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Genome research

The Genome and Personalized Medicine

Personalized medicine is “an emerging practice of medicine that uses an individual’s genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease,” according to  the National Human Genome Research Institute.

Determining an individual’s genetic profile is based on analysis of his or her genome. What is the genome?

A genome is a person’s complete set of DNA ( deoxyribonucleic acid), including all of its genes. Each genome contains all of the information needed to build and maintain that person. DNA is present in 23 pairs of chromosomes found in the nucleus of cells. DNA consists of units called nucleotides, with the distinguishing feature being four chemical bases. Genes are small segments of DNA, which act as instructions (codes) to make protein molecules.  A large portion of genomic DNA does not code for protein, but may have functions related to regulating the activities of genes. Excellent discussions on the genome, DNA, and genes are available on the internet.

The Human Genome Project completed in 2003 was a landmark study to determine the sequence of all the DNA subunits of the human genome. The long-term aim of the project was to advance the diagnosis and treatment of diseases. Now, over two decades after the project’s completion these benefits are beginning  to be realized, and serve as the basis of personalized medicine.

Coming up next time– progress on the Precision Medicine Initiative.

Further Reading

  1. A Brief Guide to Genomics. National Human Genome Research Institute.

https://www.genome.gov/18016863

2. Genomics. The Broad Institute.

http://www.broadinstitute.org/education/glossary/genome

3. DNA Genes and Chromosomes. virtual Genetics Education Centre, University of Leicester.

http://www2.le.ac.uk/departments/genetics/vgec/schoolscolleges/topics/dna-genes-chromosomes

4. About the Human Genome Project. Human Genome Project Information Archive 1990-2003.

http://web.ornl.gov/sci/techresources/Human_Genome/project/index.shtml

5. Human Genome Project produces many benefits. National Human Genome Research Institute.

https://www.genome.gov/27549135

 

Introduction to Personalized Medicine

Personalized medicine, also known as precision medicine, is much in the news today. What is it, and why is it becoming increasingly important?

Personalized medicine is a new approach to healthcare. Until recently, patient care has been based on the general population, or a “one drug fits all” approach. Treating for the average person, however, can result in a complete cure or no response at all. Also, side effects to the treatment can vary from nonexistent to very severe.

Personalized medicine is now gaining prominence in healthcare as a result of advances in medical technologies. Leading the field is genome analysis, but also includes computational biology, medical imaging, and regenerative medicine. These technologies identify the unique characteristics of each individual, allowing for a more rational and effective means of diagnosis and treatment. Using the full potential of these technologies leads to a true application of personalized medicine.

In future postings of this blog, I will discuss various aspects of personalized medicine, starting with the human genome. Other topics will include the federal Precision Medicine Initiative, diseases currently treated by personalized medicine, drugs in the pipeline, and challenges faced in the implementation of personalized medicine.

Genetic engineering-Alexander Raths/Shutterstock.com

GERD: Living With Acid Reflux Disease

Gastroesophageal reflux disease, or GERD, is a more complicated form of heartburn or acid reflux, a very common condition. This book is a comprehensive discussion of GERD for the general reader, and provides updates on many recent developments in the field.

The book is presented in question and answer format, describing the essential features of GERD in an engaging and stimulating manner that facilitates learning and reinforcement. The book is rich in illustrations, tables, charts, and boxes that highlight definitions and facts. Web site links refer the reader for more detailed information and videos.

The book is part of the MyModernHealth series published by Mercury Learning and Information. It is available as an ebook or paperback on Amazon.

Gut Microbiome

Can gut bacteria affect your behavior?

The microbiome consists of bacteria and other microbes that normally inhabit the intestinal tract, airways, and skin of the body. The concept of a healthy microbiome is now gaining credibility; that is, it is important to establish and maintain a certain population of microbial species to maintain good health. It is now well known that intestinal microbes can affect digestion, allergies, and metabolic processes. More recently, discoveries have found that the microbiome can have a profound influence on the brain, affecting a person’s mood, anxiety, and stress level. The role of the microbiome on mental disorders such as autism, visceral pain, and multiple sclerosis is currently under study. The communication system between the microbiome and the brain is known as the gut-brain axis.

