43Biomarkers are now used in many areas of medicine but are still lacking for psychiatric conditions 44 such as schizophrenia (SCZ). We have used a multiplex molecular profiling approach to measure 52demonstrate for the first time that a biological signature for SCZ can be identified in blood serum. This 53 study lays the groundwork for development of a diagnostic test that can be used as an aid for 54 distinguishing SCZ subjects from healthy controls and from those affected by related psychiatric 55 illnesses with overlapping symptoms.

Autism spectrum conditions have been hypothesized to be an exaggeration of normal male low-empathizing and high-systemizing behaviors. We tested this hypothesis at the molecular level by performing comprehensive multi-analyte profiling of blood serum from adult subjects with Asperger's syndrome (AS) compared with controls. This led to identification of distinct sex-specific biomarker fingerprints for male and female subjects. Males with AS showed altered levels of 24 biomarkers including increased levels of cytokines and other inflammatory molecules. Multivariate statistical classification of males using this panel of 24 biomarkers revealed a marked separation between AS and controls with a sensitivity of 0.86 and specificity of 0.88. Testing this same panel in females did not result in a separation between the AS and control groups. In contrast, AS females showed altered levels of 17 biomarkers including growth factors and hormones such as androgens, growth hormone and insulin-related molecules. Classification of females using this biomarker panel resulted in a separation between AS and controls with sensitivities and specificities of 0.96 and 0.83, respectively, and testing this same panel in the male group did not result in a separation between the AS and control groups. The finding of elevated testosterone in AS females confirmed predictions from the 'extreme male brain' and androgen theories of autism spectrum conditions. We conclude that to understand the etiology and development of autism spectrum conditions, stratification by sex is essential.

We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls.

This study was performed to test the hypothesis that measurements of jet area by Doppler color flow imaging can predict the angiographic severity and hemodynamic consequences of mitral regurgitation. Doppler color flow imaging was performed in 47 patients undergoing cardiac catheterization and left ventriculography. The jet area was measured as the largest clearly definable flow disturbance in the parasternal and apical views, and expressed as the maximal jet area, the mean of the largest jet area (average jet area) in two views or as the ratio of these measures to left atrial area. Correlation of all Doppler color flow measurements with angiographic grades of mitral regurgitation were comparable, maximal jet area being closest at r = 0.76. A maximal jet area greater than 8 cm2 predicted severe mitral regurgitation with a sensitivity of 82% and specificity of 94%, whereas a maximal jet area less than 4 cm2 predicted mild mitral regurgitation with a sensitivity and specificity of 85% and 75%, respectively. All patients with an average jet area greater than 8 cm2 manifested severe mitral regurgitation. However, jet area measurements showed limited correlation with regurgitant volume and fraction (r = 0.55 and 0.62, respectively) for maximal jet area, and were not predictive of hemodynamic abnormalities, including those of pulmonary wedge pressure, stroke volume or ventricular volumes. Thus, in patients with mitral regurgitation, maximal jet area from Doppler color flow imaging provides a simple measurement that predicts angiographic grade, but manifests a weak correlation with regurgitant volume and does not predict hemodynamic dysfunction.

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