The purpose of developing Computer-Aided Detection (CAD) schemes is to assist physicians (i.e., radiologists) in interpreting medical imaging findings and reducing inter-reader variability more accurately. In developing CAD schemes, Machine Learning (ML) plays an essential role because it is widely used to identify effective image features from complex datasets and optimally integrate them with the classifiers, which aims to assist the clinicians to more accurately detect early disease, classify disease types and predict disease treatment outcome. In my dissertation, in different studies, I assess the feasibility of developing several novel CAD systems in the area of medical imaging for different purposes. The first study aims to develop and evaluate a new computer-aided diagnosis (CADx) scheme based on analysis of global mammographic image features to predict the likelihood of cases being malignant. CADx scheme is applied to pre-process mammograms, generate two image maps in the frequency domain using discrete cosine transform and fast Fourier transform, compute bilateral image feature differences from left and right breasts, and apply a support vector machine (SVM) method to predict the likelihood of the case being malignant. This study demonstrates the feasibility of developing a new global image feature analysis based CADx scheme of mammograms with high performance. This new CADx approach is more efficient in development and potentially more robust in future applications by avoiding difficulty and possible errors in breast lesion segmentation. In the second study, to automatically identify a set of effective mammographic image features and build an optimal breast cancer risk stratification model, I investigate advantages of applying a machine learning approach embedded with a locally preserving projection (LPP) based feature combination and regeneration algorithm to predict short-term breast cancer risk. To this purpose, a computer-aided image processing scheme is applied to segment fibro-glandular tissue depicted on mammograms and initially compute 44 features related to the bilateral asymmetry of mammographic tissue density distribution between left and right breasts. Next, an embedded LLP algorithm optimizes the feature space and regenerates a new operational vector with 4 features using a maximal variance approach. This study demonstrates that applying the LPP algorithm effectively reduces feature dimensionality, and yields higher and potentially more robust performance in predicting short-term breast cancer risk. In the third study, to more precisely classify malignant lesions, I investigate the feasibility of applying a random projection algorithm to build an optimal feature vector from the initially CAD-generated large feature pool and improve the performance of the machine learning model. In this process, a CAD scheme is first applied to segment mass regions and initially compute 181 features. An SVM model embedded with the feature dimensionality reduction method is then built to predict the likelihood of lesions being malignant. This study demonstrates that the random project algorithm is a promising method to generate optimal feature vectors to improve the performance of machine learning models of medical images. The last study aims to develop and test a new CAD scheme of chest X-ray images to detect coronavirus (COVID-19) infected pneumonia. To this purpose, the CAD scheme first applies two image preprocessing steps to remove the majority of diaphragm regions, process the original image using a histogram equalization algorithm, and a bilateral low-pass filter. Then, the original image and two filtered images are used to form a pseudo color image. This image is fed into three input channels of a transfer learning-based convolutional neural network (CNN) model to classify chest X-ray images into 3 classes of COVID-19 infected pneumonia, other community-acquired no-COVID-19 infected pneumonia, and normal (non-pneumonia) cases. This study demonstrates that adding two image preprocessing steps and generating a pseudo color image plays an essential role in developing a deep learning CAD scheme of chest X-ray images to improve accuracy in detecting COVID-19 infected pneumonia. In summary, I developed and presented several image pre-processing algorithms, feature extraction methods, and data optimization techniques to present innovative approaches for quantitative imaging markers based on machine learning systems in all these studies. The studies' simulation and results show the discriminative performance of the proposed CAD schemes on different application fields helpful to assist radiologists on their assessments in diagnosing disease and improve their overall performance.