Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Holocene thermal maximum in the western Arctic (0-180°W)

The spatio-temporal pattern of peak Holocene warmth (Holocene thermal maximum, HTM) is traced over 140 sites across the Western Hemisphere of the Arctic (0–180°W; north of ~60°N). Paleoclimate inferences based on a wide variety of proxy indicators provide clear evidence for warmer-than-present conditions at 120 of these sites. At the 16 terrestrial sites where quantitative estimates have been obtained, local HTM temperatures (primarily summer estimates) were on average 1.6±0.8°C higher than present (approximate average of the 20th century), but the warming was time-transgressive across the western Arctic. As the precession-driven summer insolation anomaly peaked 12–10 ka (thousands of calendar years ago), warming was concentrated in northwest North America, while cool conditions lingered in the northeast. Alaska and northwest Canada experienced the HTM between ca 11 and 9 ka, about 4000 yr prior to the HTM in northeast Canada. The delayed warming in Quebec and Labrador was linked to the residual Laurentide Ice Sheet, which chilled the region through its impact on surface energy balance and ocean circulation. The lingering ice also attests to the inherent asymmetry of atmospheric and oceanic circulation that predisposes the region to glaciation and modulates the pattern of climatic change. The spatial asymmetry of warming during the HTM resembles the pattern of warming observed in the Arctic over the last several decades. Although the two warmings are described at different temporal scales, and the HTM was additionally affected by the residual Laurentide ice, the similarities suggest there might be a preferred mode of variability in the atmospheric circulation that generates a recurrent pattern of warming under positive radiative forcing. Unlike the HTM, however, future warming will not be counterbalanced by the cooling effect of a residual North American ice sheet