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Jul 09 2024
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Medical technology concept. DNA. Gene therapy.

Regulatory and Ethical Considerations of Whole Genome Sequencing

By Clinical Genomics, Ethics

As whole genome sequencing (WGS) becomes increasingly accessible, it raises several ethical and regulatory challenges that must be carefully addressed. Key issues include protecting the privacy of genomic data, ensuring proper informed consent, and determining the responsible approach for returning results to patients and research participants.

Data Privacy Concerns

An individual’s genome contains a trove of highly personal information, including predispositions to certain diseases, ancestral origins, and other traits. The potential misuse of this data by employers, insurers, or governments to discriminate against individuals based on their health risks underscores the need for robust security measures and policies to prevent unauthorized access.

There are also concerns about the potential for genetic data to be re-identified, a process that involves matching an individual’s genetic data with their personal information, such as their name or address. Even if names or other identifiers are stripped away, certain DNA sequences are so unique that they could allow for the tracing of individuals through database cross-referencing. Practices like adding noise to genomic data may be needed to further obscure identities while still allowing useful analyses.

Regulations governing genomic data storage, sharing, and usage are still evolving. Efforts are underway to develop best practices and address ongoing challenges in the responsible use of genomic data. In the United States, the Health Insurance Portability and Accountability Act (HIPAA) protects health data privacy, but its rules may not squarely address many issues raised by WGS. Other initiatives, such as the Regulatory and Ethics Work Stream through the Global Alliance for Genomics and Health, are actively working towards solutions.

Informed Consent Challenges

A core principle of biomedical research and clinical testing is that individuals must give informed consent before participating. However, informed consent raises challenges in the genomics age when WGS data may be used for a wide range of future studies beyond the initial intended purpose.

Participants need to be made aware that their genomic data could live on indefinitely in databases and be shared and reused in ways that are currently unknown. There are open questions around what constitutes a truly informed consent process—how much detail is required, what reasonable guarantees exist around future uses, and whether a tiered or meta-consent model may be more appropriate. A tiered consent model could involve participants giving consent for different levels of data sharing, while a meta-consent model could involve permitting the use of data in certain circumstances.

For example, the Personal Genome Project asks participants to agree to their WGS data being publicly available online. This approach maximizes the scientific utility of the data but may not align with privacy expectations for many individuals.

Debates Around Returning Results

As WGS becomes more affordable and widely used, questions emerge about which results should be disclosed to participants and patients whose genomes are sequenced for research or clinical purposes. There are reasonable arguments on both sides of this debate.

On one hand, some argue that all results should be disclosed regardless of their clinical significance to respect individual autonomy. Research has found that most people want to receive results related to serious health conditions if uncovered incidentally through sequencing, even if unrelated to the original reason for testing. They feel they have a right to this potentially life-saving information about health risks they were unaware of.

The opposing perspective argues that only results with clear clinical implications should be disclosed. In many cases, genomic results can be complex, incomplete, and of uncertain clinical relevance. Receiving inconclusive data could potentially cause anxiety and lead to unnecessary follow-up testing and screening procedures. There are also concerns about how to educate and counsel participants properly so they fully understand the nuances of the genomic data they receive.

With no universal guidelines in place, different institutions take divergent approaches. The American College of Medical Genetics recommends returning results only on a specific list of highly actionable genes that could lead to a clear course of action, such as a change in medication or lifestyle. Others favor a more open model of giving patients the choice of what results they receive.

Commercial WGS services are another regulatory gray area. In the United States, the FDA has approved some activities, like carrier screening, but not blanket genomic analysis unattached to specific clinical indications.

Perspectives From the Public

Ultimately, considering public perspectives is essential in shaping policy decisions around WGS, as their genomic data and rights are under consideration. Social science research has found a range of views but an overall desire for policies that prioritize individual choice and control over their data.

A 2021 survey found that 68% of respondents felt people should be able to access and share a copy of their genetic data, but 80% believed sharing an individual’s WGS data without their consent was inappropriate. Regarding the return of results, about 60% wanted to receive findings related to treatable diseases, but only half wanted results on untreatable diseases.

Studies have consistently found higher public trust in policies and governance developed through a transparent process with input from multiple stakeholder groups, including members of the public. Clear communication around risks and benefits is key to building that trust.

As WGS increasingly becomes a part of routine healthcare and research, striking the right balance among personal privacy, autonomy rights, and scientific progress will remain an ongoing challenge for policymakers, the biomedical community, and the public to navigate together.

Sources:

Global Alliance for Genomics and Health (2015) Genomic Data Policy Scoping Document. https://www.ga4gh.org/wp-content/uploads/Data-Policy-Scoping-Document.pdf

Kaye J, et al. (2022) Public Perspectives Towards Data Sharing and Return of Results from Whole Genome Sequencing. Journal of Medical Ethics, 48:1. https://jme.bmj.com/content/48/1/41

Niemiec, E. & Howard, H.C. (2016) Ethical issues in consumer genome sequencing: Use of consumers’ samples and data. Applied & Translational Genomics, 8:23-30. https://doi.org/10.1016/j.atg.2016.01.005

Stark, Z. et al. (2019) Understandings of return of genomic results: exploratory study of stakeholders in Australia. European Journal of Human Genetics, 27:1247–1255. https://doi.org/10.1038/s41431-019-0394-9

 

Jun 01 2024
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Genomic Research Through Decentralized Trials

Expanding Horizons in Genomic Research Through Decentralized Trials

By Clinical Genomics

Key Takeaways:

  1. Decentralized Randomized Trials: Enable genomic research and clinical studies to be conducted remotely, increasing access and diversity of participants.
  2. Digital Technologies: Leverage tools like telemedicine, mobile apps, and wearable devices to collect data from participants in their homes.
  3. Advantages: Reduced costs, increased enrollment, better representation, and real-world evidence generation.
  4. Challenges: Addressing data privacy/security concerns, protocol adherence, and regulatory acceptance.
  5. Potential Impact: To accelerate genomic medicine through more efficient evidence generation from diverse populations.

 

The Decentralized Trial Model

Decentralized randomized trials enable genomic research and clinical studies to be conducted remotely with participants in their homes and communities. These trials utilize a suite of tools, including telemedicine, mobile apps, wearable biosensors, and direct-to-participant drug shipments. Genomic data, such as DNA samples for sequencing, are collected via at-home testing kits.

 

Benefits of Decentralization

This digital approach offers several potential advantages. It provides increased access for populations that may live far from academic medical centers or have mobility limitations. By broadening the geographic reach, decentralized trials help increase diversity and better represent the genetic variation across different racial, ethnic, and socioeconomic groups. Additionally, conducting research in real-world settings generates more naturalistic data on how investigational products perform in participants’ daily lives.

 

Operational Efficiencies

The decentralized model offers operational efficiencies that can streamline logistics and reduce infrastructure costs associated with traditional brick-and-mortar trial sites. This efficiency can accelerate study timelines and improve enrollment and retention rates by making participation more convenient for volunteers.

