Multilevel Matrix-Variate Analysis and its Application to Accelerometry-Measured Physical Activity in Clinical Populations

<p>The number of studies where the primary measurement is a matrix is exploding. In response to this, we propose a statistical framework for modeling populations of repeatedly observed matrix-variate measurements. The 2D structure is handled via a matrix-variate distribution with decomposable row/column-specific covariance matrices and a linear mixed effect framework is used to model the multilevel design. The proposed framework flexibly expands to accommodate many common crossed and nested designs and introduces two important concepts: the between-subject distance and intraclass correlation coefficient, both defined for matrix-variate data. The computational feasibility and performance of the approach is shown in extensive simulation studies. The method is motivated by and applied to a study that monitored physical activity of individuals diagnosed with congestive heart failure (CHF) over a 4- to 9-month period. The long-term patterns of physical activity are studied and compared in two CHF subgroups: with and without adverse clinical events. Supplementary materials for this article, that include de-identified accelerometry and clinical data, are available online.</p

Pathway analysis of exosomal proteins expressed at higher levels in the group 2 breast cancer patients (taxane treated and no change in neuropathy) derived from Ingenuity Pathway Analysis (IPA).

<p>(A). Top 10 canonical pathways emerged after IPA core analysis. Threshold indicates the minimal significance level [scored as–log (B-H p-value) from Benjamini-Hochberg procedure for multiple testing correction]. (B). Overlapping canonical pathways that were significantly enriched in this dataset. B-H p-value was listed below each pathway. (C). Network #1 from significantly enriched canonical pathways displaying proteins involved in the network. Proteins identified in the network were colored in red. Blue lines connected interacting proteins in the Coagulation System. (D). Network #1 from significantly enriched canonical pathways displaying proteins involved in the network. Proteins identified in the network were colored in red. Blue lines connected interacting proteins in the Acute Phase Response Signaling. (E). Network #2 from significantly enriched canonical pathways displaying proteins involved in the network. Proteins identified in the network were colored in red. Blue lines connected interacting proteins in the Acute Phase Response Signaling. (F). Network #2 from significantly enriched canonical pathways displaying proteins involved in the network. Proteins identified in the network were colored in red. Blue lines connected interacting proteins in the IL-12 signaling and production in macrophages. Significantly different proteins (q<0.2) were marked by *.</p

Statistical analysis of different protein lists using the Qlucore Omics Explorer.

<p>(A). Principal Component Analysis (PCA) of proteins identified in the serum exosome from baseline and endpoint blood draws for Group 1 (>20% increase in neuropathy) and Group 2 (no change in neuropathy). (B). PCA of proteins identified in the unique peptide-based list (left) and unsupervised hierarchical clustering of the unique peptide-based protein signature (right).</p

Pro-inflammatory signaling was identified in the exosomal proteins expressed at higher levels in the group 2 breast cancer patients (taxane treated and no change in neuropathy) based on the upstream analysis of IPA.

<p>(A). Higher levels of IL-6 targets found in the group 2 breast cancer patients compared to the group 1 breast cancer patients. P-value of the prediction is listed next to the upstream regulator, IL-6. (B). Interacting networks of C/EBPβ signaling proteins found in the group 2 breast cancer patients and their predicted physiological functions. (C). Scatter plots of representative proteins in the pro-inflammatory signaling networks in group 1 and 2 breast cancer patients and their expression in two time points (T0 and T12). T0 represents the baseline blood draws, and T12 represents the endpoint blood draws. Spectral counts of these proteins in patients were represented in the linear log scale (ln). p-values are included in the comparison between the group 1 and group 2 patients at the baseline. (D). Peak area of a peptide, HYEGSTVPEK (2+), from haptoglobin (HP) showed higher level of expression in group 2 patients than in group 1 patients. Significantly different proteins (q<0.2) were marked by *.</p