<strong>Cardiovascular autonomic neuropathy and risk of kidney function decline in type 1 and type 2 diabetes: findings from the PERL and ACCORD cohorts </strong>

Previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among persons with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N=469) and with type 2 diabetes (T2D) from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (N=7,973). Baseline CAN was ascertained using ECG-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss ≥-5 ml/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed effect, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 (95%CI [-1.93, -0.37], P= 4.0x10-3) ml/min/1.73m2/year in PERL and 0.34 (95%CI [-0.49, -0.19], P= 6.3x10-6) ml/min/1.73m2/year in ACCORD. This translated in 2.11 (95% CI [1.23-3.63], P=6.9x10-3) and 1.39 (95% CI [1.20-1.61], P=1.1x10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (HR=2.60, 95%CI [1.15-5.45], p=0.02 in PERL and HR=1.54, 95%CI [1.28-1.84], P=3.8×10-6 in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help develop new therapies to prevent kidney function decline in patients with diabetes.  </p

Predictive Big Data Analytics: A Study of Parkinson’s Disease Using Large, Complex, Heterogeneous, Incongruent, Multi-Source and Incomplete Observations

<div><p>Background</p><p>A unique archive of Big Data on Parkinson’s Disease is collected, managed and disseminated by the Parkinson’s Progression Markers Initiative (PPMI). The integration of such complex and heterogeneous Big Data from multiple sources offers unparalleled opportunities to study the early stages of prevalent neurodegenerative processes, track their progression and quickly identify the efficacies of alternative treatments. Many previous human and animal studies have examined the relationship of Parkinson’s disease (PD) risk to trauma, genetics, environment, co-morbidities, or life style. The defining characteristics of Big Data–large size, incongruency, incompleteness, complexity, multiplicity of scales, and heterogeneity of information-generating sources–all pose challenges to the classical techniques for data management, processing, visualization and interpretation. We propose, implement, test and validate complementary model-based and model-free approaches for PD classification and prediction. To explore PD risk using Big Data methodology, we jointly processed complex PPMI imaging, genetics, clinical and demographic data.</p><p>Methods and Findings</p><p>Collective representation of the multi-source data facilitates the aggregation and harmonization of complex data elements. This enables joint modeling of the complete data, leading to the development of Big Data analytics, predictive synthesis, and statistical validation. Using heterogeneous PPMI data, we developed a comprehensive protocol for end-to-end data characterization, manipulation, processing, cleaning, analysis and validation. Specifically, we (i) introduce methods for rebalancing imbalanced cohorts, (ii) utilize a wide spectrum of classification methods to generate consistent and powerful phenotypic predictions, and (iii) generate reproducible machine-learning based classification that enables the reporting of model parameters and diagnostic forecasting based on new data. We evaluated several complementary model-based predictive approaches, which failed to generate accurate and reliable diagnostic predictions. However, the results of several machine-learning based classification methods indicated significant power to predict Parkinson’s disease in the PPMI subjects (consistent accuracy, sensitivity, and specificity exceeding 96%, confirmed using statistical n-fold cross-validation). Clinical (e.g., Unified Parkinson's Disease Rating Scale (UPDRS) scores), demographic (e.g., age), genetics (e.g., rs34637584, chr12), and derived neuroimaging biomarker (e.g., cerebellum shape index) data all contributed to the predictive analytics and diagnostic forecasting.</p><p>Conclusions</p><p>Model-free Big Data machine learning-based classification methods (e.g., adaptive boosting, support vector machines) can outperform model-based techniques in terms of predictive precision and reliability (e.g., forecasting patient diagnosis). We observed that statistical rebalancing of cohort sizes yields better discrimination of group differences, specifically for predictive analytics based on heterogeneous and incomplete PPMI data. UPDRS scores play a critical role in predicting diagnosis, which is expected based on the clinical definition of Parkinson’s disease. Even without longitudinal UPDRS data, however, the accuracy of model-free machine learning based classification is over 80%. The methods, software and protocols developed here are openly shared and can be employed to study other neurodegenerative disorders (e.g., Alzheimer’s, Huntington’s, amyotrophic lateral sclerosis), as well as for other predictive Big Data analytics applications.</p></div

Best machine learning based classification results (according to average measures of 5-fold cross-validation).

<p>Best machine learning based classification results (according to average measures of 5-fold cross-validation).</p

Exponential growth model of PD prevalence with age.

<p>Exponential growth model of PD prevalence with age.</p

(Partial) Varplots illustrating some of the critical predictive data elements for AdaBoost classifier predicting HC vs. (PD+SWEDD).

<p>(Partial) Varplots illustrating some of the critical predictive data elements for AdaBoost classifier predicting HC vs. (PD+SWEDD).</p

Between-cohort differences in some demographic, genetic and clinical variables.

<p>Between-cohort differences in some demographic, genetic and clinical variables.</p

Frequency plot of data elements that appear as more reliable predictors of subject diagnosis, ranked by counts using rebalanced URPRS data (see Table B in S1 File for the complete numerical results).

<p>Frequency plot of data elements that appear as more reliable predictors of subject diagnosis, ranked by counts using rebalanced URPRS data (see Table B in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0157077#pone.0157077.s001" target="_blank">S1 File</a> for the complete numerical results).</p

Summary of UPDRS ratings.

<p>Summary of UPDRS ratings.</p

Most significant GEE model coefficients for covariates contributing to segregating mean cohort differences.

<p>Most significant GEE model coefficients for covariates contributing to segregating mean cohort differences.</p

GEE and GLMM predictive model summaries.

<p>GEE and GLMM predictive model summaries.</p