 

Challenges and Barriers

While promising, the adoption of decentralized trials faces challenges, particularly around data privacy and security. Robust protocols must protect participant confidentiality, and ensuring adherence can be more difficult remotely compared to in-clinic visits. Regulators will require thorough evidence to prove that decentralized approaches reliably achieve research objectives.

 

Current Applications in Genomics

Despite these hurdles, many initiatives are utilizing decentralized trials across disease areas. The NIH’s All of Us Research Program and genomic screening studies like CIRCLE employ digital technologies and at-home sample collection. Pharmaceutical companies have launched decentralized trials for genomically-targeted cancer therapies.

 

The Future of Decentralized Genomic Research

As supportive evidence grows, the decentralized paradigm is poised to transform genomic research. By capitalizing on digital health tools, this model can accelerate precision medicine by enabling more efficient generation of real-world genomic evidence from diverse populations worldwide. Prioritizing the overcoming of barriers is crucial to achieving this goal.

 

Sources:

 

  1. Khozin, S., & Coravos, A. (2019). Decentralized trials in the age of real-world evidence and inclusiveness in clinical investigations. Clinical Pharmacology & Therapeutics, 106(1), 25-27. [Journal article discussing benefits and challenges of decentralized trials]
  2. Fogel, D. B. (2017). Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemporary Clinical Trials Communications, 11, 156-164. [Review analyzing factors impacting clinical trial success rates]
  3. Walter, J., Fried, J., & Haeussler, J. (2020). Decentralized versus Traditional Clinical Trials. Digitrx (white paper). [White paper from digital clinical trials company Digitrx comparing models]
  4. Sommer, C., Zuckerman, B., Moore, K., & Applicators, P. T. (2020). Decentralized clinical trials: a data-driven introduction. Applied Clinical Trials, 29, 25-27. [Article providing data-driven overview of decentralized trials]
  5. Nabizadeh, S., Phillips, S., Grennan, D., & Walton, S. M. (2022). Decentralized clinical trials: benefits and challenges. Therapeutic Innovation & Regulatory Science, 56(4), 537-548. [Recent journal article analyzing benefits and challenges]
Jun 01 2024
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drug discovery

Advancing Drug Discovery Through Multi-Omics Integration

By Uncategorized

In the rapidly evolving field of pharmaceutical research and development, the integration of multi-omics data is emerging as a pivotal innovation. Multi-omics—the concurrent analysis of genomic, transcriptomic, proteomic, metabolomic, and other omics data—offers an unprecedented systems-level perspective of biological processes. This comprehensive approach is crucial not only for enhancing our understanding of complex biological systems but also for driving the next generation of drug discovery and development. By delving into the significance and transformative potential of multi-omics, this article highlights its integral role in the advent of more effective and precisely targeted therapies.

 

Key Takeaways:

  • Multi-omics, the integration of data from genomics, transcriptomics, proteomics, metabolomics, and other omics disciplines, provides a systems-level understanding of biology.
  • This holistic approach is transforming drug discovery by enabling the identification of novel drug targets, patient stratification biomarkers, and mechanisms of action insights.
  • Advances in multi-omics technologies like next-generation sequencing and mass spectrometry are driving adoption in pharmaceutical research and development (R&D).
  • Key challenges include managing and integrating large, complex multi-omics datasets and validating findings through experimental validation.
  • Multi-omics offers great promise for developing more effective, targeted therapies by leveraging a comprehensive view of disease pathways and mechanisms.

 

The Rise of Multi-Omics in Drug R&D

The explosion of high-throughput omics technologies is revolutionizing drug discovery and development. Traditional approaches, which focus on single biomolecules like genes or proteins, are rapidly giving way to more comprehensive multi-omics strategies that integrate data across the biological scales of genomes, transcriptomes, proteomes, metabolomes, and more.

 

Benefits of the Multi-Omics Approach

This holistic, systems-level view offers significant advantages over reductionist methods. By studying the interplay between different omics layers, multi-omics can reveal novel insights into disease mechanisms, identify previously unknown drug targets, and discover potential predictive biomarkers for patient stratification and response monitoring.

 

Applications in Target ID and Validation

In target identification, multi-omics enables the discovery of new therapeutic targets beyond the “low-hanging fruit” of simplistic, single-gene associations. Integrating transcriptomic and proteomic data can reveal dysregulated cellular pathways. Metabolomic profiling illuminates disruptions within biochemical networks. These systems-level perspectives highlight targets that may be missed with single-omics approaches.

Multi-omics is also crucial for comprehensive target validation, assessing off-target effects and toxicity risks through holistic profiling of drug responses across omics dimensions.

 

Patient Stratification and Precision Medicine

Moreover, multi-omics datasets can uncover molecular subtypes and patient stratification biomarkers that predict responsiveness to therapies. Integrating genomic variants, transcriptomic signatures, proteomic profiles, and other omics features promises to deliver on the vision of precision medicine.

As an example, multi-omics analysis elucidates heterogeneity in diseases like breast cancer. Integrating genomic, transcriptomic, and proteomic breast tumor profiles has revealed distinct molecular subtypes with differing prognoses and therapeutic vulnerabilities.

 

Technological Drivers

The rise of multi-omics is enabled by transformative analytical technologies. Revolutionary high-throughput genomic sequencing platforms like Illumina, PacBio, and Oxford Nanopore have democratized large-scale DNA and RNA sequencing. Advances in mass spectrometry and nuclear magnetic resonance have enabled large-scale characterization of proteins, metabolites, and other biomolecules.

 

Data Integration and Computational Challenges

However, the massive scale and complexity of multi-omics datasets pose significant computational and data integration challenges. Specialized bioinformatics pipelines and databases are needed to process, analyze, and interpret this “multi-omics big data.” Machine learning approaches like deep learning and graph neural networks show promise for extracting insights from multi-omics profiles but require robust methods for fusing heterogeneous omics data types.

 

Experimental Validation

Additionally, while computational multi-omics can highlight promising therapeutic hypotheses, rigorous experimental validation is required to establish clinical relevance. Functional genomics techniques, pharmacological profiling, and in vivo disease models remain critical for substantiating multi-omics findings and advancing drug development.

 

Multi-Omics Momentum in Pharma

Despite the challenges, multi-omics momentum continues building in the pharmaceutical industry. Many major drug companies have launched multi-omics initiatives and partnered with technology providers to implement multi-omics platforms.

As examples, AstraZeneca and Sano Genetics are applying multi-omics to find novel oncology and neurological disease targets. Pfizer utilizes multi-omics in their Precision Medicine Analytics group. GlaxoSmithKline and Biogen have multi-omics research collaborations with proteomics leaders like Seer and Olink.

 

Looking Ahead

As multi-omics technologies and analytical methods mature, the approach is poised to increasingly drive therapeutic breakthroughs by enabling more comprehensive biological insights, better molecular stratification of patient populations, and differentiated drug development strategies tailored to this molecular understanding of diseases.

