with diverse health outcomes: mortality, frailty, cardiovascular disease (CVD), diabetes, and comorbidity number., Results: A nine- (DM9) and a seventeen-biomarker set (DM17) were identified as highly stable regardless of the chosen RP (e.g.: mean correlation among versions generated by interchanging RPs across dataset of r = 0.94 for both DM9 and DM17). In general, DM17 and DM9 were both competitive compared with AL and SAH in predicting aging correlates, with some exceptions for DM9. For example, DM9, DM17, AL, and SAH all predicted mortality to a similar extent (ranges of hazard ratios of 1.15-1.30, 1.21-1.36, 1.17-1.38, and 1.17-1.49, respectively). On the other hand, DM9 predicted CVD less well than DM17 (ranges of odds ratios of 0.97-1.08, 1.07-1.85, respectively)., Conclusions: The metrics we propose here are easy to measure with data that are already available in a wide array of panel, cohort, and clinical studies. The standardized versions here lose a small amount of predictive power compared to more complete versions, but are nonetheless competitive with existing metrics of overall health. DM17 performs slightly better than DM9 and should be preferred in most cases, but DM9 may still be used when a more limited number of biomarkers is available., (© 2022. The Author(s).)

Background: It is widely assumed that variation in fitness components has a physiological basis that might underlie selection on trade-offs, but the mechanisms driving decreased survival and future fecundity remain elusive. Here, we assessed whether physiological variables are related to workload ability or immediate fitness consequences and if they mediate future survival or reproductive success. We used data on 13 physiological variables measured in 93 female European starlings ( Sturnus vulgaris ) at two breeding stages (incubation, chick-rearing), for first-and second-broods over two years (152 observations)., Results: There was little co-variation among the physiological variables, either in incubating or chick-rearing birds, but some systematic physiological differences between the two stages. Chick-rearing birds had lower hematocrit and plasma creatine kinase but higher hemoglobin, triglyceride and uric acid levels. Only plasma corticosterone was repeatable between incubation and chick-rearing. We assessed relationships between incubation or chick-rearing physiology and measures of workload, current productivity, future fecundity or survival in a univariate manner, and found very few significant relationships. Thus, we next explored the utility of multivariate analysis (principal components analysis, Mahalanobis distance) to account for potentially complex physiological integration, but still found no clear associations., Conclusions: This implies either that a) birds maintained physiological variables within a homeostatic range that did not affect their performance, b) there are relatively few links between physiology and performance, or, more likely, c) that the complexity of these relationships exceeds our ability to measure it. Variability in ecological context may complicate the relationship between physiology and behavior. We thus urge caution regarding the over-interpretation of isolated significant findings, based on single traits in single years, in the literature., Competing Interests: All research was conducted under Simon Fraser University Animal Care permits # 657B-96, 829B-96, and 1018B-96.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Polybrominated diphenyl ethers are known endocrine disrupting environmental contaminants used as flame retardants. Their levels have increased in humans over the last ten years, raising concerns about their consequences on human health. Some animal studies suggest that PBDEs can affect fetal growth; however, the results of human studies are contradictory. This study evaluates the association between the most common PBDEs in maternal blood measured in early pregnancy and birth weight., Methods: BDE-47, BDE-99, BDE-100 and BDE-153 levels were measured in 349 women during their first prenatal care visit at the University Hospital Center of Sherbrooke (Quebec, Canada). Birth weight and relevant medical information were collected from medical records. In contrast with previous studies, we examined the full range of clinical risk factors known to affect fetal growth as potential confounders, as well as other environmental pollutants that are likely to interact with fetal growth (polychlorinated biphenyls (PCBs), mercury, lead, cadmium and manganese)., Results: There was no statistically significant relationship between PBDE levels in early pregnancy and birth weight in both unadjusted and multivariate regression models., Conclusions: Our results suggest that PBDEs in early pregnancy have little or no direct impact on birth weight, at least at the levels of exposure in our population.

Background: Understanding health care utilization by neighbourhood is essential for optimal allocation of resources, but links between neighbourhood immigration and health have rarely been explored. Our objective was to understand how immigrant composition of neighbourhoods relates to health outcomes and health care utilization of individuals living with diabetes., Methods: This is a secondary analysis of administrative data using a retrospective cohort of 111,556 patients living with diabetes without previous cardiovascular diseases (CVD) and living in the metropolitan region of Montreal (Canada). A score for immigration was calculated at the neighbourhood level using a principal component analysis with six neighbourhood-level variables (% of people with maternal language other than French or English, % of people who do not speak French or English, % of immigrants with different times since immigration (<5 years, 5-10 years, 10-15 years, 15-25 years)). Dependent variables were all-cause death, all-cause hospitalization, CVD event (death or hospitalization), frequent use of emergency departments, frequent use of general practitioner care, frequent use of specialist care, and purchase of at least one antidiabetic drug. For each of these variables, adjusted odds ratios were estimated using a multilevel logistic regression., Results: Compared to patients with diabetes living in neighbourhoods with low immigration scores, those living in neighbourhoods with high immigration scores were less likely to die, to suffer a CVD event, to frequently visit general practitioners, but more likely to visit emergency departments or a specialist and to use an antidiabetic drug. These differences remained after controlling for patient-level variables such as age, sex, and comorbidities, as well as for neighbourhood attributes like material and social deprivation or living in the urban core., Conclusions: In this study, patients with diabetes living in neighbourhoods with high immigration scores had different health outcomes and health care utilizations compared to those living in neighbourhoods with low immigration scores. Although we cannot disentangle the individual versus the area-based effect of immigration, these results may have an important impact for health care planning.

Background: Malaria in India has been difficult to measure. Mortality and morbidity are not comprehensively reported, impeding efforts to track changes in disease burden. However, a set of blood measures has been collected regularly by the National Malaria Control Program in most districts since 1958., Methods: Here, we use principal components analysis to combine these measures into a single index, the Summary Index of Malaria Surveillance (SIMS), and then test its temporal and geographic stability using subsets of the data., Results: The SIMS correlates positively with all its individual components and with external measures of mortality and morbidity. It is highly consistent and stable over time (1995-2005) and regions of India. It includes measures of both vivax and falciparum malaria, with vivax dominant at lower transmission levels and falciparum dominant at higher transmission levels, perhaps due to ecological specialization of the species., Conclusions: This measure should provide a useful tool for researchers looking to summarize geographic or temporal trends in malaria in India, and can be readily applied by administrators with no mathematical or scientific background. We include a spreadsheet that allows simple calculation of the index for researchers and local administrators. Similar principles are likely applicable worldwide, though further validation is needed before using the SIMS outside India.