Search

Patients, life science industry and regulatory authorities are united in their goal to reduce the disease burden of patients by closing remaining unmet needs. Patients have, however, not always been systematically and consistently involved in the drug development process. Recognizing this gap, regulatory bodies worldwide have initiated patient-focused drug development (PFDD) initiatives to foster a more systematic involvement of patients in the drug development process and to ensure that outcomes measured in clinical trials are truly relevant to patients and represent significant improvements to their quality of life. As a source of real-world evidence (RWE), social media has been consistently shown to capture the first-hand, spontaneous and unfiltered disease and treatment experience of patients and is acknowledged as a valid method for generating patient experience data by the Food and Drug Administration (FDA). While social media listening (SML) methods are increasingly applied to many diseases and use cases, a significant piece of uncertainty remains on how evidence derived from social media can be used in the drug development process and how it can impact regulatory decision making, including legal and ethical aspects. In this policy paper, we review the perspectives of three key stakeholder groups on the role of SML in drug development, namely patients, life science companies and regulators. We also carry out a systematic review of current practices and use cases for SML and, in particular, highlight benefits and drawbacks for the use of SML as a way to identify unmet needs of patients. While we find that the stakeholders are strongly aligned regarding the potential of social media for PFDD, we identify key areas in which regulatory guidance is needed to reduce uncertainty regarding the impact of SML as a source of patient experience data that has impact on regulatory decision making.

Abstract Drug resistance caused by mutations is a public health threat for existing and emerging viral diseases. A wealth of evidence about these mutations and their clinically associated phenotypes is scattered across the literature, but a comprehensive perspective is usually lacking. This work aimed to produce a clinically relevant view for the case of Hepatitis B virus (HBV) mutations by combining a chronic HBV clinical study with a compendium of genetic mutations systematically gathered from the scientific literature. We enriched clinical mutation data by systematically mining 2,472,725 scientific articles from PubMed Central in order to gather information about the HBV mutational landscape. By performing this analysis, we were able to identify mutational hotspots for each HBV genotype (A-E) and gene (C, X, P, S), as well as the location of disulfide bonds associated with these mutations. Through a modelling study, we also identified a mutation position common in both the clinical data and the literature that is located at the binding pocket for a known anti-HBV drug, namely entecavir. The results of this novel approach show the potential of integrated analyses to assist in the development of new drugs for viral diseases that are more robust to resistance. Such analyses should be of particular interest due to the increasing importance of viral resistance in established and emerging viruses, such as for newly developed drugs against SARS-CoV-2.

Abstract Background Numerous efforts have been poured into annotating the wealth of knowledge contained in biomedical articles. Thanks to such efforts, it is now possible to quantitatively explore relations between these annotations and the citation network at large scale. Results With the aid of several large and small annotation databases, this study shows that articles share annotations with their citation neighborhood to the point that the neighborhood’s most common annotations are likely to be those appearing in the article. Conclusions These findings posit that an article’s citation neighborhood defines to a large extent the article’s annotated content. Thus, citations should be considered as a foundation for future knowledge management and annotation of biomedical articles.

Delays in the propagation of scientific discoveries across scientific communities have been an oft-maligned feature of scientific research for introducing a bias towards knowledge that is produced within a scientist’s closest community. The vastness of the scientific literature has been commonly blamed for this phenomenon, despite recent improvements in information retrieval and text mining. Its actual negative impact on scientific progress, however, has never been quantified. This analysis attempts to do so by exploring its effects on biomedical discovery, particularly in the discovery of relations between diseases, genes and chemical compounds. Results indicate that the probability that two scientific facts will enable the discovery of a new fact depends on how far apart these two facts were originally within the scientific landscape. In particular, the probability decreases exponentially with the citation distance. Thus, the direction of scientific progress is distorted based on the location in which each scientific fact is published, representing a path-dependent bias in which originally closely-located discoveries drive the sequence of future discoveries. To counter this bias, scientists should open the scope of their scientific work with modern information retrieval and extraction approaches.

BackgroundThe abundance of online content contributed by patients is a rich source of insight about the lived experience of disease. Patients share disease experiences with other members of the patient and caregiver community and do so using their own lexicon of words and phrases. This lexicon and the topics that are communicated using words and phrases belonging to the lexicon help us better understand disease burden. Insights from social media may ultimately guide clinical development in ways that ensure that future treatments are fit for purpose from the patient’s perspective. ObjectiveWe sought insights into the patient experience of chronic obstructive pulmonary disease (COPD) by analyzing a substantial corpus of social media content. The corpus was sufficiently large to make manual review and manual coding all but impossible to perform in a consistent and systematic fashion. Advanced analytics were applied to the corpus content in the search for associations between symptoms and impacts across the entire text corpus. MethodsWe conducted a retrospective, cross-sectional study of 5663 posts sourced from open blogs and online forum posts published by COPD patients between February 2016 and August 2019. We applied a novel neural network approach to identify a lexicon of community words and phrases used by patients to describe their symptoms. We used this lexicon to explore the relationship between COPD symptoms and disease-related impacts. ResultsWe identified a diverse lexicon of community words and phrases for COPD symptoms, including gasping, wheezy, mucus-y, and muck. These symptoms were mentioned in association with specific words and phrases for disease impact such as frightening, breathing discomfort, and difficulty exercising. Furthermore, we found an association between mucus hypersecretion and moderate disease severity, which distinguished mucus from the other main COPD symptoms, namely breathlessness and cough. ConclusionsWe demonstrated the potential of neural networks and advanced analytics to gain patient-focused insights about how each distinct COPD symptom contributes to the burden of chronic and acute respiratory illness. Using a neural network approach, we identified words and phrases for COPD symptoms that were specific to the patient community. Identifying patterns in the association between symptoms and impacts deepened our understanding of the patient experience of COPD. This approach can be readily applied to other disease areas.