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Sources:

  1. Bayes, J., & Golkar, L. (2022). Multi-omics in disease biology and drug discovery. Nature Reviews Drug Discovery. [Review article overviewing multi-omics applications in drug discovery]
  2. Huang, S., Chaudhary, K., & Garmiri, I.X. (2017). Your omics data should get proteins: Advances in proteomics informatics. Current Opinion in Systems Biology, 1, 23-32. [Review highlighting advances in multi-omics proteomics informatics]
  3. Byron, S.A. et al. (2016) Prospective multiomics integration in cancer drug discovery and development. Nature Reviews Drug Discovery, 15, 668-686. [Perspective article discussing integration of omics in oncology R&D]
  4. Gligorijević, V., Malmström, L., & Hirsch, C.M. (2022). Challenges and opportunities for data integration approaches in clinical multi-omics studies. Journal of Proteome Research, 21(1), 32-44. [Recent journal article examining multi-omics data integration methods and challenges]
  5. Zhou, W., Cox, D.B.T., et al. (2021). Multiomics modeling of cancer: assessing interactions between genome-scale processes for improved treatment prediction. Trends in Cancer, 7(6), 488-504. [Research article applying multi-omics modeling to cancer biology and treatment response prediction]
May 15 2024
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dark_genome

Unveiling the Secrets of the Dark Genome: A Journey into the Hidden Depths of Human DNA

By Clinical Genomics, Healthcare Data

The human genome, comprising both coding and non-coding regions, holds crucial information for understanding biological processes and disease mechanisms. While only two percent of the human genome encodes proteins, the remaining 98 percent, often referred to as the “dark genome,” has long been a mystery. Researchers once thought that the dark genome primarily consisted of “junk” DNA, a term used to describe non-coding regions of DNA that were believed to have no functional purpose. However, recent advancements in genomic research have shed light on the regulatory functions of non-coding DNA, challenging the traditional view of this genomic “junk” (1). These non-coding regions have gained attention for their regulatory roles in gene expression and disease development.

Redefining the Role of Non-Coding Regions

Once dismissed as genetic material of no importance, these non-coding regions are now gaining recognition for their pivotal role in regulating gene expression. The dark genome regulates gene expression through various mechanisms, including the modulation of protein-coding genes by non-coding RNAs. These molecules act as conductors in the cellular orchestra, coordinating responses to environmental cues, modulating disease processes, and maintaining genomic stability. Dysregulation of non-coding RNAs has been implicated in various diseases, including cancer, cardiovascular disorders, and neurological conditions (2).
The non-coding regions of DNA contain various elements and sequences that do not directly encode proteins. These include:

 

1. Regulatory elements: Sequences that control the activity of genes, such as promoters, enhancers, silencers, and insulators.
2. Repeat sequences: DNA portions repeated multiple times throughout the genome, including short tandem repeats (microsatellites) and longer repetitive sequences.
3. Intergenic regions: Spaces between genes that contain no coding sequences.
4. Non-coding RNAs (ncRNAs): RNA molecules that are transcribed from non-coding regions and play various regulatory roles in the cell, such as microRNAs (miRNAs), long non-coding RNAs, and transfer RNAs.
5. Pseudogenes: Non-functional copies of genes that have lost their protein-coding ability through mutations.
6. Introns: Non-coding segments within genes that are removed during RNA splicing, allowing exons to join together to form mature messenger RNA (mRNA).
7. Telomeres and centromeres: Specialized non-coding DNA sequences found at the ends and centers of chromosomes, respectively, with essential roles in chromosome stability and replication.
8. Heterochromatin: Regions of tightly packed chromatin associated with gene silencing and chromosome structure.

 

Genetic Diversity in Non-Coding Regions

Genetic diversity within these regions of the genome significantly influences biological function through various mechanisms. Non-coding RNAs within the dark genome play diverse roles in gene regulation and cellular function, with genetic variation impacting their sequence or expression, leading to dysregulation of target genes and perturbation of biological pathways (2). Genetic diversity within the dark genome contributes to evolutionary dynamics by providing raw material for adaptation and speciation, variations in non-coding regions influencing phenotypic traits, reproductive success, and population fitness, thereby shaping genetic diversity over time. Understanding the functional significance of genetic diversity in these regions is crucial for understanding the complexities of genome biology and its implications for health and disease (2).

 

The dark genome’s regulatory functions significantly affect disease development and progression. Alterations in non-coding DNA sequences have been linked to cancer, developmental disorders, and other chronic illnesses. Understanding the role of the dark genome in disease pathogenesis provides new opportunities for targeted therapies and precision medicine approaches. Traditionally, researchers focused on targeting proteins to combat neoplastic conditions. However, growing evidence suggests that disrupting non-coding RNAs could be a game-changer in cancer treatment. Pharmaceutical companies are developing therapies that target specific non-coding RNAs associated with tumor growth and progression (3).

 

Leveraging Clinical Data for Genomic Insights

So, how do we unravel the mysteries of the dark genome? One promising approach is to leverage clinical data derived from electronic health records (EHRs). By combining genomic information with clinical data, researchers can efficiently uncover patterns and correlations that might otherwise go unnoticed or require extensive resources to acquire. Integrating clinical data from EHRs with non-coding genomic information obtained through whole genome sequencing enables actionable steps in clinical research and drug discovery. This integration aids researchers in comprehending the intricate relationship between genetic predisposition and environmental factors, encompassing comorbidities, medication usage, and lifestyle habits that might impact disease susceptibility and progression. This approach holds the potential to revolutionize genomics research, accelerating the pace of discovery and bringing us closer to personalized medicine (4).
As we delve deeper into the dark genome, we’re not just exploring genetic code—we’re unraveling the story of human biology and health. The journey may be challenging, but the rewards are boundless and will transform the future of research and healthcare.

 

Sources:

1. Blaxter, M., et al. (2010). Revealing the Dark Matter of the Genome. https://doi.org/10.1126/science.1200700

2. Zhang, X.,et al. (2020). Illuminating the noncoding genome in cancer. https://doi.org/10.1038/s43018-020-00114-3

3. Villar, D.,et al. (2020). The contribution of non-coding regulatory elements to cardiovascular disease. https://doi.org/10.1098/rsob.200088

4. Kullo, I. J.,et al. (2010). Leveraging informatics for genetic studies: Use of the electronic medical record to enable a genome-wide association study of peripheral arterial disease. https://doi.org/10.1136/jamia.2010.004366

May 15 2024
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dark_genome

Understanding the Dark Genome: Insights for Therapeutic Breakthroughs

By Clinical Genomics, Healthcare Data

Emerging evidence suggests that targeting the dark genome, particularly non-coding RNAs, holds promise for developing novel therapeutics. By modulating gene expression patterns, these approaches aim to restore cellular homeostasis and mitigate disease progression. Ongoing research efforts are focused on identifying disease-specific non-coding RNA signatures and developing targeted interventions for various disorders (1). We will take a look at some specific examples within different therapeutic areas that have proved to be impacted by the research of non-coding regions.

