Variability of metabolomic profiles in terms of variables related to clinical and laboratory parameters in the four principal components identified and expressed as F-values together with the corresponding p-values (in brackets).

<p>ANOVA test, significant values (p<0.05) are in bold.</p><p>The results showed a correlation between PC3 scores and CRP levels and between PC1 scores and tender joint count. This last parameter only could affect the response to etanercept: in fact, the median tender joint count 28 (range) was 8 (0–21) and 12 (6–25) for responder and non-responder groups, respectively.</p><p>ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; VAS: visual analogue scale; HAQ: Health Assessment Questionnaire; DAS28: disease activity score based on 28 joint counts.</p><p>Variability of metabolomic profiles in terms of variables related to clinical and laboratory parameters in the four principal components identified and expressed as F-values together with the corresponding p-values (in brackets).</p

¹H-NMR metabolomic fingerprinting of RA patients before treatment with etanercept.

<p>(A) score plot from PCA analysis according to EULAR-ESR; (B) score plot from PCA analysis according to EULAR-CRP; for A and B white circles represent good responders, gray circles represent moderate responders, black circles represent non-responders. (C) score plot from OPLS-DA separating responder and non-responder patients according to both EULAR-ESR and EULAR-CRP criteria. White circles represent responders (good and moderate) and black circles represent non-responders. (D) score plot from OPLS-DA separating good, moderate, and non-responders according to EULAR-ESR; (E) score plot from OPLS-DA separating good, moderate, and non-responders according to EULAR-CRP criteria, respectively; for D and E white circles represent good responders, gray circles represent moderate responders, black circles represent non-responders.</p

Variability of the metabolomic profiles in terms of potential confounding variables in the four principal components identified by PCA and expressed as F-values together with the corresponding p-values (in brackets).

<p>ANOVA test, significant values (p<0.05) are in bold.</p><p>Smoking, co-morbidity, ACPA and RF variables are defined as presence or absence; dietary habits variable is defined as mediterranean diet or non-mediterranean diet; age and disease duration variables are defined as numerical values (number of months); concomitant treatment variable is defined as four groups: glucocorticoids, DMARDs, DMARDs and glucocorticoids and no immunosuppressants.</p><p>Among subject-related and disease-related factors, co-morbidity and RF, respectively, affected the clustering of metabolic profiles in terms of a minor likelihood of response to treatment in patients positive for either of them. However, by using Pearson’s simple and partial correlation analysis to simultaneously investigate PCA score, responder or non-responder status, and co-morbidities, the metabolic variations on PC1 were mainly associated with the prediction of response to etanercept.</p><p>ACPA: anti-citrullinated protein/peptide antibodies; RF: rheumatoid factor.</p><p>Variability of the metabolomic profiles in terms of potential confounding variables in the four principal components identified by PCA and expressed as F-values together with the corresponding p-values (in brackets).</p

TB-infection case: Best-fit coefficients.

<p>Best fit parameters obtained through the maximum likelihood method (see Eqs. 15, 16, respectively). Here we used , consistently with clinical data. The fit was accomplished with the constraint that the parameters and are the same for both therapies, as they are drug-independent. The average relative error on these parameters is .</p

Etanercept caused changes in the metabolism of good responder patients according to EULAR-ESR criteria.

<p>Both unsupervised (A) (PCA) and supervised analysis (B)(OPLS-DA) revealed a good separation between serum spectra of patients with a good response to etanercept therapy collected at baseline (white circles) and after six months of treatment (black circles).</p

Baseline characteristics of rheumatoid arthritis patients (n = 27) by response to etanercept therapy at six months.

<p>*As determined by EUropean League Against Rheumatism criteria.</p><p>**Prednisone equivalent.</p><p>Ever smokers include past and current smokers.</p><p>There were no significant differences between the two groups (comparison assessed with Mann-Whitney test for independent samples).</p><p>RF: rheumatoid factor; ACPA: anti-citrullinated protein/peptide antibodies; DAS28: disease activity score based on 28 joint counts; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; DMARDs: disease-modifying anti-rheumatic drugs [include for responders and non responders, respectively: methotrexate (10 and 4), sulfasalazine (1 and 0), hydroxychloroquine (3 and 0), cyclosporine (1 each), leflunomide (0 and 1]; HAQ: Health Assessment Questionnaire; VAS: visual analogue scale.</p><p>Baseline characteristics of rheumatoid arthritis patients (n = 27) by response to etanercept therapy at six months.</p

Comparison between experimental, analytical and numerical results for the NTM-infection case.

<p>Cumulative number of patients undergoing active NTM-infection. Experimental data from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055017#pone.0055017-Winthrop1" target="_blank">[23]</a> ( for infliximab-treated patients and for etanercept-treated patients) are compared with the approximated analytical solution (see Eq. , solid curves) and with data from numerical simulation (dashed curves). The parameters used to draw the analytical curves correspond to the best-fit coefficient and are reported in Table . Notice that here we consider the extensive number of patients affected by NTM over the whole population of treated patients, according to experimental results.</p

Deviations between experimental, analytical and numerical results for the NTM-infection case.

<p>Absolute difference between experimental data and theoretical data reported in Fig. 5; the same legend holds.</p

Comparison between experimental, analytical and numerical results for the TB-infection case.

<p>Cumulative number of patients undergoing active TB-infection. Experimental data from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055017#pone.0055017-Wallis3" target="_blank">[9]</a> ( for infliximab-treated patients and for etanercept-treated patients) are compared with the approximated analytical solution (see Eq. 15 and Eq. 16, respectively, solid curves) and with data from numerical simulation (dashed curves). The parameters used to draw the analytical curves correspond to the best-fit coefficients and are reported in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055017#pone-0055017-t001" target="_blank">Table 1</a>. Notice that here we consider the extensive number of patients affected by TB over a population of treated patients, according to experimental results.</p

Toy Markov chain.

<p>From the state there is a potential flux of probability at rate toward the state , hence we expect that, after a proper amount of time, a fraction of the probability will be drained from to . The same holds for the situation linking to . After an infinite time the probability of having the patient in the state is one, while it is zero for the states .</p