Results of the high-value case biological test analyses between very high TPMT activity patients and other patients with normal and low TPMT activity.

<p>Global approach: a low-value case is defined as at least one occurrence, over the study period, of biological test result below the low threshold defined in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003405#pcbi-1003405-t001" target="_blank">Table 1</a>. Frequency-based approach: for a given patient, the frequency of low-value encounters is defined as the number of encounters with at least one occurrence below the low threshold divided by the number of encounters (mean low-value encounter frequencies are reported).</p><p>TPMTa: thiopurine <i>S</i>-methyltransferase activity. lowTPMTa: low TPMTa (<8.5 nmol/h/mL red blood cells); vhTPMTa: very high TPMTa (≥15.0 nmol/h/mL red blood cells); nTPMTa: normal TPMTa (in between).</p

Pseudo-Manhattan plot of −log10 (P-values) for the 11 biological tests between very high TPMT activity patients and other TPMT activity patients.

<p>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.</p

Schematic representation of a PheWAS on a quantitative trait, analyzing ICD codes and biological test results.

<p>PheWAS: Phenome-wide association study; ICD: International classification of diseases; TPMT: thiopurine <i>S</i>-methyltransferase. Patients are assigned to a group depending on the level of a quantitative trait (<i>e.g.</i> TPMT activity). ICD codes and biological test results are screened to find systematic differences between the groups.</p

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.

<p>ICD-9-CM: International classification of diseases 9 clinically modified; TPMT: thiopurine <i>S</i>-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.</p

Description of electronic health records (EHRs) of the thiopurine S-methyltransferase activity tested patients (TPMT cohort) and the control patients.

<p>Control patients are randomly extracted from the clinical data warehouse (CDW) of the Hôpital européen Georges Pompidou.</p><p>TPMTa: thiopurine <i>S</i>-methyltransferase activity; low TPMTa: <8.5 nmol/h/mL red blood cells; very high TPMTa: ≥15.0 nmol/h/mL red blood cells; normal TPMTa: in between.</p

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.

<p>ICD-10: International classification of diseases 10; TPMT: thiopurine <i>S</i>-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.</p

Flow chart.

<p>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.</p