 

Neurology:

Alzheimer’s disease, a complex neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral changes, exhibits significant clinical variation despite common features. Onset can occur early (before age 65 years) or late (after age 65), a phenomenon influenced by both genetics and environment. The age of onset of symptoms can also vary, with some individuals experiencing symptoms in their 40s while others may not manifest them until their 70s. Cognitive decline further demonstrates this variability, with some individuals experiencing gradual deterioration over years while others undergo more rapid decline. Various factors, including health, genetics, and lifestyle, contribute to this heterogeneity. Additionally, comorbidities such as cardiovascular disease have been shown to expedite cognitive decline. Although Alzheimer’s is characterized by the accumulation of plaques in the brain, the severity of symptoms does not always correlate with the presence of plaques alone. Other factors, such as inflammation and neuronal loss, also play significant roles in symptom manifestation. While early-onset Alzheimer’s exhibits strong genetic links, late-onset cases are more multifaceted. Although the APOE ε4 allele is a well-known risk factor, not all carriers develop the disease, highlighting the complexity of genetic influences on disease risk and progression. These variations emphasize the need for personalized approaches to diagnosis and treatment.

 

Understanding the etiology of Alzheimer’s disease poses a significant challenge, particularly given its polygenic nature and the presence of non-coding genetic variants. These non-coding variants can modulate gene expression by influencing miRNA binding and altering chromatin states within enhancers, affecting brain gene expression (2). Transcriptome-wide association studies have emerged to explore the genetic links between disease risk and gene expression, revealing involvement of Alzheimer’s disease-associated loci in immune system pathways crucial for neuroinflammation and β-amyloid clearance. While Alzheimer’s disease risk variants often reside in non-coding regions, their functional impact on gene regulation remains incompletely understood. Integrating whole-genome sequencing data with phenotyping analyses will offer insights into the molecular mechanisms responsible for Alzheimer’s susceptibility and drive the efforts to understand the complex pathogenesis of Alzheimer’s disease (2).

 

Cardiovascular:

Similarly, genetic variation is found in the clinical presentation, diagnosis, and treatment of long QT syndrome (LQTS). LQTS is a cardiac disorder characterized by prolongation of the QT interval on ECG, which can predispose individuals to life-threatening arrhythmias, particularly torsades de pointes, and sudden cardiac death. Clinical manifestations of LQTS can vary widely, ranging from asymptomatic individuals to those experiencing syncope, seizures, or sudden cardiac arrest. Some individuals may have symptoms triggered by specific factors, such as physical exertion or emotional stress, while others may experience symptoms without any identifiable triggers. LQTS can present as a congenital condition, typically caused by mutations in genes encoding cardiac ion channels or associated proteins involved in cardiac repolarization, such as KCNQ1, KCNH2, and SCN5A (3). However, acquired forms of LQTS can also occur due to medications, electrolyte imbalances, or other underlying medical conditions. The clinical presentation of LQTS can be influenced by various factors, including the specific genetic mutation involved, environmental triggers, and individual differences in cardiac physiology. Genetic testing plays a crucial role in diagnosing LQTS and identifying at-risk family members, allowing for early intervention and management strategies such as beta-blockers, implantable cardioverter-defibrillators, and lifestyle modifications to reduce the risk of life-threatening arrhythmias and sudden cardiac death.

 

The diverse symptoms seen in individuals with LQTS, even among those with the same genetic mutations, have prompted investigations into other genes that might influence the severity or presentation of the condition. These studies, including research on non-coding genetic variations, aim to explain why some individuals with LQTS are more prone to life-threatening arrhythmias. For example, a study in a specific South African population revealed that certain non-coding variants in the NOS1AP gene are associated with a higher risk of severe arrhythmias in LQTS patients, and these variants have also been linked to an increased risk of drug-induced LQTS (4). Conversely, another study identified a different non-coding variant in the KCNQ1 gene that seems to lower the risk of arrhythmias in individuals with LQTS (5). Additionally, research using induced pluripotent stem cells from a family with LQTS found specific genetic mutations that either protect against or exacerbate the condition. These findings highlight the existence of genes that can either predispose individuals to LQTS or offer protection against its effects. Recent studies have shown that assessing multiple genetic factors together could help predict an individual’s risk of developing LQTS and guide their clinical management more effectively.

 

Oncology:

With the growing understanding of non-coding alterations in different types of cancers and their precise roles in disrupting gene regulation and tumor development, researchers are exploring them as potential new indicators for detecting, classifying, and tracking cancer progression. For instance, various ways in which the MYC gene becomes active in different tissues, like gene duplications or changes in enhancers, are being studied as markers for diagnosing cancer, as MYC activation is a common feature in many cancer types (6). Similarly, duplications of enhancers associated with the AR gene have been linked to advanced prostate cancer, offering a new marker for tracking its progression (7). Advances in detecting mutations in the TERT promoter gene have improved early detection of glioblastomas (8). Compared to changes in the DNA code, alterations in non-coding regions are more widespread and specific to certain tissues and cancer types, making them potentially more reliable markers. Methods like analyzing DNA methylation patterns and nucleosome occupancy in circulating free DNA hold promise for noninvasive cancer detection and classification. These new biomarkers could complement existing ones based on changes in the coding regions of cancer genes.

 

Gastrointestinal:

Through advanced genomic techniques, specific non-coding DNA variants associated with inflammatory bowel disease (IBD) susceptibility and disease severity have been identified. These variants disrupt gene regulatory mechanisms, leading to dysregulated expression of genes involved in immune response and inflammation (9). Genetic variations within enhancers and promoters can disrupt the binding of transcription factors or alter chromatin structure, leading to dysregulated gene expression patterns associated with IBD phenotypes. Through genome-wide association studies and functional genomic approaches, researchers have identified specific non-coding DNA variants that are significantly enriched in IBD patients compared to healthy individuals (9). Variants in enhancer regions associated with genes involved in innate and adaptive immunity, mucosal barrier function, and cytokine signaling have been implicated in IBD pathogenesis. Understanding the functional consequences of these variants provides valuable insights into the molecular mechanisms driving IBD development and progression (9).

 

New therapeutic approaches for IBD involve targeting histone modifiers and key regulators within IBD networks. However, a potential challenge with this approach is that these compounds may affect tissues beyond those affected by the disease. Despite this concern, the predictive value of IBD-associated single nucleotide polymorphisms (SNPs) regarding the pathogenic cell types could guide the development of targeted therapeutics delivered to specific cells, although adverse effects may occur, similar to other therapies targeting general processes like immune modulation and chemotherapy. Ongoing clinical trials are evaluating the efficacy and adverse effects of these potential new compounds, with outcomes likely relevant for IBD treatment (9).

 

Genome editing technologies, epigenetic modulators, and RNA-based therapies offer promising avenues for selectively modulating gene expression and alleviating inflammation in IBD patients. Understanding the functional consequences of sequence variations in DNA regulatory elements provides valuable insights into IBD pathophysiology and facilitates the development of personalized treatment strategies tailored to individual patients (9).

 

The exploration of the dark genome, particularly non-coding RNAs, presents a promising frontier in the search for new therapies. Manipulating gene expression patterns hold the potential to restore cellular balance and halt disease progression. Ongoing research provides more insights into disease-specific non-coding RNA signatures, the prospect of targeted interventions for multiple therapeutic areas seems more possible than ever. Genome editing technologies and RNA-based therapies continue to evolve, the promise of precision medicine holds the potential to revolutionize patient care, offering hope for improved outcomes and quality of life. Exploring the mysteries of the dark genome holds a lot of promise in guiding the research for groundbreaking medical advances that will change modern medicine.

 

Sources:

1. Zhang, X.,et al. (2020). Illuminating the noncoding genome in cancer. https://doi.org/10.1038/s43018-020-00114-3

2. Novikova, G.,et al. (2021). Beyond association: linking non-coding genetic variation to Alzheimer’s disease risk. https://doi.org/10.1186/s13024-021-00449-0

3. Giudicessi, J. R., Ackerman, M. J. (2013). Genotype- and phenotype-guided management of congenital long QT syndrome. https://doi.org/10.1016/j.cpcardiol.2013.08.001

4. Crotti, L., et al. (2009). NOS1AP is a genetic modifier of the long-QT syndrome. https://doi.org/10.1161/CIRCULATIONAHA.109.879643

5. Duchatelet, S., et al. (2013). Identification of a KCNQ1 Polymorphism Acting as a Protective Modifier Against Arrhythmic Risk in Long-QT Syndrome. https://doi.org/10.1161/CIRCGENETICS.113.000023

6. Kalkat, M.,et al. (2017). MYC deregulation in primary human cancers. https://doi.org/10.3390/genes8060151

7. Ku, S. Y.,et al. (2019). Towards precision oncology in advanced prostate cancer. https://doi.org/10.1038/s41585-019-0237-8

8. Hasanau, T., et al. (2022). Detection of TERT promoter mutations as a prognostic biomarker in gliomas: Methodology, prospects, and advances. https://doi.org/10.3390/biomedicines10030728

9. Meddens, C. A., et al. (2019). Non-coding DNA in IBD: from sequence variation in DNA regulatory elements to novel therapeutic potential. https://doi.org/10.1136/gutjnl-2018-317516

May 14 2024
Love0

Decrypting the Non-Coding Genome: Unlocking Disease Insights

By Clinical Genomics

Key Takeaways:

  • Regulatory elements in non-coding DNA regions play critical roles in controlling gene expression and biological processes.
  • Misregulation of enhancers, promoters, and other non-coding elements contributes to the pathogenesis of various diseases, including rheumatoid arthritis, coronary artery disease, and melanoma.
  • Integrating whole genome sequencing with clinical phenotypic information from electronic health records can uncover new insights into disease mechanisms driven by non-coding variants.
  • Elucidating the roles of regulatory elements will facilitate development of more precise therapeutics and diagnostics tailored to individuals.

 

The quest to decipher the intricate underpinnings of human disease has long fixated on protein-coding genes. However, a rapidly burgeoning field is shining a spotlight on the proverbial dark matter of the genome – the vast, enigmatic expanse of non-coding DNA regions harboring regulatory elements that orchestrate gene expression. Enhancers, promoters, insulators, and other regulatory sequences exert exquisite control over when, where, and to what extent genes are expressed, shaping the symphony of cellular processes that sustain life. Yet, when these regulatory elements go awry, the consequences can be catastrophic, manifesting as devastating diseases that have long confounded researchers and clinicians alike.

 

Rheumatoid Arthritis and Non-Coding Dysregulation 

Rheumatoid arthritis (RA), characterized by excruciating joint inflammation and debilitating pain, exemplifies the profound impact of dysregulated non-coding elements. Enhancers and promoters governing the expression of pivotal inflammatory genes, such as those encoding the cytokines TNF-alpha and IL-6, have been implicated in the pathogenesis of RA. Mutations or epigenetic modifications in these regulatory regions can trigger aberrant cytokine production, fueling the vicious cycle of autoimmune attack and joint destruction that defines this debilitating condition.

 

Coronary Artery Disease and Lipid Metabolism 

Another striking example is coronary artery disease (CAD), a leading cause of mortality worldwide. The insidious buildup of atherosclerotic plaques within the coronary arteries, narrowing these vital conduits and heightening the risk of heart attacks, is intimately linked to disruptions in lipid metabolism and inflammation. Regulatory elements controlling the expression of genes such as PCSK9, a master regulator of cholesterol homeostasis, have been implicated in CAD etiology. Variants within these non-coding regions can dysregulate PCSK9, precipitating dyslipidemia and promoting the relentless progression of atherosclerosis.

 

Melanoma and Telomerase Regulation 

Melanoma, a deadly form of skin cancer arising from pigment-producing melanocytes, further underscores the profound influence of non-coding regulatory aberrations. Researchers have identified mutations in the TERT gene’s promoter region in a significant proportion of melanoma cases. These mutations lead to enhanced telomerase activity, conferring cellular immortality and fueling the unchecked proliferation that characterizes this aggressive malignancy.

 

The Tip of the Iceberg 

While these examples illuminate the pivotal roles of non-coding regulatory elements in disease pathogenesis, they represent merely the tip of the iceberg. The majority of disease-associated variants identified through genome-wide association studies reside within non-coding regions, and their functional implications are largely unexplored. However, interpreting the functional significance of these complex regions is challenging due to their diverse roles and interactions. This underscores the pressing need to delve deeper into the intricate regulatory landscapes governing gene expression and to elucidate how non-coding variants contribute to disease susceptibility, progression, and severity.

 

Harnessing Genomics and Clinical Data 

Fortunately, the advent of transformative technologies is ushering in a new era of scientific discovery. For example, integrating whole genome sequencing data with clinical phenotypic information from electronic health records (EHRs) provides the means to uncover insights into disease mechanisms driven by non-coding variants.

 

Envisioning a Future of Precision Medicine 

Imagine a future where an individual’s genomic information, meticulously annotated with regulatory element annotations, is seamlessly integrated with their EHR to capture a rich tapestry of clinical manifestations, treatment responses, and diagnostic imaging data. This convergence of multimodal data streams would empower researchers and clinicians to unravel the intricate interplay between non-coding regulatory variants and disease phenotypes, illuminating novel etiological factors that have long evaded detection.

 

Transformative Diagnostics and Therapeutics 

By decoding the enigmatic language of non-coding regulatory elements and their misregulation in disease, we stand to gain profound insights that will catalyze the development of groundbreaking diagnostics and therapeutics. For instance, personalized genetic screens could assess an individual’s risk of developing specific diseases based on their unique constellation of non-coding variants and enable early intervention. Similarly, tailored therapeutic interventions that precisely modulate the activity of dysregulated enhancers or promoters could restore homeostasis and alleviate disease burden, offering more effective and targeted treatments.

