Additional file 1 of Item response models for the longitudinal analysis of health-related quality of life in cancer clinical trials

Annotated SAS codes to fit the adjacent and cumulative models described in simulation section with the PROC nlmixed. (PDF 558 Kb

Table_1_HE4 and CA-125 kinetics to predict outcome in patients with recurrent epithelial ovarian carcinoma: the META4 clinical trial.docx

HE4 and CA-125 are used for epithelial ovarian cancer (EOC) screening, diagnosis, and follow-up. Our objective was to study HE4 and CA-125 kinetics in patients treated for recurrent EOC. Serum samples were prospectively collected before the first chemotherapy cycle and every 3 months until disease progression. Data from 89/101 patients could be analyzed. At baseline, the median CA-125 and HE4 concentrations were 210 IU/L (7–10,310) and 184 pM (31–4,836). Among the 12 patients (13%) with normal CA-125 (14 weeks, HR 0.37, 95% CI: 0.20–0.70 and >12 weeks, HR 0.43, 95% CI: 0.23–0.83) were prognostic factors of progression-free survival. More investigations on HE4 kinetics could help to better monitor patients with CA-125 concentration within normal values.</p

Table_2_HE4 and CA-125 kinetics to predict outcome in patients with recurrent epithelial ovarian carcinoma: the META4 clinical trial.docx

HE4 and CA-125 are used for epithelial ovarian cancer (EOC) screening, diagnosis, and follow-up. Our objective was to study HE4 and CA-125 kinetics in patients treated for recurrent EOC. Serum samples were prospectively collected before the first chemotherapy cycle and every 3 months until disease progression. Data from 89/101 patients could be analyzed. At baseline, the median CA-125 and HE4 concentrations were 210 IU/L (7–10,310) and 184 pM (31–4,836). Among the 12 patients (13%) with normal CA-125 (14 weeks, HR 0.37, 95% CI: 0.20–0.70 and >12 weeks, HR 0.43, 95% CI: 0.23–0.83) were prognostic factors of progression-free survival. More investigations on HE4 kinetics could help to better monitor patients with CA-125 concentration within normal values.</p

Clinical characteristics of patients included in the training set.

<p>Clinical characteristics of patients included in the training set.</p

Functional annotation enrichment analysis of the 33-gene signature.

<p>Gene Ontology terms significantly over-represented in the 33-gene signature were identified and plotted using ClueGO. A) The size of the nodes are inversely proportional to the pvalue in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-g005" target="_blank">Fig. 5B</a>. Line widths between GO terms are proportional to the kappa scores used to define the categories. B) Table giving the results of the ClueGO analysis. Nr: Number of genes in our 33-gene signature associated with the GO term.%: Percentage of the genes of the considered GO term presents in our signature. Pvalue: pvalue of the GO term, corrected for multiple testing. C) Relation between the GO annotations of the 11 “cell adhesion”-associated genes in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-g005" target="_blank">Fig. 5B</a> and GO:0007155 term. Black arrows: “is a”. Green arrows: “Positively regulates”.</p

Upregulated genes in hepatic metastases compared to the paired primary colon tumor.

<p>Upregulated genes in hepatic metastases compared to the paired primary colon tumor.</p

Downregulated genes in hepatic metastases compared to the paired primary colon tumor.

<p>Downregulated genes in hepatic metastases compared to the paired primary colon tumor.</p

Expression of identified genes in three studies.

<p>Datasets from three intendant studies were renormalized together using an empirical Bayes method. Among the 33 genes of the gene signature, 32 genes were present in our (red), Sheffer (green) and Kleivi (blue) datasets (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-t004" target="_blank">Table 4</a>). The log2 ratio of HM to CT is plotted. Genes were ordered from the most downregulated to the most upregulated gene in HM versus CT in our study.</p

Identification of the 34-probe gene signature.

<p>The CT/HM values for the 13 pairs of samples and the 34 probes identified using paired SAM analysis were plotted versus the CT/HN values obtained in one paired sample from Sheffer's study <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone.0074599-Sheffer1" target="_blank">[7]</a>. The horizontal axis and the diagonal (HM = HN) separate the graph in four quadrants. (a) Genes over-expressed in HM versus CT, and downregulated in HM versus HN. (b) Genes over-expressed in HM versus CT, and in HM versus HN. (c) Genes downregulated in HM versus CT, and over-expressed in HM versus HN. (d) Genes downregulated in HM versus CT, and in HM versus HN. The red dashed line corresponds to a simulated contamination of a CT sample with 50% of a HN sample (see equation 1 in results section). The hatched region corresponds to HM samples that either are expressed at a comparable level (less than a 2-fold difference) in HM and CT or HM and HN, or whose variation between CT and HM can be explained by a contamination of HM by HN.</p

External validation.

<p>nc: non correctly classified</p>1<p>Number of the genes of our 33 gene signature present on the used platform.</p>2<p>Number of samples correctly classified using our signature (restricted to the number of genes in column “Nb genes”).</p>3<p>Genes in common between our 33 gene signature and those published in each study (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-t002" target="_blank">Table 2</a> in Ki, Supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-t002" target="_blank">Table 2</a> in Koh, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-g002" target="_blank">Fig. 2</a> in Kleivi, Supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-t002" target="_blank">Table 2</a> in Lin).</p>4<p>Ten of the CN samples are from the 13 paired patients used to identify the 34-probe signature.</p>5<p>CT and CP are not clearly separated and are in a single class (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-g003" target="_blank">Fig. 3</a>).</p>6<p>LN and LM clustered in independent groups but were not separated from CT (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-g003" target="_blank">Fig. 3</a>).</p>7<p>27 CT with synchronous and 20 CT with metachronous metastases.</p>8<p>12 rectum and 3 colon tumors.</p>9<p>HM and LM are not separated and are in a single class.</p>10<p>8 right and 5 left colon tumors. 5 rectum tumors.</p>11<p>Only SPP1 is in the top 35 ranking genes in Lin's study (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074599#pone-0074599-g001" target="_blank">Fig. 1</a> in Lin).</p