Extended Data Fig. 4: Operational classification of microbiome and metabolome features from the perspective of IHD pathology.

A classification tree was constructed based on significance and alignment of effect size and directionality of microbiome and metabolome features in the various group comparisons leading to the identification of: Features that reflect metabolic dysregulation in the individual but are not associated with diagnosed IHD: dysmetabolism features (DMF). Features that are significantly associated with IHD but are also significantly altered in metabolically dysregulated individuals in the same direction; we suggest that these features are early markers of IHD pathogenesis in individuals with metabolic dysregulation: IHD escalation features (ESCF). Features that are significantly associated with IHD but are also significantly altered in metabolically dysregulated individuals in the reverse direction; we suggest that these features are early markers of IHD seen in metabolically dysregulated individuals. However, they exhibit reversibility. This may plausibly be due to 1) long-term drug-treatment and improvement in overall lifestyle of the IHD individuals, 2) a compensatory response to the initiation of disease or 3) a trajectory-associated differential response to disease development. We propose that some of these features contribute to the stabilization of IHD and dysmetabolism and we coin those IHD de-escalation features (DSCF). IHD-specific features (IHDF) that achieve a significant shift only under IHD diagnoses. Two-sided MWU tests were used for assessing the significance of group-wise comparisons using HC (n = 275), MMC (n = 372), UMMC (n = 222), IHD (n = 372), ACS (n = 112), CIHD (n = 158), HF (n = 102) groups. Multiple testing corrections were done using Benjamini-Hochberg method and FDR < = 0.1 was considered significant. HC: healthy controls, MMC: metabolically matched controls, UMMC unmedicated metabolically matched controls, IHD: ischemic heart disease, ACS: acute coronary syndrome, CIHD: chronic IHD, HF: heart failure due to IHD, MWU: Mann-Whitney U, FDR: false-discovery rate.