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      Digital Pharmaceutical Sciences

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          Abstract

          Artificial intelligence (AI) and machine learning, in particular, have gained significant interest in many fields, including pharmaceutical sciences. The enormous growth of data from several sources, the recent advances in various analytical tools, and the continuous developments in machine learning algorithms have resulted in a rapid increase in new machine learning applications in different areas of pharmaceutical sciences. This review summarizes the past, present, and potential future impacts of machine learning technologies on different areas of pharmaceutical sciences, including drug design and discovery, preformulation, and formulation. The machine learning methods commonly used in pharmaceutical sciences are discussed, with a specific emphasis on artificial neural networks due to their capability to model the nonlinear relationships that are commonly encountered in pharmaceutical research. AI and machine learning technologies in common day-to-day pharma needs as well as industrial and regulatory insights are reviewed. Beyond traditional potentials of implementing digital technologies using machine learning in the development of more efficient, fast, and economical solutions in pharmaceutical sciences are also discussed.

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          Most cited references69

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          Evaluating Random Forests for Survival Analysis using Prediction Error Curves.

          Prediction error curves are increasingly used to assess and compare predictions in survival analysis. This article surveys the R package pec which provides a set of functions for efficient computation of prediction error curves. The software implements inverse probability of censoring weights to deal with right censored data and several variants of cross-validation to deal with the apparent error problem. In principle, all kinds of prediction models can be assessed, and the package readily supports most traditional regression modeling strategies, like Cox regression or additive hazard regression, as well as state of the art machine learning methods such as random forests, a nonparametric method which provides promising alternatives to traditional strategies in low and high-dimensional settings. We show how the functionality of pec can be extended to yet unsupported prediction models. As an example, we implement support for random forest prediction models based on the R-packages randomSurvivalForest and party. Using data of the Copenhagen Stroke Study we use pec to compare random forests to a Cox regression model derived from stepwise variable selection. Reproducible results on the user level are given for publicly available data from the German breast cancer study group.
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            Basic concepts of artificial neural network (ANN) modeling and its application in pharmaceutical research.

            Artificial neural networks (ANNs) are biologically inspired computer programs designed to simulate the way in which the human brain processes information. ANNs gather their knowledge by detecting the patterns and relationships in data and learn (or are trained) through experience, not from programming. An ANN is formed from hundreds of single units, artificial neurons or processing elements (PE), connected with coefficients (weights), which constitute the neural structure and are organised in layers. The power of neural computations comes from connecting neurons in a network. Each PE has weighted inputs, transfer function and one output. The behavior of a neural network is determined by the transfer functions of its neurons, by the learning rule, and by the architecture itself. The weights are the adjustable parameters and, in that sense, a neural network is a parameterized system. The weighed sum of the inputs constitutes the activation of the neuron. The activation signal is passed through transfer function to produce a single output of the neuron. Transfer function introduces non-linearity to the network. During training, the inter-unit connections are optimized until the error in predictions is minimized and the network reaches the specified level of accuracy. Once the network is trained and tested it can be given new input information to predict the output. Many types of neural networks have been designed already and new ones are invented every week but all can be described by the transfer functions of their neurons, by the learning rule, and by the connection formula. ANN represents a promising modeling technique, especially for data sets having non-linear relationships which are frequently encountered in pharmaceutical processes. In terms of model specification, artificial neural networks require no knowledge of the data source but, since they often contain many weights that must be estimated, they require large training sets. In addition, ANNs can combine and incorporate both literature-based and experimental data to solve problems. The various applications of ANNs can be summarised into classification or pattern recognition, prediction and modeling. Supervised 'associating networks can be applied in pharmaceutical fields as an alternative to conventional response surface methodology. Unsupervised feature-extracting networks represent an alternative to principal component analysis. Non-adaptive unsupervised networks are able to reconstruct their patterns when presented with noisy samples and can be used for image recognition. The potential applications of ANN methodology in the pharmaceutical sciences range from interpretation of analytical data, drug and dosage form design through biopharmacy to clinical pharmacy.
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              COVID-19 and artificial intelligence: protecting health-care workers and curbing the spread