 

Interdisciplinary Collaboration 

As we embark on this exhilarating journey, fostering collaborations between geneticists, bioinformaticians, clinicians, and pharmaceutical partners will be paramount. By aligning interdisciplinary expertise and leveraging cutting-edge technologies, we can unlock the transformative potential of non-coding regulatory elements, ushering in a new era of precision medicine that promises to redefine our understanding and treatment of human disease.

 

Sources:

  1. Hnisz, D., et al. (2013). Super-enhancers in the control of cell identity and disease. Cell, 155(4), 934-947.
  2. Tak, P. P., & Firestein, G. S. (2001). NF-κB: a key role in inflammatory diseases. The Journal of clinical investigation, 107(1), 7-11.
  3. Abifadel, M., et al. (2003). Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nature genetics, 34(2), 154-156.
  4. Huang, F. W., et al. (2013). Highly recurrent TERT promoter mutations in human melanoma. Science, 339(6122), 957-959.
  5. Maurano, M. T., et al. (2012). Systematic localization of common disease-associated variation in regulatory DNA. Science, 337(6099), 1190-1195.
May 14 2024
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Disease Prevention, Diagnosis and Treatment in Underrepresented Populations

By Uncategorized

Key Takeaways:

  • Many diseases disproportionately affecting underrepresented populations remain understudied and poorly understood.
  • The historical lack of diverse representation in genomic research has hindered progress in understanding the biological and environmental factors contributing to disease risk across varied ancestries.
  • Conditions such as sickle cell disease, Chagas disease, and type 2 diabetes highlight the pressing need for increased research focus on populations that are not of European descent.
  • Prioritizing inclusive research will benefit populations underrepresented in research and deepen our fundamental understanding of human health and disease.

 

For far too long, medical research has largely overlooked the health challenges faced by populations of diverse ancestry, resulting in underrepresentation in research and a greater need for understanding diseases that disproportionately affect these populations. As we strive to achieve health equity and advance precision medicine, it is essential to acknowledge this historical disparity and prioritize research efforts that encompass the breadth of human diversity.

 

The Legacy of Genomic Underrepresentation

A primary driver of this research gap is the historical lack of diversity in genomic studies. Despite the profound insights gained from initiatives such as the Human Genome Project, most participants have been of European ancestry. This bias has resulted in an incomplete picture of the complex interplay between genetic variation, ancestral backgrounds, and disease risk, hampering the development of targeted interventions for underrepresented populations.

 

Disease-Specific Insights

Sickle Cell Disease: A Paradigm of Historical Inequity

Sickle cell disease (SCD) primarily affects individuals of African descent. Despite its prevalence and significant impact on quality of life, SCD stands as a stark example of a chronically underfunded and understudied condition. This inequity has left affected individuals and their families grappling with a lack of targeted treatments and comprehensive care strategies tailored to their needs.

 

The Chagas Conundrum

Chagas disease, caused by the parasite Trypanosoma cruzi, predominantly affects individuals living in Latin America. This chronic, potentially life-threatening condition remains a significant public health concern, yet its mechanisms and treatment options are poorly understood due to insufficient research.

 

Type 2 Diabetes: A Global Epidemic with Uneven Focus

Even conditions with a global impact, such as type 2 diabetes , have been disproportionately studied in populations of European descent. This hinders the understanding of possible unique genetic and environmental factors that contribute to the high prevalence of type 2 diabetes in underrepresented populations.

 

Breaking Down Barriers, Elevating Understanding

The consequences of this historical research disparity extend beyond the immediate health burden on disproportionately affected communities. Studying diseases across diverse ancestries is crucial for deepening our understanding of human biology and disease mechanisms. The unique genetic, environmental, and cultural contexts of each population offer invaluable insights for new prevention, diagnosis, and treatment avenues – benefiting everyone.

 

Paving the Way for Inclusive Research

To rectify this historical disparity, researchers must recognize diversity as a strength and prioritize inclusive research practices. This endeavor requires a multifaceted approach, fostering collaborations among researchers, community leaders, policymakers, and funding agencies.

Engaging underrepresented communities through community-based participatory research (CBPR) models is crucial. Active involvement in the research process, from study design to dissemination, builds trust, ensures cultural sensitivity, and addresses barriers and concerns that may have deterred historical participation.

 

Diversifying Cohorts and Biobanks

Efforts to diversify research cohorts and biobanks are essential. This will enable a robust representation of diverse ancestries and facilitate large-scale genomic and epidemiological studies. Leveraging precision multi-ancestry genotyping arrays and whole genome sequencing is crucial for capturing the full spectrum of genetic variation and its disease implications.

 

Fostering Interdisciplinary Collaboration

Bridging genomics, epidemiology, social sciences, and public health through interdisciplinary collaboration is necessary to address this research gap. Integrating diverse perspectives and expertise develops holistic approaches that account for the complex biological, environmental, and sociocultural factors shaping disease manifestations.

 

A Path Toward Health Equity

Prioritizing research on diseases prevalent in underrepresented populations is a scientific and ethical imperative. Illuminating these diseases paves the way for targeted interventions, personalized care, and better health outcomes for historically marginalized communities. Moreover, this commitment to inclusive research will deepen our understanding of human health and disease,  guiding healthcare  toward a future where precision medicine is attainable for all.

 

As we embark on this journey, a steadfast commitment to health equity ensures no community is left behind. Elevating the voices and addressing the needs of an underrepresented population helps forge a just and inclusive path forward that recognizes the value of every human life and embraces a collective pursuit of well-being.

 

Sources:

  1. Petrovski, S., & Goldstein, D. B. (2016). Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome biology, 17(1), 1-3.
  2. Rotimi, C. N., & Ngcungcu, T. N. (2021). Genomics of sickle cell disease: a perspective from Africa. The Lancet Haematology, 8(6), e415-e424.
  3. Hotez, P. J. (2010). Neglected infections of poverty among the indigenous peoples of the Arctic. PLoS neglected tropical diseases, 4(1), e606.
  4. Nair, G. G., & Morse, S. A. (2021). A call for research on type 2 diabetes mellitus in underrepresented populations. Nature Reviews Endocrinology, 17(5), 273-274.
  5. Isler, M. R., & Corbie-Smith, G. (2012). Practical steps to community engaged research: from inputs to outcomes. The Journal of Law, Medicine & Ethics, 40(4), 904-914.
Apr 09 2024
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US vs European Healthcare

The Healthcare Divide: Privatized US vs Public European Models

By Healthcare

Key Takeaways:

  • The US has a primarily private, market-based healthcare system, while most European countries have universal, tax-funded public healthcare systems.
  • Healthcare spending per capita is substantially higher in the US compared to Europe, yet the US lags behind on metrics like life expectancy and infant mortality.
  • European healthcare systems aim to provide comprehensive coverage to all citizens, while millions remain uninsured in the US despite the Affordable Care Act.
  • Wait times for non-urgent care tend to be longer in European public systems, though the US has longer wait times for emergency room visits.
  • The US healthcare system is dominated by for-profit providers and private insurance companies, leading to higher costs but more cutting-edge treatments. 

The Opposing Models

For decades, the healthcare systems of the United States and Europe have taken vastly different approaches, sparking heated debate over which model delivers better care at a sustainable cost. While the US relies primarily on private insurance and market competition, most European nations have adopted tax-funded universal healthcare as a basic right for all citizens.

 

Aspect United States Europe
System Type Private, market-based healthcare system. Universal, tax-funded public healthcare systems.
Healthcare Spending Substantially higher per capita compared to Europe. 2019: $11,072 per person. Lower per capita compared to the US. Average across wealthy European nations in 2019: $5,505.
Health Outcomes Lags behind Europe on metrics like life expectancy and infant mortality. Better life expectancy and lower infant mortality rates compared to the US.
Coverage Millions remain uninsured despite the Affordable Care Act. Approximately 28 million non-elderly Americans are uninsured. Comprehensive coverage for all citizens. Nearly universal coverage with little to no out-of-pocket costs for services.
Provider System Dominated by for-profit providers and private insurance companies. Predominantly public-funded healthcare systems, with some countries incorporating a mix of private and public insurance schemes.
Wait Times Longer wait times for emergency room visits. More efficient access to specialized treatments and newly approved therapies. Longer wait times for non-urgent care in public systems due to budget and capacity management. Generally quicker access to emergency services.
Innovation and Costs High healthcare spending contributes to cutting-edge medical innovations. Costs driven up by profit motives, administrative complexities, and fee-for-service model. Emphasizes cost controls, standardized fee schedules, and integrated care delivery. While innovative, may have slower access to some new treatments due to budget considerations.
Future Challenges Aging population, rising chronic disease burden, and debates over the extent of government involvement. Calls for “Medicare for All” reflect ongoing debates. Similar challenges with aging populations and chronic diseases. Experiments with public-private hybrid schemes and value-based reimbursements to maintain sustainability.
Philosophical Approach Healthcare often viewed as a market commodity, with ongoing debates about its status as a human right. Healthcare generally considered a basic right for all citizens, funded through taxation.

 

US: Private Markets vs. Europe: Public Coverage

At its core, the American healthcare system is a private, decentralized collection of for-profit hospitals, clinics, insurance companies, and other providers incentivized to maximize revenues. Employers typically offer private insurance plans, and government programs like Medicare and Medicaid cover the elderly and low-income populations. However, an estimated 28 million non-elderly Americans remain uninsured despite the Affordable Care Act’s coverage expansions.

 

In stark contrast, European healthcare systems are overwhelmingly publicly-funded through taxation to ensure universal coverage for all legal residents. Countries like the UK, Spain, and Sweden operate single-payer national health services, while others like Germany, France, and the Netherlands have multi-payer universal systems that incorporate a mix of private and public insurance schemes.

 

Higher Costs, Lagging Outcomes in the US

One indisputable fact is that the US healthcare system is exorbitantly more expensive per capita than any European model, yet its health outcomes lag behind on metrics like life expectancy and infant mortality. In 2019, US healthcare spending reached $11,072 per person – over double the average of $5,505 across wealthy European nations.

 

Many experts attribute the US system’s high costs to profit-driven incentives, administrative complexities associated with private insurers, and a fee-for-service payment structure that encourages more treatment over quality outcomes. European systems emphasize cost controls, standardized fee schedules, and integrated care delivery as more efficient alternatives.

 

The Trade-Off: Innovation vs. Wait Times

However, America’s high healthcare spending does contribute to cutting-edge medical innovations and reduced wait times for specialized treatments like newly approved cancer therapies. European systems often face longer delays for non-urgent services as public health authorities aim to manage finite budgets and capacity. Although the US has lengthier emergency room wait times on average than European countries.

 

Universal Coverage vs. Uninsured Millions

Access to healthcare also differs significantly between the US and Europe. The Affordable Care Act brought the US’s uninsured rate below 10% for the first time, but millions still lack coverage and face potentially bankrupting medical bills. European universal systems cover all citizens cradle-to-grave – services like preventative screenings, hospital stays, specialist visits, surgeries, prescribed medications, and prenatal care are fully covered with little or no out-of-pocket costs beyond modest copays.

 

Challenges for the Future

Both systems face mounting challenges from aging populations and rising costs associated with chronic diseases and new technologies. European nations are experimenting with public-private hybrid schemes and value-based reimbursements, while American policymakers continue debating the role of government involvement amidst calls for “Medicare for All.”

 

Differing Philosophies

Ultimately, the US and Europe represent vastly different philosophical and economic approaches to the simple question: Should healthcare be considered a human right or a market commodity? The answer, and the path forward, remains highly contentious for two world powers with no easy solutions in sight.

 

Sources:

  • “U.S. Health Care Resources.” American Hospital Association, 2021.
  • “Health Insurance Coverage in the United States.” Centers for Disease Control and Prevention, 2022.
  • “Health Systems Characteristics.” OECD Health Statistics, 2021.
  • “Health Care Systems in the EU.” European Union, 2021.
  • “How Does the Quality of the U.S. Health-Care System Compare to Other Countries?” Peterson-KFF Health System Tracker, 2022.
  • “Health Expenditure Per Capita.” OECD Health Statistics, 2022.
  • Sawyer, B., et al. “Why Do Health Care Costs Keep Rising?” Peterson-KFF, 2022.
  • “The United States Leads Rising Availability of Cancer Medicines.” IQVIA, 2021.
  • “Waiting Times for Health Services Next?” EuroHealth, 2020.
  • “U.S. Emergency Department Visit Data Visualizations.” CDC, 2018.
  • “Universal Health Coverage.” World Health Organization, 2021.
  • “Value-Based Healthcare in Europe.” EIT Health, 2022.
Mar 22 2024
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unstructured data

From Doctors’ Notes to New Therapies: The Promise of Unstructured Data

By Health Data Types, Healthcare Data

Key Takeaways:

  • Unstructured data from sources like clinical notes can provide valuable real-world insights to augment structured clinical trial data in drug development.
  • Natural language processing (NLP) enables mining of unstructured text data for information on drug efficacy, side effects, patient behaviors, and more.
  • Challenges include data privacy, integration across sources, and developing reliable NLP models to extract accurate insights.
  • Proper governance and cross-functional collaboration is needed to safely and effectively leverage unstructured data.
  • Responsible use of unstructured notes has the potential to accelerate drug development, improve safety monitoring, and support value-based care models.

The Untapped Potential of Unstructured Data

In the meticulous world of drug development, every data point is precious. Clinical trials generate a wealth of rigorously structured efficacy and safety data. During routine clinical care, computerized physician order entry systems and electronic health records capture structured data that can enhance drug efficacy and safety monitoring. However, an underutilized treasure trove of real-world information exists in the unstructured text of clinical notes, hospital records, and other loosely formatted sources gathered as part of standard medical practice.

 

Unleashing Insights with Natural Language Processing

Historically, this unstructured data has been difficult to integrate and analyze alongside its structured counterparts. This is partly due to variability in documentation practices among different healthcare providers. Additionally, the extraction of relevant data has traditionally relied on manual review and interpretation by clinically trained personnel. But major pharmaceutical companies are now investing heavily in natural language processing (NLP) to mine these unstructured sources for insights.

