Within population variability.

<p>Comparison of the dispersion of fields belonging to the same wells (boxplot A) and randomly selected fields (boxplot B). The measure of dispersion is the sum of squared pairwise distances. The population descriptors (cell count and proportions of cells in S, G2, M and apoptotic states) have been scaled beforehand.</p

Novelty detection and positive controls.

<p>Density plot of cell population descriptors averaged over wells (panel <b>(a)</b> to <b>(e)</b>) and log likelihood (panel <b>(f)</b>) given by the model trained on negative controls. Positive controls are very different from negative controls. It is easy to distinguish them from negative controls only looking at cell count. The log likelihood given by the model separates the two type of controls. We observe that the discriminative power of the univariate descriptors is not lost when considering the model likelihood.</p

Model fitting.

<p>Train (a) and test (b) log likelihood of the negative control data for the two proposed models, and the baseline, varying the number of phenotypic classes. Green corresponds to the copula based model, red corresponds to the gaussian model, and black corresponds to the baseline model. For training log likelihood, we picked the best model among 10 random restarts of the algorithm. For the test log likelihood, the boxes account for the variability among ten different splits of the data in a cross validation setting. Given a data split, for each fold and each number of classes, we picked the best model among 5 random restarts of the algorithm.</p

Example of a well.

<p><b>Panels</b> (<b>a</b>) <b>to</b> (<b>e</b>), the density plots represent the distribution of cell population descriptors averaged over wells for the negative control dataset. Red lines are the values of the 4 fields of the considered well and the blue lines are the population descriptors averaged over the 4 fields. <b>Panel</b> (<b>f</b>) represents the density of the log likelihood for all negative controls. The blue vertical line represents the log-likelihood of the considered well.</p

Association between population descriptors.

<p>Association between cell count and proportion of cells in different states based on negative controls. The measure of association is Spearman's rho and the p-value is computed via the asymptotic t approximation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042715#pone.0042715-Hollander1" target="_blank">[36]</a>.</p

Model and empirical distributions.

<p>Examples of classes found by the model (Copula model on the left, gaussian model on the right). The proportion of cells in apoptotic state is represented for the cell populations belonging to those classes. We compare for two classes the univariate marginal densities. For each class the empirical density is represented with a solid line and the density fitted by the model is represented with a broken line.</p

Histogram of the distribution of methylome-similarity score (MS) between unrelated PT/LR pairs.

<p>MS score for matched pairs is represented by circles. The vertical dashed line corresponds to the 95% quantile of the distribution of the MS scores for the unrelated pairs, used as a threshold to define clonal pairs ().</p

Summarized PT/LR Clinical and histological features.

<p><b>Cor</b> (Correspondence): correspondence number with the Bollet/Servant cohort from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103986#pone.0103986-Bollet1" target="_blank">[16]</a>, <b>Type</b>: histological type of the tumor (D =  ductal, L =  lobular), <b>Grade</b>: Aggressiveness of the tumor (1 to 3), <b>ER</b>: presence of estrogen receptors, <b>PR</b>: presence of progesterone receptors, <b>HER2</b>: presence of HER2 receptors, <b>Loc</b> (Location): 1 if the recurrence was located less than 4cm from the PT.</p

Correlation between methylation and copy-number scores.

<p>The horizontal red line (resp. vertical dashed blue line) corresponds to the 95% quantile of the distribution of the methylation-scores (resp. partial identity scores) for the unrelated pairs: (resp. ). PT/AM (resp. PT/LR, resp. PT/CL) pairs are colored in yellow (resp. blue, resp. pink). The black line corresponds to the linear regression between methylation and copy-number scores for all the datasets.</p

Comparison of classification methods for clonality between pairs in the PT/LR cohort.

<p><b>Cor</b> (Correspondence): correspondence number with the Bollet/Servant cohort. <b>scores</b>: scores obtained with partial identity (PIS) or methylation (MS). <b>Time</b>: time elapsed between diagnosis of the PT and diagnosis of the recurrence. <b>Classification</b>: classification of the recurrence based on copy number (PIS), methylation (MS) or clinical features (clinical). <b>Divergence</b>: which method deviated from the others.</p