              Confirmed cases of coronavirus disease 2019 (COVID-19) exceed those of severe acute respiratory syndrome (SARS), and, at time of publication, now stand at over 73,435 confirmed cases and over 2000 deaths globally, nearly all in China. By comparison, SARS killed 774 people in 2003, again mostly in China, the epicentre of both outbreaks. Both COVID-19 and SARS spread across continents, infect animals and humans, and use similar mechanics to enter and infect the cell. On the frontline, tactical response to COVID-19 is similar to that of SARS but one major difference exists: in the 17 years since SARS, a powerful new tool has emerged that could potentially be instrumental in keeping this virus within reasonable limits—namely, artificial intelligence (AI). Few would argue that AI is causing a paradigm shift in health care and there might be value in the application of AI to the current COVID-19 outbreak, for example, in predicting the location of the next outbreak. This application is effectively what the Canadian company, Blue Dot, has attempted to do and as such was widely reported as the first organisation to reveal news of the outbreak in late December. Various other applications of AI that have emerged in response to the latest epidemic include BenevolentAI and Imperial College London, which report that a drug approved for rheumatoid arthritis, baricitinib, might be effective against the virus, while Insilico Medicine based in Hong Kong recently announced that its AI algorithms had designed six new molecules that could halt viral replication. But to what extent is AI really at the point where it can deliver effective insights and solutions in a timely, widescale fashion to help halt the current epidemic? As Executive Director of the Communicable Diseases Cluster, WHO, David Heymann led the international response to SARS. He explains that AI or no AI, several key factors are required for a successful public health response to an outbreak of a new infection. These factors include understanding of transmissibility and risk populations; establishing the natural history of infection, including incubation period and mortality rate; identifying and characterising the causative organism; and, in some instances, epidemiological modelling to suggest effective prevention and control measures. This information can be collected from those working at outbreak sites virtually linked with WHO. This strategy worked for SARS and is, again, a major source of information for COVID-19, he stresses. Collectively these data can be used to train and prime the AI application for its dedicated task. “We can't replace the human brain at this point, nor the epidemiologist or virologist with anything that can analyse and rapidly do what is necessary at the onset of an outbreak. We still need to prime that AI with information from study of the evidence and link this to events in the outbreak,” Heymann highlights. Taking a balanced view of where AI sits in the current armamentarium to tackle COVID-19, Heymann adds “By monitoring social media, newsfeeds, or airline ticketing systems for example, we can tell if there's something wrong that requires further exploration. All these things together are very important.” However, Heymann cautions that the source of the data needed to inform AI in this outbreak, “won't necessarily come from China because it hasn't been able to get hold of the data it needs because of the disorder and panic. This virus has spread to 24 other countries and these countries have set up extremely good systems of contact-tracing and patient isolation. This is where our information will come from.” Peter Hotez (Baylor College of Medicine, Houston, TX, USA) asserts that AI can make a major contribution to the current outbreak and can be used to predict how the COVID-19 outbreak might be affected by seasonality. “Historically in the Northern hemisphere, upper respiratory coronaviruses peak in the winter months and then decline. AI might help predict how warmer weather, come April and May, might have a beneficial effect on the spread.” Such an application could really help stabilise financial markets right now in Asia, he remarks. “People think the apocalypse is coming but a statement reflecting that this epidemic is going to diminish substantially as we move into spring might provide some reassurance, and AI can play a role here.” Echoing Heymann, Hotez also reflects that effective AI needs high quality input data and says in no uncertain terms that, “it's a case of garbage in, garbage out”. Describing previous work collating disease-related data in sub-Saharan Africa, he points out that there are “gaping doughnut” holes with little or no data that are not due to an absence of disease, but because there is no surveillance. The same applies to COVID-19. “Flights are going into Africa, for example, into Ethiopia from China all the time and who knows what's happening there,” he notes. In declaring the situation a public health emergency of international concern, WHO Director-General, Tedros Adhanom Ghebreyesus, reflected on the impact in less developed countries, “… we don't know what type of damage the virus could do if it were to spread to a country with a weaker health system”. Moritz Kraemer, a spatial epidemiologist (University of Oxford, Oxford, UK) is involved with tracking the spread of COVID-19 as represented on the web-based platform, Healthmap, which visually represents global disease outbreaks according to location, time, and infectious disease agent. “In sub-Saharan Africa, our model predicted that the main entry points would be in South Africa, Ethiopia, and Nigeria, which are high population centres. But it is dependent on where, in China, the outbreak is focussed because the number of flights to parts of Africa varies by Chinese city,” Kraemer points out. “In most AI applications, we consider the question and ask what are the best data available to answer it?” Kraemer says. One of the multiple data streams relevant to pathogens spread is accurate case reporting for COVID-19. Kraemer receives news reports and twice daily government reports that provide datasets on how many cases