Optimisation of machine learning methods for cancer detection using vibrational spectroscopy

Early cancer detection drastically improves the chances of cure and therefore methods are required, which allow early detection and screening in a fast, reliable and inexpensive manner. A prospective method, featuring all these characteristics, is vibrational spectroscopy. In order to take the next step towards the development of this technology into a clinical diagnostic tool, classification and imaging methods for an automated diagnosis based on spectral data are required. For this study, Raman spectra, derived from axillary lymph node tissue from breast cancer patients, were used to develop a diagnostic model. For this purpose different classification methods were investigated. A support vector machine (SVM) proved to be the best choice of classification method since it classified 100% of the unseen test set correctly. The resulting diagnostic models were thoroughly tested for their robustness to the spectral corruptions that would be expected to occur during routine clinical analysis. It showed that sufficient robustness is provided for a future diagnostic routine application. SVMs demonstrated to be a powerful classifier for Raman data and due to that they were also investigated for infrared spectroscopic data. Since it was found that a single SVM was not capable of reliably predicting breast cancer pathology based on tissue calcifications measured by infrared micro-spectroscopy a SVM ensemble system was implemented. The resulting multi-class SVM ensemble predicted the pathology of the unseen test set with an accuracy of 88.9%, in comparison a single SVM assessed with the same unseen test set achieved 66.7% accuracy. In addition, the ensemble system was extended for analysing complete infrared maps obtained from breast tissue specimens. The resulting imaging method successfully detected and staged calcification in infrared maps. Furthermore, this imaging approach revealed new insights into the calcification process in malignant development, which was not previously well understood.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Circulating Proteomic Signatures of Chronological Age

To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10−46) and pleiotrophin (0.012 [0.005], p = 3.88 × 10−41). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10−5). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and agin

Candidate Blood Proteome Markers of Alzheimer's Disease Onset and Progression: A Systematic Review and Replication Study

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Circulating Proteomic Signatures of Chronological Age.

To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis β [SE] = 0.013 [0.001], p = 3.66 × 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 × 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 × 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging

Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology

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Association of blood lipids with Alzheimer's disease: A comprehensive lipidomics analysis

Introduction: The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimer’s disease (AD) (Proitsi et al 2015) and (2) identify novel associations between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex). Methods: We performed untargeted lipidomic analysis on 148 AD and 152 elderly control plasma samples and used univariate and multivariate analysis methods. Results: We replicated our previous lipids associations and reported novel associations between lipids molecules and all phenotypes. A combination of 24 molecules classified AD patients with .70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R2 5 0.10, test data set) and brain atrophy (R2 0.14, all test data sets except left entorhinal cortex). We putatively identified a number of metabolic features including cholesteryl esters/triglycerides and phosphatidylcholines. Discussion: Blood lipids are promising AD biomarkers that may lead to new treatment strategies

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology

Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ 4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo