Predicting mortality in critically ill patients requiring renal replacement therapy for acute kidney injury in a retrospective single-center study of two cohorts

Half of the critically ill patients with renal replacement therapy (RRT) dependent acute kidney injury (AKI) die within one year despite RRT. General intensive care prediction models perform inadequately in AKI. Predictive models for mortality would be an invaluable complementary tool to aid clinical decision making. We aimed to develop and validate new prediction models for intensive care unit (ICU) and hospital mortality customized for patients with RRT dependent AKI in a retrospective single-center study. The models were first developed in a cohort of 471 critically ill patients with continuous RRT (CRRT) and then validated in a cohort of 193 critically ill patients with intermittent hemodialysis (IHD) as the primary modality for RRT. Forty-two risk factors for mortality were examined at ICU admission and CRRT initiation, respectively, in the first univariate models followed by multivariable model development. Receiver operating characteristics curve analyses were conducted to estimate the area under the curve (AUC), to measure discriminative capacity of the models for mortality. AUCs of the respective models ranged between 0.76 and 0.83 in the CRRT model development cohort, thereby showing acceptable to excellent predictive power for the mortality events (ICU mortality and hospital mortality). The models showed acceptable external validity in a validation cohort of IHD patients. In the IHD validation cohort the AUCs of the MALEDICT RRT initiation model were 0.74 and 0.77 for ICU and hospital mortality, respectively. The MALEDICT model shows promise for mortality prediction in critically ill patients with RRT dependent AKI. After further validation, the model might serve as an additional clinical tool for estimating individual mortality risk at the time of RRT initiation

An Infancy-Onset 20-Year Dietary Counselling Intervention and Gut Microbiota Composition in Adulthood

The randomized controlled Special Turku Coronary Risk Factor Intervention Project (STRIP) has completed a 20-year infancy-onset dietary counselling intervention to reduce exposure to atherosclerotic cardiovascular disease risk factors via promotion of a heart-healthy diet. The counselling on, e.g., low intake of saturated fat and cholesterol and promotion of fruit, vegetable, and whole-grain consumption has affected the dietary characteristics of the intervention participants. By leveraging this unique cohort, we further investigated whether this long-term dietary intervention affected the gut microbiota bacterial profile six years after the intervention ceased. Our sub-study comprised 357 individuals aged 26 years (intervention n = 174, control n = 183), whose gut microbiota were profiled using 16S rRNA amplicon sequencing. We observed no differences in microbiota profiles between the intervention and control groups. However, out of the 77 detected microbial genera, the Veillonella genus was more abundant in the intervention group compared to the controls (log(2) fold-change 1.58, p < 0.001) after adjusting for multiple comparison. In addition, an association between the study group and overall gut microbiota profile was found only in males. The subtle differences in gut microbiota abundances observed in this unique intervention setting suggest that long-term dietary counselling reflecting dietary guidelines may be associated with alterations in gut microbiota

