Discovery of distinct immune phenotypes using machine learning in pulmonary arterial hypertension

RATIONALE: Accumulating evidence implicates inflammation in pulmonary arterial hypertension (PAH) and therapies targeting immunity are under investigation, though it remains unknown if distinct immune phenotypes exist. OBJECTIVE: Identify PAH immune phenotypes based on unsupervised analysis of blood proteomic profiles. METHODS AND RESULTS: In a prospective observational study of Group 1 PAH patients evaluated at Stanford University (discovery cohort, n=281) and University of Sheffield (validation cohort, n=104) between 2008-2014, we measured a circulating proteomic panel of 48 cytokines, chemokines, and factors using multiplex immunoassay. Unsupervised machine learning (consensus clustering) was applied in both cohorts independently to classify patients into proteomic immune clusters, without guidance from clinical features. To identify central proteins in each cluster, we performed partial correlation network analysis. Clinical characteristics and outcomes were subsequently compared across clusters. Four PAH clusters with distinct proteomic immune profiles were identified in the discovery cohort. Cluster 2 (n=109) had low cytokine levels similar to controls. Other clusters had unique sets of upregulated proteins central to immune networks- cluster 1 (n=58)(TRAIL, CCL5, CCL7, CCL4, MIF), cluster 3 (n=77)(IL-12, IL-17, IL-10, IL-7, VEGF), and cluster 4 (n=37)(IL-8, IL-4, PDGF-β, IL-6, CCL11). Demographics, PAH etiologies, comorbidities, and medications were similar across clusters. Non-invasive and hemodynamic surrogates of clinical risk identified cluster 1 as high-risk and cluster 3 as low-risk groups. Five-year transplant-free survival rates were unfavorable for cluster 1 (47.6%, CI 35.4-64.1%) and favorable for cluster 3 (82.4%, CI 72.0-94.3%)(across-cluster p<0.001). Findings were replicated in the validation cohort, where machine learning classified four immune clusters with comparable proteomic, clinical, and prognostic features. CONCLUSIONS: Blood cytokine profiles distinguish PAH immune phenotypes with differing clinical risk that are independent of World Health Organization Group 1 subtypes. These phenotypes could inform mechanistic studies of disease pathobiology and provide a framework to examine patient responses to emerging therapies targeting immunity

Feasibility study of parallel optical correlation-decoding analysis of lightning

The optical correlator described in this report is intended to serve as an attention-focusing processor. The objective is to narrowly bracket the range of a parameter value that characterizes the correlator input. The input is a waveform collected by a satellite-borne receiver. In the correlator, this waveform is simultaneously correlated with an ensemble of ionosphere impulse-response functions, each corresponding to a different total-electron-count (TEC) value. We have found that correlation is an effective method of bracketing the range of TEC values likely to be represented by the input waveform. High accuracy in a computational sense is not required of the correlator. Binarization of the impulse-response functions and the input waveforms prior to correlation results in a lower correlation-peak-to-background-fluctuation (signal-to-noise) ratio than the peak that is obtained when all waveforms retain their grayscale values. The results presented in this report were obtained by means of an acousto-optic correlator previously developed at SNL as well as by simulation. An optical-processor architecture optimized for 1D correlation of long waveforms characteristic of this application is described. Discussions of correlator components, such as optics, acousto-optic cells, digital micromirror devices, laser diodes, and VCSELs are included

Optimization of retardance for a complete Stokes polarimeter

The authors present two figures of merit based on singular value decomposition which can be used to assess the noise immunity of a complete Stokes polarimeter. These are used to optimize a polarimeter consisting of a rotatable retarder and fixed polarizer. A retardance of 132{degree} (approximately three eights wave) and retarder orientation angles of {+-}51.7{degree} and {+-}15.1{degree} are found to be optimal when four measurements are used. Use of this retardance affords a factor of 1.5 improvement in signal-to-noise ratio over systems employing a quarter wave plate. A geometric means of visualizing the optimization process is discussed, and the advantages of the use of additional measurements are investigated. No advantage of using retarder orientation angles spaced uniformly through 360{degree} is found over repeated measurements made at the four angles given previously

Portable Imaging Polarimeter and Imaging Experiments

Polarimetry is the method of recording the state of polarization of light. Imaging polarimetry extends this method to recording the spatially resolved state of polarization within a scene. Imaging-polarimetry data have the potential to improve the detection of manmade objects in natural backgrounds. We have constructed a midwave infrared complete imaging polarimeter consisting of a fixed wire-grid polarizer and rotating form-birefringent retarder. The retardance and the orientation angles of the retarder were optimized to minimize the sensitivity of the instrument to noise in the measurements. The optimal retardance was found to be 132{degree} rather than the typical 90{degree}. The complete imaging polarimeter utilized a liquid-nitrogen cooled PtSi camera. The fixed wire-grid polarizer was located at the cold stop inside the camera dewar. The complete imaging polarimeter was operated in the 4.42-5 {micro}m spectral range. A series of imaging experiments was performed using as targets a surface of water, an automobile, and an aircraft. Further analysis of the polarization measurements revealed that in all three cases the magnitude of circular polarization was comparable to the noise in the calculated Stokes-vector components

Endogenous retroviral elements generate pathologic neutrophils in pulmonary arterial hypertension

Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: Relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion and migration were assessed in neutrophils from pulmonary arterial hypertension patients and control subjects. Proteomic analyses were applied to explain functional perturbations, and transcriptomic data were used to find underlying mechanisms. CD66b-specific neutrophil EVs were isolated from plasma of patients with pulmonary arterial hypertension and we determined whether they produce pulmonary hypertension in mice. Measurements and Main Results: Neutrophils from pulmonary arterial hypertension patients produce and release increased neutrophil elastase, associated with enhanced extracellular traps. They exhibit reduced migration and increased adhesion attributed to elevated β1integrin and vinculin identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature that we related to an increase in human endogenous retrovirus k envelope protein. Transfection of human endogenous retrovirus k envelope in a neutrophil cell line (HL-60) increases neutrophil elastase and interferon genes, whereas vinculin is increased by human endogenous retrovirus k dUTPase that is elevated in patient plasma. Neutrophil EVs from patient plasma contain increased neutrophil elastase and human endogenous retrovirus k envelope and induce pulmonary hypertension in mice, mitigated by elafin, an elastase inhibitor. Conclusions: Elevated human endogenous retroviral elements and elastase link a neutrophil innate immune response to pulmonary arterial hypertension