A blood DNA methylation biomarker for predicting short-term risk of cardiovascular events

Clinical Epigenetics

Table 2 List of newly developed DNAm surrogate biomarkers

Model training, EPIC Italy training set, n = 1352			Results on EPIC ITALY test set n = 451		Results on the validation set
Risk factor/biomarker	Model type	Number of CpGs	Pearson R	P	Validation data sets (N)	Pearson R	P	Validated DNAm surrogate
BMI	Mixed-effect LASSO	405	0.59	< 0.0001	US, TILDA, EXPOsOMICS, GSE174848 (2,045)	0.27	< 0.0001	Yes
CRP	LASSO	265	0.57	< 0.0001	US, TILDA, EXPOsOMICS, GSE174849 (1,893)	0.23	< 0.0001	Yes
D-dimer	LASSO	483	0.72	< 0.0001	EXPOsOMICS, GSE174848 (248)	0.17	0.56	No
Diastolic blood pressure	Mixed-effect LASSO	401	0.57	< 0.0001	EXPOsOMICS, TILDA (772)	0.10	0.36	No
Glucose	Mixed-effect LASSO	354	0.67	< 0.0001	EXPOsOMICS, TILDA, US (1,810)	0.28	0.007	Yes
HDL cholesterol	Mixed-effect LASSO	151	0.58	< 0.0001	EXPOsOMICS, TILDA, US (1,829)	0.08	0.001	Yes
Insulin	Mixed-effect LASSO	574	0.66	< 0.0001	EXPOsOMICS (170)	0.44	< 0.0001	Yes
LDL cholesterol	Mixed-effect LASSO	368	0.62	< 0.0001	EXPOsOMICS, TILDA (661)	0.15	0.36	No
PAI-1	LASSO	90	0.43	< 0.0001	EXPOsOMICS (171)	0.28	0.0001	Yes
Systolic blood pressure	Mixed-effect LASSO	275	0.64	< 0.0001	EXPOsOMICS, TILDA (772)	0.28	0.001	Yes
Tissue factor (CD142)	Mixed-effect LASSO	197	0.62	< 0.0001	EXPOsOMICS (171)	0.16	0.03	Yes
Total cholesterol	Mixed-effect LASSO	257	0.53	< 0.0001	EXPOsOMICS, TILDA, US (1,830)	0.13	0.14	No
Triglycerides	LASSO	471	0.73	< 0.0001	EXPOsOMICS, TILDA (661)	0.22	0.0003	Yes

For each candidate marker, we reported: the model used to extract significant CpGs (LASSO or mixed-effect LASSO depending on the association with the centre of recruitment), the number of CpGs whose linear combination constitute the best marker prediction, the Pearson correlation coefficient and p value in the primary test set (random 25% of EPIC Italy samples), the Pearson correlation coefficient and p value in independent test sets (random effect meta-analysis across studies). Nine out of 13 DNAm surrogates for CVD risk factors/markers were validated in independent testing set (P value for the Pearson correlation test lower than 0.05). The lists of CpGs and their weights to compute DNAm surrogates in independent data sets are provided in Additional file 1

ISSN: 1868-7083