Figure 1.
Three steps terminology construction, from PheWAS codes based on ICD-9-CM to PheWAS codes based on ICD-10 using ICD-9-CM-A to ICD-10-AM mapping file and manual mapping.
PheWAS: Phenome-wide association study; ICD: International classification of diseases; ICD-9-CM: International classification of diseases clinically modified; ICD-9-CM-A: Australian version of the ICD-9-CM, with custom codes added. ICD-10-AM: Australian version of the ICD-10, with custom codes added. 1: Mapping file from the New-Zealand Ministry of Health was used to project ICD-10 codes on ICD-9-CM. 2: Mapping of the previous projection with existing ICD-9-CM PheWAS codes. 3: File with correspondence between ICD-10 codes and ICD-9-CM PheWAS codes.
Figure 2.
Schematic representation of a PheWAS on a quantitative trait, analyzing ICD codes and biological test results.
PheWAS: Phenome-wide association study; ICD: International classification of diseases; TPMT: thiopurine S-methyltransferase. Patients are assigned to a group depending on the level of a quantitative trait (e.g. TPMT activity). ICD codes and biological test results are screened to find systematic differences between the groups.
Table 1.
Description of electronic health records (EHRs) of the thiopurine S-methyltransferase activity tested patients (TPMT cohort) and the control patients.
Figure 3.
HEGP CDW: Clinical data warehouse from Hôpital Européen Georges Pompidou, France. TPMT Cohort: patients with a thiopurine S-methyltransferase (TPMT) activity assessment in HEGP between January 2000 and July 2013. ICD: International Statistical Classification of Diseases and Related Health Problems. PheWAS: phenome-wide association study.
Figure 4.
Manhattan plot of −log10 (P-values) for the 771 ICD-9-CM based aggregated codes between very high TPMT activity patients and other TPMT activity patients.
ICD-9-CM: International classification of diseases 9 clinically modified; TPMT: thiopurine S-methyltransferase. The dotted line represents a P-value of 0.05 and the dashed line represents the FDR corrected level of significance for q = 0.2.
Figure 5.
Manhattan plot of −log10 (P-values) for the 256 ICD-10 based aggregated codes between very high TPMT activity patients and other TPMT activity patients.
ICD-10: International classification of diseases 10; TPMT: thiopurine S-methyltransferase. The dotted line represents a P-value of 0.05 and the dashed line represents the FDR corrected level of significance for q = 0.2.
Figure 6.
Pseudo-Manhattan plot of −log10 (P-values) for the 11 biological tests between very high TPMT activity patients and other TPMT activity patients.
Using the global approach, a high-value case, resp. low-value case, is defined as at least one occurrence of a biological test result above, resp. below, the high or low threshold. Low-value case analyses have not been performed on alanine aminotransferase, aspartate aminotransferase and gamma glutamyl-transpeptidase test results, as a low threshold is not relevant for these tests. The dotted line represents a P-value of 0.05. Grey triangles represent the results above the high threshold and black triangles represent the results below the low threshold.
Table 2.
Results of the low-value case biological test analyses between very high TPMT activity patients and other patients with normal and low TPMT activity.
Table 3.
Results of the high-value case biological test analyses between very high TPMT activity patients and other patients with normal and low TPMT activity.
Figure 7.
Kaplan-Meier survival analysis of the time without anemia after starting thiopurine therapy in very high TPMT activity patients versus other TPMT activity patients.
TPMT: thiopurine S-methyltransferase. Analysis based on biological test results. Anemia was censored for hemoglobin test results below 9 g/100 mL. All events occurring within the first week after starting thiopurine therapy were excluded from the analysis. Follow-up was censored after 360 days. A log-rank test was used for this analysis.