exist in any one specific location (eg, in Wuhan city). “This is a baseline for us.. Before Chinese New Year we looked at how many people left Wuhan over a day, and this information comes from search engines including Baidu. WeChat, a messaging, social media and mobile payment app, provides data on travel around Wuhan,” he explains. “Machine learning models use these data to predict the most likely location of where novel coronavirus might arrive next and this might inform where and how to run border checks.” A study by Kaiyuan Sun and colleagues published today in The Lancet Digital Health testifies to the strength of monitoring news reports and social media to help reconstruct the progression of an outbreak and to provide detailed patient-level data in the context of a health emergency. Not only is China central to the outbreak, but the country is also playing a large role in using AI to help manage the COVID-19 outbreak. Infervision, a Beijing-based AI company uses its algorithm to spot COVID-19 on images of the lung as distinct from other respiratory infections. Velislava Petrova is a virologist (University of Cambridge, Cambridge, UK), who is currently working at UNAIDS, Geneva, on the latest and most effective AI applications. “We are trying to find a more sustainable way to control the impact of the novel coronavirus rather than having to shut down borders, businesses and similar,” she says. Petrova highlights that Infervision's AI application minimises the burden of these processes by expediting the diagnoses and monitoring of COVID-19. “As more and more scans are done then the algorithm learns and improves accuracy together with the virus.” “The value of AI comes into play by reducing the burden on clinicians in a scenario such as the current COVID-19 outbreak,” Petrova explains. Reflecting on a rapidly growing concern in the current outbreak that regards the infection of health-care professionals, Kuan Chen, founder of Infervision, points out that the Infervision AI application can help protect staff. The death of medical doctor, Li Wenliang, on Feb 7, 2020, who was reprimanded by Chinese authorities for warning about the virus, highlights the plight of clinicians on the frontline. “An article in JAMA states that human-to-human hospital-associated transmission accounted for 41% of all cases in a study of patients at Zhongnan Hospital of Wuhan University,” Chen notes. “We also know that more than 1000 hospital staff in the city of Wuhan have been confirmed infected.” This is where Infervision's AI application could help. From a lung CT scan, the AI is designed to quickly detect lesions of possible coronavirus pneumonia, to measure its volume, shape, and density, and to compare changes of multiple lung lesions from the image, which all provide a quantitative report to assist doctors making fast judgement. “While a manual read of a CT scan can take up to 15 minutes, AI can finish reading the image in 10 seconds.” Application of this technology in COVID-19 has not yet been published in a peer-reviewed journal. Chen adds that in Wuhan, where there are far too many cases to test and PCR-based diagnosis takes too long (sometimes over a week), CT imaging with AI could serve as a surrogate for doctors when fast judgement is needed. “Doctors no longer need to engage in the lengthy process of manually reading images one by one to identify high risk cases, while coronavirus-probable patients wait around the hospital posing a severe risk of infecting other patients and hospital staff.” It is still too early to tell if—and to what extent—AI will have an impact on the COVID-19 outbreak. The numbers of confirmed cases and deaths rise daily and so too does the supply of data. One thing is certain, “AI is relevant to this outbreak and in the future it will become even more so,” says Moritz. Heymann is more conservative and remarks that, “AI is one part of the final understanding”. Time will tell. For more on the mechanism of viral infection of coronaviruses see DOI:10.1128/JVI.00127-20 For more on Blue Dot AI prediction of outbreak locations see https://www.wired.com/story/how-ai-tracking-coronavirus-outbreak/ For more on AI driven design of new drugs against COIVD-19 see https://insilico.com/ncov-sprint For more on the potential for international dissemination of COVID-19 see https://academic.oup.com/jtm/advance-article/doi/10.1093/jtm/taaa008/5704418 For more on countries at the highest importation risk of COVID-19 see non-peer-reviewed study here https://www.medrxiv.org/content/10.1101/2020.02.05.20020792v1) © 2020 Kuan Chen/Infervision 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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                Author and article information

                Contributors
                smdamiati@kau.edu.sa
                Journal
                AAPS PharmSciTech
                AAPS PharmSciTech
                AAPS PharmSciTech
                Springer International Publishing (Cham )
                1530-9932
                26 July 2020
                August 2020
                : 21
                : 6
                : 206
                Affiliations
                GRID grid.412125.1, ISNI 0000 0001 0619 1117, Department of Pharmaceutics, Faculty of Pharmacy, , King Abdulaziz University, ; P.O.Box 80260, Jeddah 21589, Saudi Arabia
                Author information
                http://orcid.org/0000-0001-7559-5799
                Article
                1747
                10.1208/s12249-020-01747-4
                7382958
                810fa797-de75-4a9e-bbb9-009b88765faa
                © American Association of Pharmaceutical Scientists 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 7 April 2020
                : 6 July 2020
                Categories
                Review Article
                Custom metadata
                © American Association of Pharmaceutical Scientists 2020

                Pharmacology & Pharmaceutical medicine
                artificial intelligence,machine learning,artificial neural networks,pharmaceutical sciences,pharmaceutical industry

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