The use of digital twins (DTs) has proliferated across various fields and industries, with a recent surge in the healthcare sector. The concept of digital twin for health (DT4H) holds great promise to revolutionize the entire healthcare system, including management and delivery, disease treatment and prevention, and health well-being maintenance, ultimately improving human life. The rapid growth of big data and continuous advancement in data science (DS) and artificial intelligence (AI) have the potential to significantly expedite DT research and development by providing scientific expertise, essential data, and robust cybertechnology infrastructure. Although various DT initiatives have been underway in the industry, government, and military, DT4H is still in its early stages. This paper presents an overview of the current applications of DTs in healthcare, examines consortium research centers and their limitations, and surveys the current landscape of emerging research and development opportunities in healthcare. We envision the emergence of a collaborative global effort among stakeholders to enhance healthcare and improve the quality of life for millions of individuals worldwide through pioneering research and development in the realm of DT technology.

Due to the high cost of flow and mass cytometry, there has been a recent surge in the development of computational methods for estimating the relative distributions of cell types from the gene expression profile of a bulk of cells. Here, we review the five common ‘digital cytometry’ methods: deconvolution of RNA-Seq, cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), CIBERSORTx, single sample gene set enrichment analysis and single-sample scoring of molecular phenotypes deconvolution method. The results show that CIBERSORTx B-mode, which uses batch correction to adjust the gene expression profile of the bulk of cells (‘mixture data’) to eliminate possible cross-platform variations between the mixture data and the gene expression data of single cells (‘signature matrix’), outperforms other methods, especially when signature matrix and mixture data come from different platforms. However, in our tests, CIBERSORTx S-mode, which uses batch correction for adjusting the signature matrix instead of mixture data, did not perform better than the original CIBERSORT method, which does not use any batch correction method. This result suggests the need for further investigations into how to utilize batch correction in deconvolution methods.

Motivation: One of the main challenges in machine learning (ML) is choosing an appropriate normalization method. Here, we examine the effect of various normalization methods on analyzing FPKM upper quartile (FPKM-UQ) RNA sequencing data sets. We collect the HTSeq-FPKM-UQ files of patients with colon adenocarcinoma from TCGA-COAD project. We compare three most common normalization methods: scaling, standardizing using z-score and vector normalization by visualizing the normalized data set and evaluating the performance of 12 supervised learning algorithms on the normalized data set. Additionally, for each of these normalization methods, we use two different normalization strategies: normalizing samples (files) or normalizing features (genes). Results: Regardless of normalization methods, a support vector machine (SVM) model with the radial basis function kernel had the maximum accuracy (78%) in predicting the vital status of the patients. However, the fitting time of SVM depended on the normalization methods, and it reached its minimum fitting time when files were normalized to the unit length. Furthermore, among all 12 learning algorithms and 6 different normalization techniques, the Bernoulli naive Bayes model after standardizing files had the best performance in terms of maximizing the accuracy as well as minimizing the fitting time. We also investigated the effect of dimensionality reduction methods on the performance of the supervised ML algorithms. Reducing the dimension of the data set did not increase the maximum accuracy of 78%. However, it leaded to discovery of the 7SK RNA gene expression as a predictor of survival in patients with colon adenocarcinoma with accuracy of 78%.

As the immune system has a significant role in tumor progression, in this paper, we develop a data-driven mathematical model to study the interactions between immune cells and the osteosarcoma microenvironment. Osteosarcoma tumors are divided into three clusters based on their relative abundance of immune cells as estimated from their gene expression profiles. We then analyze the tumor progression and effects of the immune system on cancer growth in each cluster. Cluster 3, which had approximately the same number of naive and M2 macrophages, had the slowest tumor growth, and cluster 2, with the highest population of naive macrophages, had the highest cancer population at the steady states. We also found that the fastest growth of cancer occurred when the anti-tumor immune cells and cytokines, including dendritic cells, helper T cells, cytotoxic cells, and IFN-$\gamma$, switched from increasing to decreasing, while the dynamics of regulatory T cells switched from decreasing to increasing. Importantly, the most impactful immune parameters on the number of cancer and total cells were the activation and decay rates of the macrophages and regulatory T cells for all clusters. This work presents the first osteosarcoma progression model, which can be later extended to investigate the effectiveness of various osteosarcoma treatments.

Breast cancer is the most prominent type of cancer among women. Understanding the microenvironment of breast cancer and the interactions between cells and cytokines will lead to better treatment approaches for patients. In this study, we developed a data-driven mathematical model to investigate the dynamics of key cells and cytokines involved in breast cancer development. We used gene expression profiles of tumors to estimate the relative abundance of each immune cell and group patients based on their immune patterns. Dynamical results show the complex interplay between cells and molecules, and sensitivity analysis emphasizes the direct effects of macrophages and adipocytes on cancer cell growth. In addition, we observed the dual effect of IFN-$\gamma$ on cancer proliferation, either through direct inhibition of cancer cells or by increasing the cytotoxicity of CD8+ T-cells.

Every colon cancer has its own unique characteristics, and therefore may respond differently to identical treatments. Here, we develop a data driven mathematical model for the interaction network of key components of immune microenvironment in colon cancer. We estimate the relative abundance of each immune cell from gene expression profiles of tumors, and group patients based on their immune patterns. Then we compare the tumor sensitivity and progression in each of these groups of patients, and observe differences in the patterns of tumor growth between the groups. For instance, in tumors with a smaller density of naive macrophages than activated macrophages, a higher activation rate of macrophages leads to an increase in cancer cell density, demonstrating a negative effect of macrophages. Other tumors however, exhibit an opposite trend, showing a positive effect of macrophages in controlling tumor size. Although the results indicate that for all patients the size of the tumor is sensitive to the parameters related to macrophages, such as their activation and death rate, this research demonstrates that no single biomarker could predict the dynamics of tumors.