Childhood Cardiovascular Risk Factors and Adult Cardiovascular Events

BACKGROUND Childhood cardiovascular risk factors predict subclinical adult cardiovascular disease, but links to clinical events are unclear. METHODS In a prospective cohort study involving participants in the International Childhood Cardiovascular Cohort (i3C) Consortium, we evaluated whether childhood risk factors (at the ages of 3 to 19 years) were associated with cardiovascular events in adulthood after a mean follow-up of 35 years. Body-mass index, systolic blood pressure, total cholesterol level, triglyceride level, and youth smoking were analyzed with the use of i3C-derived age- and sex-specific z scores and with a combined-risk z score that was calculated as the unweighted mean of the five risk z scores. An algebraically comparable adult combined-risk z score (before any cardiovascular event) was analyzed jointly with the childhood risk factors. Study outcomes were fatal cardiovascular events and fatal or nonfatal cardiovascular events, and analyses were performed after multiple imputation with the use of proportional-hazards regression. RESULTS In the analysis of 319 fatal cardiovascular events that occurred among 38,589 participants (49.7% male and 15.0% Black; mean [±SD] age at childhood visits, 11.8±3.1 years), the hazard ratios for a fatal cardiovascular event in adulthood ranged from 1.30 (95% confidence interval [CI], 1.14 to 1.47) per unit increase in the z score for total cholesterol level to 1.61 (95% CI, 1.21 to 2.13) for youth smoking (yes vs. no). The hazard ratio for a fatal cardiovascular event with respect to the combined-risk z score was 2.71 (95% CI, 2.23 to 3.29) per unit increase. The hazard ratios and their 95% confidence intervals in the analyses of fatal cardiovascular events were similar to those in the analyses of 779 fatal or nonfatal cardiovascular events that occurred among 20,656 participants who could be evaluated for this outcome. In the analysis of 115 fatal cardiovascular events that occurred in a subgroup of 13,401 participants (31.0±5.6 years of age at the adult measurement) who had data on adult risk factors, the adjusted hazard ratio with respect to the childhood combined-risk z score was 3.54 (95% CI, 2.57 to 4.87) per unit increase, and the mutually adjusted hazard ratio with respect to the change in the combined-risk z score from childhood to adulthood was 2.88 (95% CI, 2.06 to 4.05) per unit increase. The results were similar in the analysis of 524 fatal or nonfatal cardiovascular events. CONCLUSIONS In this prospective cohort study, childhood risk factors and the change in the combined-risk z score between childhood and adulthood were associated with cardiovascular events in midlife.publishedVersionPeer reviewe

Mixed-Eff ects Smoothing Splines in Modeling Subject-Speci fic Trajectories of Cardiovascular Disease Risk Factors

In this thesis, spline methods for modeling longitudinal non-linear risk factor trajectories of cardiovascular diseases (CVDs) are reviewed. These methods are applied to data from the International Childhood Cardiovascular Cohort (i3C) consortium, a large collaboration of longitudinal studies on CVD risk factors. Three risk factors are considered in this work, body mass index (BMI), systolic blood pressure and the level of total cholesterol. Anthropometric measurements tend to behave in a non-linear manner over time, and thus methods for modeling longitudinal non-linear data are needed. In particular, this thesis covers different types of spline functions, including natural cubic regression splines, interpolating splines and smoothing splines. To account for non-linear individual-specific risk factor profiles, the spline methods can be extended to a mixed-effects framework. Mixed-effects smoothing splines are presented in more detail and applied to simulated data as well as to empirical i3C data to model risk factor profiles. The use of mixed-effects smoothing splines is demonstrated by using area under curve (AUC) values, based on estimates of individual-specific risk factor profiles in childhood and adolescence, as explanatory variables in the Cox proportional hazards model for CVD. The AUC is used as a proxy for the cumulative burden by the respective risk factor. The cumulative burden of BMI and total cholesterol was found to be associated with the hazard of CVD in adulthood. In conclusion, the mixed-effects smoothing splines offer a flexible approach to model subject-specific risk factor profiles. They are especially beneficial in case of unbalanced data with missing observations

An Infancy-Onset 20-Year Dietary Counselling Intervention and Gut Microbiota Composition in Adulthood

The randomized controlled Special Turku Coronary Risk Factor Intervention Project (STRIP) has completed a 20-year infancy-onset dietary counselling intervention to reduce exposure to atherosclerotic cardiovascular disease risk factors via promotion of a heart-healthy diet. The counselling on, e.g., low intake of saturated fat and cholesterol and promotion of fruit, vegetable, and whole-grain consumption has affected the dietary characteristics of the intervention participants. By leveraging this unique cohort, we further investigated whether this long-term dietary intervention affected the gut microbiota bacterial profile six years after the intervention ceased. Our sub-study comprised 357 individuals aged 26 years (intervention n = 174, control n = 183), whose gut microbiota were profiled using 16S rRNA amplicon sequencing. We observed no differences in microbiota profiles between the intervention and control groups. However, out of the 77 detected microbial genera, the Veillonella genus was more abundant in the intervention group compared to the controls (log2 fold-change 1.58, p < 0.001) after adjusting for multiple comparison. In addition, an association between the study group and overall gut microbiota profile was found only in males. The subtle differences in gut microbiota abundances observed in this unique intervention setting suggest that long-term dietary counselling reflecting dietary guidelines may be associated with alterations in gut microbiota