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Independent-model diagnostics for a priori identification and interpretation of outliers from a full PK (PD) dataset. Nabil SEMMAR 1,3 , Saik URIEN 2,4 , Bernard BRUGUEROLLE 1 and Nicolas SIMON 1. 3: ISSBAT, High Institute of Applied Biological . Sciences of Tunis, Tunisia.

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Independent-model diagnostics for a priori identification and interpretation of outliers from a full PK (PD) dataset

Nabil SEMMAR1,3, Saik URIEN2,4, Bernard BRUGUEROLLE1 and Nicolas SIMON1

3: ISSBAT, High Institute of Applied Biological . Sciences of Tunis, Tunisia

4: INSERM, Paris, France

1: Laboratory of Clinical Pharmacology, EA3784, . Medical School of Marseilles, Marseilles, France

2: Pharmacology Department, Centre René Huguenin, . Saint-Cloud, France

Different kinds of outliers

Multivariate outlier diagnostics and corresponding metric distances

AIMS

A priori identification of outliers requires distance computations by reference to an average or a middle state: Higher a distance value is, more the corresponding case tends to be outlier compared with all the other individual cases. There are three kinds of outliers:

1) Outliers due to high absolute values can be detected from euclidean distance, computed by multivariate Andrews curves.

2) Outliers due to high relative values or significant shift can be detected from the chi-square distance, computed by correspondence analysis method.

1) Points that are far because of high absolute coordinates;

2) Points occupying neighbor spaces but non shared by other points;

3) Outliers tending to stretch the global direction of the cloud of points can be detected from Mahalanobis distance, computed as jackknifed robust distance.

3) Points oriented along atypical directions in the multivariate space.

Graphical representations of factorial coordinates

Decomposition of residual matrix into linear combinations based on eigenvectors computation

How much observed data are far from independence states?

Correspondence analysis: Principle and illustration

Residual matrix

(R) = (T) – (T0)

Standard and Jackknifed Mahalanobis distance: Principle and illustration

Identification and interpretation of outliers based on ² criterion

Andrews curves: Principle and illustration

Graphical representation of Andrews function values

Correspondence analysis

Recalculation of JMD without different time variables to identify outlier concentrations

Outlier diagnostics from a full PK dataset: Capecitabin administrated orally two times in 40 patients

Jackknifed Mahalanobis distance (JMD)

Patients with relatively high concentrations at some times compared with all the values of the same times in the whole population

Plasma samplings at 0.5, 1, 2, 3, 4, 6h after each dosing

Is there a link between a priori outlier diagnostics and a posteriori PK modeling?

Andrews curves

What are the outlier concentrations?

Outlier PK profiles: High absolute concentrations

Without times 0.5, 1, 24.5 and 25h

The outlier curves became non-outliers after removing of outlier

Overdose risk…

Without time 2h

Without time 28h

concentration

time values

More detected was an outlier concentration a priori, higher was its residual (NPDE) after PK modeling


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