 

While NLP does not eliminate the need for human involvement, it can significantly streamline the process. NLP serves as a tool that works in conjunction with human interaction, combining the efficiency of intelligent automation with the ability to incorporate human feedback. This combination allows for more effective extraction of insights from unstructured data, which ultimately aids in accelerating research, optimizing clinical trials, and enhancing drug safety monitoring.

 

Applications: From Safety Signals to Patient Experiences

So when and how can unstructured data provide value? One key application is using NLP models trained on doctors’ notes to identify potential safety signals that may not surface until after a drug is approved and prescribed at scale. These real-world signals can prompt further investigations and narrow the “surrogate to reality” gap between clinical trials and clinical practice.

 

Unstructured data has also shown promise in two critical areas: better defining appropriate inclusion/exclusion criteria for clinical trials and identifying under-represented patient populations who may benefit from a treatment. By processing clinical records from diverse practices, researchers can find more suitable study cohorts for targeted recruitment efforts to ensure that clinical trials are more representative of real-world patient populations. Furthermore, analyzing unstructured data allows for a better understanding of real-world behaviors like treatment adherence or self-reporting of side effects.

 

Another valuable application of NLP is in tracking and codifying patients’ experiences based on anecdotal descriptions found in clinical notes. For example, phrases such as “The medicine made me feel queasy” can provide qualitative context around drug effects and quality-of-life. This context could support reporting requirements for post-marketing adverse events. Additionally, other qualitative context could complement clinical scoring tools used in the trial setting, potentially expediting label expansions for new indications.

 

Overcoming Obstacles to Implementation

Despite the opportunities, integrating unstructured data is not without challenges. Concerns around patient privacy and data security pose hurdles. While unstructured text provided for research purposes is typically de-identified, residual identifying information can remain. Utilizing data sources that have gone through multiple layers of de-identification efforts is crucial to mitigate this risk effectively. Further, reliably extracting structured insights from unstructured text across multiple source systems using NLP also presents difficulties.

 

Developing robust, production-grade NLP models requires immense training data, careful tuning to the healthcare/biomedical domain, and systematic quality testing. Merging unstructured insights with existing structured pipelines is also an intricate systems engineering challenge.

 

Data Governance and the Path Forward

Looking ahead, stakeholders agree that managed responsibly and embedded into robust data frameworks, unstructured real-world datasets can help drive high quality healthcare to its full potential. Pharmaceutical companies may find accelerated paths to drug approvals and label expansions. Payers could gain transparency to optimize formularies and pricing models. And ultimately, patients may benefit from better targeted treatments.

 

Sources:

  • “Unlocking the Power of Unstructured Data in Drug Discovery.” DrugDiscoveryToday, 2021..
  • “Natural Language Processing in Drug Safety.” Pharmaceutical Medicine, 2021.
  • “Bridging the ‘Efficacy-to-Effectiveness’ Gap.” BioPharmaDive, 2022.
  • “NLP for Clinical Trial Eligibility Criteria.” NEJM Catalyst, 2021.
  • “NLP Applications in Life Sciences and Healthcare.” Optum, 2022.
  • “Challenges of Integrating Unstructured Data in Healthcare.” MIT, 2020.
  • “Data, RWE and the Future of Value-Based Care.” IQVIA, 2022.
Feb 28 2024
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data diversity

Diversity in Data: Why It Matters for Drug Discovery

By Healthcare Data

Key Takeaways:

  • The absence of diversity in clinical trial data can lead to biases and inequities in healthcare.
  • Regulators like the FDA are emphasizing the need for more diverse and representative data through initiatives like the Real World Evidence Program.
  • Having accurate, diverse real world data leads to more equitable and effective treatments by ensuring safety and efficacy across populations.
  • Pharmaceutical companies should prioritize capturing diverse real-world data and applying advanced analytics to identify variabilities in treatment response.

 

In recent years, a growing understanding has emerged regarding the critical need for diversity and representation in clinical research data. Historically, certain demographic groups such as women, minorities, and the elderly have been underrepresented in many clinical trials. This lack of diversity in the underlying data can lead to significant biases and inequities when new therapies are approved and launched.

 

For example, a landmark study in the early 1990s showed that women had been excluded from most major clinical trials, leading to gaps in knowledge about women’s responses to medications. The study found that eight out of ten prescription drugs withdrawn from the market posed greater health risks to women than men. This exemplifies the real dangers of not gathering data across diverse populations.

 

More recently, the COVID-19 pandemic has further revealed disparities in health outcomes and treatment responses between different demographic groups. Regulators have emphasized the need for clinical trials that are more representative of real-world diversity. In the United States, the Food and Drug Administration (FDA) now requires inclusion of underrepresented populations in clinical trials under the Improving Representation in Clinical Trials initiative.

 

The FDA has also created the Real World Evidence Program to evaluate the potential use of real-world data (RWD) from sources like electronic health records, insurance claims databases, and registries. The goal is to complement data from traditional trials with more diverse, real-world information on safety, effectiveness, and treatment response variabilities across patient subgroups.

 

Having access to accurate, representative real-world data enables more equitable and effective treatments in several key ways:

  1. Identifying safety issues or side effects that disproportionately impact certain populations based on factors like age, race, or comorbidities. This allows for better labeling and monitoring.
  2. Ensuring adequate efficacy across all segments of the patient population. Understanding variabilities in treatment response is key for optimal dosing guidance.
  3. Enabling development of targeted therapies for population subgroups where the risk-benefit profile may differ, such as pregnant women.
  4. Avoiding biases and inequities in access to treatment. Diverse data helps prevent therapies from being indicated for only limited populations.
  5. Informing appropriate use criteria and payor coverage decisions based on real-world comparative effectiveness across groups.

 

From a regulatory compliance perspective, lack of representation in trial data can also lead to delays or rejection of new drug and device applications. The FDA has advised that drugs may not be approvable if safety and efficacy has not been demonstrated across demographics.

 

Looking ahead, embracing diversity and representativeness throughout the drug discovery process will be critical. Pharmaceutical companies should make gathering inclusive, real-world data a priority. Advanced analytics techniques like machine learning can then help unlock insights about treatment response variabilities within diverse patient populations.

 

Ultimately, leveraging diverse and representative data will lead to more equitable, effective personalized healthcare and better outcomes for all patients.

 

Sources:

  • Improving Representation in Clinical Trials and Research: FDA’s New Efforts to Bridge the Gap – FDA
  • Real-World Evidence – FDA
  • Racial and Ethnic Differences in Response to Medicines: Towards Individualized Pharmaceutical Treatment – NIH
  • Addressing sex, gender, and intersecting social identities across the translational science spectrum – NIH
  • Utilizing Real-World Data for Clinical Trials: The Role of Data Curators – NIH

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Nashville, TN 37215-2691

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Suites 100 & 200
San Diego, California 92122

(615) 208-5462
info@nashbio.com

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