Abstract Background We have previously described evidence for a statistically significant, global, supra-chromosomal representation of the human body that appears to stretch over the entire genome. Results Here, we extend the genome mapping model, zooming down to the typical individual animal cell. Its cellular organization appears to be significantly mapped onto the human genome: Evidence is reported for a “cellunculus” — on the model of a homunculus, on the H. sapiens genome. Conclusions Basic cell structure turns out to map similarly onto the total genome, mirrored via genes that express in particular cell organelles (e.g., “nuclear membrane”). Similar cell maps may also appear on individual chromosomes that map topologically on the dorsoventral body axis. This seems to constitute some of the basic structural and functional organization of nucleus and chromosome architecture.

Abstract Background Differential gene expression is important to understand the biological differences between healthy and diseased states. Two common sources of differential gene expression data are microarray studies and the biomedical literature. Methods With the aid of text mining and gene expression analysis we have examined the comparative properties of these two sources of differential gene expression data. Results The literature shows a preference for reporting genes associated to higher fold changes in microarray data, rather than genes that are simply significantly differentially expressed. Thus, the resemblance between the literature and microarray data increases when the fold-change threshold for microarray data is increased. Moreover, the literature has a reporting preference for differentially expressed genes that (1) are overexpressed rather than underexpressed; (2) are overexpressed in multiple diseases; and (3) are popular in the biomedical literature at large. Additionally, the degree to which diseases are similar depends on whether microarray data or the literature is used to compare them. Finally, vaguely-qualified reports of differential expression magnitudes in the literature have only small correlation with microarray fold-change data. Conclusions Reporting biases of differential gene expression in the literature can be affecting our appreciation of disease biology and of the degree of similarity that actually exists between different diseases.

Drugs are often seen as ancillary to the purpose of fighting diseases. Here an alternative view is proposed in which they occupy a spearheading role. In this view, drugs are technologies with an inherent therapeutic potential. Once created, they can spread from disease to disease independently of the drug creator's original intentions. Through the analysis of extensive literature and clinical trial records, it can be observed that successful drugs follow a life cycle in which they are studied at an increasing rate, and for the treatment of an increasing number of diseases, leading to clinical advancement. Such initial growth, following a power law on average, has a degree of momentum, but eventually decelerates, leading to stagnation and decay. A network model can describe the propagation of drugs from disease to disease in which diseases communicate with each other by receiving and sending drugs. Within this model, some diseases appear more prone to influence other diseases than be influenced, and vice versa. Diseases can also be organized into a drug-centric disease taxonomy based on the drugs that each adopts. This taxonomy reflects not only biological similarities across diseases, but also the level of differentiation of existing therapies. In sum, this study shows that drugs can become contagious technologies playing a driving role in the fight against disease. By better understanding such dynamics, pharmaceutical developers may be able to manage drug projects more effectively.

We have generated and made publicly available two very large networks of molecular interactions: 49,493 mouse-specific and 52,518 human-specific interactions. These networks were generated through automated analysis of 368,331 full-text research articles and 8,039,972 article abstracts from the PubMed database, using the GeneWays system. Our networks cover a wide spectrum of molecular interactions, such as bind, phosphorylate, glycosylate, and activate; 207 of these interaction types occur more than 1,000 times in our unfiltered, multi-species data set. Because mouse and human genes are linked through an orthological relationship, human and mouse networks are amenable to straightforward, joint computational analysis. Using our newly generated networks and known associations between mouse genes and cerebellar malformation phenotypes, we predicted a number of new associations between genes and five cerebellar phenotypes (small cerebellum, absent cerebellum, cerebellar degeneration, abnormal foliation, and abnormal vermis). Using a battery of statistical tests, we showed that genes that are associated with cerebellar phenotypes tend to form compact network clusters. Further, we observed that cerebellar malformation phenotypes tend to be associated with highly connected genes. This tendency was stronger for developmental phenotypes and weaker for cerebellar degeneration.

Text-mining algorithms make mistakes in extracting facts from natural-language texts. In biomedical applications, which rely on use of text-mined data, it is critical to assess the quality (the probability that the message is correctly extracted) of individual facts--to resolve data conflicts and inconsistencies. Using a large set of almost 100,000 manually produced evaluations (most facts were independently reviewed more than once, producing independent evaluations), we implemented and tested a collection of algorithms that mimic human evaluation of facts provided by an automated information-extraction system. The performance of our best automated classifiers closely approached that of our human evaluators (ROC score close to 0.95). Our hypothesis is that, were we to use a larger number of human experts to evaluate any given sentence, we could implement an artificial-intelligence curator that would perform the classification job at least as accurately as an average individual human evaluator. We illustrated our analysis by visualizing the predicted accuracy of the text-mined relations involving the term cocaine.