A New Calibrated Bayesian Internal Goodness-of-Fit Method: Sampled Posterior p-Values as Simple and General p-Values That Allow Double Use of the Data

Background: Recent approaches mixing frequentist principles with Bayesian inference propose internal goodness-of-fit (GOF) p-values that might be valuable for critical analysis of Bayesian statistical models. However, GOF p-values developed to date only have known probability distributions under restrictive conditions. As a result, no known GOF p-value has a known probability distribution for any discrepancy function. Methodology/Principal Findings: We show mathematically that a new GOF p-value, called the sampled posterior p-value (SPP), asymptotically has a uniform probability distribution whatever the discrepancy function. In a moderate finite sample context, simulations also showed that the SPP appears stable to relatively uninformative misspecifications of the prior distribution. Conclusions/Significance: These reasons, together with its numerical simplicity, make the SPP a better canonical GOF p-value than existing GOF p-values

An automated integrated platform for rapid and sensitive multiplexed protein profiling using human saliva samples

During the last decade, saliva has emerged as a potentially ideal diagnostic biofluid for noninvasive testing. In this paper, we present an automated, integrated platform useable by minimally trained personnel in the field for the diagnosis of respiratory diseases using human saliva as a sample specimen. In this platform, a saliva sample is loaded onto a disposable microfluidic chip containing all the necessary reagents and components required for saliva analysis. The chip is then inserted into the automated analyzer, the SDReader, where multiple potential protein biomarkers for respiratory diseases are measured simultaneously using a microsphere-based array via fluorescence sandwich immunoassays. The results are read optically, and the images are analyzed by a custom-designed algorithm. The fully automated assay requires as little as 10 μL of saliva sample, and the results are reported in 70 min. The performance of the platform was characterized by testing protein standard solutions, and the results were comparable to those from the 3.5-h lab bench assay that we have previously reported. The device was also deployed in two clinical environments where 273 human saliva samples collected from different subjects were successfully tested, demonstrating the device’s potential to assist clinicians with the diagnosis of respiratory diseases by providing timely protein biomarker profiling information. This platform, which combines non-invasive sample collection and fully automated analysis, can also be utilized in point-of-care diagnostics

Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P = .003) and natural killer (NK) cell (P = .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P = .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progression-free survival (P = .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression

Correlations of Salivary Biomarkers with Clinical Assessments in Patients with Cystic Fibrosis

<div><p>Rationale</p><p>Monitoring clinical disease status in cystic fibrosis frequently requires invasive collection of clinical samples. Due to its noninvasive collection process and direct anatomic relationship with the lower airway, saliva shows great potential as a biological fluid for cystic fibrosis monitoring.</p><p>Objectives</p><p>To measure the levels of multiple protein markers in human saliva supernatants and investigate the possibility of utilizing them to provide a more quantitative measure of disease state for use in research and monitoring of patients with cystic fibrosis clinically.</p><p>Methods</p><p>Whole saliva samples were collected and processed from cystic fibrosis patients at two distinct time points (2010 and 2013) and measured by two separate platforms. In this cross sectional study, a convenience sample of 71 participants were recruited with samples measured by multiplexed fluorescence microarray (fiber microarray) and another 117 participant samples were measured by an automated, point-of-care, analyzer (SDReader) using a microsphere-based array via fluorescence sandwich immunoassay. For comparison, saliva from 56 and 50 healthy subjects were collected, respectively. The levels of six target proteins were quantified. Various demographic and clinical data, including spirometry, medical history, and clinicians’ assessments were also collected from patients with cystic fibrosis on the day of saliva collection.</p><p>Measurements and Main Results</p><p>Similar trends were observed with both platforms and compared with healthy subjects, cystic fibrosis patients had significantly elevated levels of VEGF, IP-10, IL-8, and EGF as well as lower levels of MMP-9 (<i>P</i> ≤ 0.005) using fiber microarray and significantly elevated levels of IP-10, IL-8 with lower levels of MMP-9 and IL-1<i>β</i> (<i>P</i> ≤ 0.02) using the SDReader. The levels of the six proteins correlated with each other significantly, and in some cases, biomarker levels could be used to differentiate between subgroups of patients with different clinical presentations. For example, IP-10 levels significantly correlated with FEV₁ and disease severity (as evaluated by clinicians) with both platforms (<i>P</i> < 0.05).</p><p>Conclusions</p><p>Significant variations of the levels of six proteins in saliva supernatants, and the correlations of these levels with clinical assessments, demonstrated the potential of saliva for cystic fibrosis research and monitoring.</p></div

The concentrations of six proteins in the saliva supernatants collected from CF patients (n = 117) and healthy subjects (n = 50) tested by the SDReader.

<p>The levels of IP-10 and IL-8 in CF patients were significantly (<i>P</i> < 0.01) elevated compared with those from healthy subjects. On the contrary, the levels of MMP-9 and IL-1<i>β</i> were significantly lower in CF patients (<i>P</i> < 0.02). VEGF and EGF were not significantly different (<i>P</i> > 0.1) between the two groups.</p

Statistical results for six proteins measured in patients with CF and healthy control subjects tested by the fiber microarray.

<p>^*: Concentrations in ng/mL.</p><p>Protein levels in the different groups are presented as median (25th–75th percentile). The statistical results of the same groups have been reported in another format in a previous publication [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135237#pone.0135237.ref029" target="_blank">29</a>]).</p

Characteristics of adults and children with CF tested by the fiber microarray.

<p>^*n = 42.</p><p>^†n = 24.</p><p>^‡n = 41.</p><p>^§n = 23.</p><p>Characteristics of adults and children with CF tested by the fiber microarray.</p

Statistical results for six proteins measured in patients with CF and healthy control subjects by the SDReader.

<p>^*: Concentrations in ng/mL.</p><p>Protein levels in the different groups are presented as median (25th–75th percentile).</p

Correlation of protein levels with clinical assessments of disease severity tested by the SDReader (n = 108).

<p>^*CF severity: a semi-quantitative evaluation of individual patients by the clinicians, ranging from 1 to 4 (1: mild, 2: moderate, 3: mod-severe, 4: severe).</p><p>Correlation of protein levels with clinical assessments of disease severity tested by the SDReader (n = 108).</p

Correlation of protein levels with clinical assessments of disease severity tested by the fiber microarray (n = 63).

<p>^*CF severity: a semi-quantitative evaluation of individual patients by the clinicians, ranging from 1 to 4 (1: mild, 2: moderate, 3: mod-severe, 4: severe).</p><p>Correlation of protein levels with clinical assessments of disease severity tested by the fiber microarray (n = 63).</p