Yu Yang Fredik Liu , Yin Lu, Steve Oh, Gareth J. Conduit
Inconsistent therapeutic efficacy of mesenchymal stem cells (MSCs) in regenerative medicine has been documented in many clinical trials. Precise prediction on the therapeutic outcome of a MSC therapy based on the patient’s conditions would provide valuable references for clinicians to decide the treatment strategies. In this article, we performed a meta-analysis on MSC therapies for cartilage repair using machine learning. A small database was generated from published in vivo and clinical studies. The unique features of our neural network model in handling missing data and calculating prediction uncertainty enabled precise prediction of post-treatment cartilage repair scores with coefficient of determination of 0.637 ± 0.005. From this model, we identified defect area percentage, defect depth percentage, implantation cell number, body weight, tissue source, and the type of cartilage damage as critical properties that significant impact cartilage repair. A dosage of 17 − 25 million MSCs was found to achieve optimal cartilage repair. Further, critical thresholds at 6% and 64% of cartilage damage in area, and 22% and 56% in depth were predicted to significantly compromise on the efficacy of MSC therapy. This study, for the first time, demonstrated machine learning of patient-specific cartilage repair post MSC therapy. This approach can be applied to identify and investigate more critical properties involved in MSC-induced cartilage repair, and adapted for other clinical indications.
Articular cartilage is a critical tissue with multifaceted mechanical functions. It holds compression, absorbs shock, and enables smooth articulation at the joints. Cartilage injury is unfortunately common due to tears, accidents and arthritis, which often leads to joint pain, stiffness, and inflammation. Cartilage disorders affect millions of people worldwide, including 52.2 million adults in US , and more than 10 million in UK . In particular, osteoarthritis alone affects more than 200 million people globally . Adult cartilage has limited self-repair capacity due to its avascular nature , thus treatments are often necessary to accelerate repair and relieve pain during joint motions. Besides the conservative treatments and conventional surgical options, such as microfracture and autologous chondrocyte implantation (ACI), mesenchymal stem cell (MSC) has also been widely investigated in the management of cartilage damages in recent decades .
We collected data from 36 published articles on PubMed [13–48] to train and validate our machine learning models. Some articles comprised more than one type of cartilage injury models or treatment conditions. In total, 15 clinical trial conditions and 29 animal model conditions (1 goat, 6 pigs, 2 dogs, 9 rabbits, 9 rats, and 2 mice) on osteochondral injury or osteoarthritis were included, where MSCs were transplanted to repair the cartilage tissue. We documented each case into an entry of a database. We considered the cell- and treatment target-related factors as input properties, including species, body weight, tissue source, cell number, cell concentration, defect area, defect depth, and type of cartilage damage. The therapeutic outcomes were considered as output properties, which were evaluated using integrated clinical and histological cartilage repair scores, including the international cartilage repair society (ICRS) scoring system, the O’Driscoll score, the Pineda score, the Mankin score, the osteoarthritis research society international (OARSI) scoring system, the international knee documentation committee (IKDC) score, the visual analog score (VAS) for pain, the knee injury and osteoarthritis outcome score (KOOS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Lyscholm score. In this study, these scores were linearly normalized to a number between 0 and 1, with 0 representing the worst damage or pain, and 1 representing the completely healthy tissue. The list of entries was combined together to form a database.
In this study, we have developed a neural network model that exploits the inter-property and property-property correlations to predict the therapeutic efficacy of MSC transplantation for cartilage repair based on animal results and human clinical trials. We started with cartilage injury models where different MSCs were given and measures of their performance were recorded. We characterized the cartilage repair score and filled the missing information using the neural network while training the model. The assessment of new patient would provide input information for the model to make predictions on human clinical trial outcomes and the recommended properties, clinicians would be given the uncertainty in the prediction along with the confidence level to decide the most suitable therapy for treatment.
Citation: Liu YYF, Lu Y, Oh S, Conduit GJ (2020) Machine learning to predict mesenchymal stem cell efficacy for cartilage repair. PLoS Comput Biol 16(10): e1008275. https://doi.org/10.1371/journal.pcbi.1008275
Editor: Qing Nie, University of California Irvine, UNITED STATES
Received: January 30, 2020; Accepted: August 20, 2020; Published: October 7, 2020
Copyright: © 2020 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All data files are available from the Open Access database (https://doi.org/10.17863/CAM.52036).
Funding: Our Financial Disclosure statement has been amended to read: Y.Y.F.L. acknowledges support from the Agency for Science, Technology and Research for NSS scholarship. Y.L. and S.O. acknowledge the Agency for Science, Technology and Research for funding of this research through Bioprocessing Technology Institute. G.J.C. acknowledges support from the Royal Society with grant number UF130122. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Y.Y.F.L. declares a potential financial conflict of interest as chief technology officer of DeepVerse. G.J.C. declares a potential financial conflict of interest as chief technology officer of Intellegens, UK.