How is the microbiome able to exert its effects on brain function? Gut bacteria produce neurotransmitters such as serotonin, dopamine and GABA which have a role in mood. Other organisms affect how people metabolize these compounds. Gut bacteria may generate other neuroactive compounds, such as butyrate, that reduce anxiety and depression. Some microbes can activate the vagus nerve, and can be interconnected to the immune system.

How can a disordered microbiome be improved? Probiotics are living organisms present in fermented foods such as yogurt and kefir that can have a beneficial effect of improving microbial balance. Probiotics have found application in treating intestinal disorders, although much needs to be learned about the most effective ways to use probiotics. Probiotics may exert beneficial effects by suppression of pathogenic bacteria, by enhancement of immunity, and by serving as a protective barrier at the intestinal wall to harmful bacteria. A more radical approach of modifying the microbiome is by introducing fecal samples from healthy persons into the gut.

The microbiome can be altered after antibiotic treatments or as a result of certain disease conditions such as irritable bowel syndrome. Researchers have shown interest in controlling how the microbiome is established in the newborn.

Further Reading

1. Dietert, R. & J. Dietert. The Sum of Our Parts. The Scientist. July 2015, pages 44-49.
http://www.the-scientist.com/?articles.view/articleNo/43379/title/The-Sum-of-Our-Parts/

2. Kohn, D. When Gut Bacteria Changes Brain Function. The Atlantic. June 24, 2015.
http://www.theatlantic.com/health/archive/2015/06/gut-bacteria-on-the-brain/395918/

3. Smith, P. Gut Feelings. The New York Times Magazine. June 28, 2015, pages 44-49, 68

4. Williams, M. et al. Probiotics as Therapy in Gastroenterology. J Clin Gastoenterol 2010 Oct. 44(9): 631-636.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094138/

DNA molecule

Accurate Genome Sequencing

Personalized medicine recognizes that individuals respond differently to medicines and that it can be more effective and safe to tailor the dose or regimen to that individual rather than to a “one dose fits all” approach that has been common medical practice. According to the National Human Genome Research Institute, personalized medicine is “an emerging practice of medicine that uses an individual’s genetic profile to guide decisions made in regard to the prevention, diagnosis, and treatment of disease.” Personalized medicine can also encompass the application of medical imaging and regenerative medicine techniques.

The effective application of personalized medicine is based on the assumption that the genome of the individual is accurately known. In a recent posting, Jason Koeber of Motherboard points out that even the best genome sequencing techniques have an error rate of around 1%. (1)

Two years ago, the National Institute of Standards and Technology (NIST) hosted a consortium to develop genomic reference standards that could be used to evaluate the accuracy of genome sequencing processes. (2)This consortium is called Genome in a Bottle. The reference standards are designed to overcome problems of bias and “blind spots” among sequencing technologies that lead to significant differences in results.

The results of a pilot study were reported in a recent Nature Biotechnology paper. (3)The researchers studied 14 genome and 3 exome data set results obtained from five sequencing platforms to find regions of agreement or disagreement. An arbitration method was used to overcome biases. A reference genomic data set was obtained that can be used with high confidence to evaluate new sequencing methods.

The FDA recently granted marketing approval for the first next-generation genomic synthesizer, Illumina’s MiSeqDx. (4) They have been working with the NIST to develop genomic reference standards.

References
1. Koeber,Jason “If We Can’t Get Genome Accuracy Right, Personalized Medicine Is a Pipe Dream” March 1, 2014

http://motherboard.vice.com/read/if-we-cant-get-genome-accuracy-right-personalized-medicine-is-a-pipe-dream

2. How Well Did You Sequence that Genome?’ NIST, Consortium Partners Have Answer

http://www.nist.gov/mml/bbd/dna-022514.cfm

3. Zook, Justin, et al. “Integrating human sequence data sets provides a resource of benchmark SNP and indel genotype calls.” 32, 246-251 (2014) doi: 10.1038/nbt.2835

http://www.nature.com/nbt/journal/v32/n3/full/nbt.2835.html

4. Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development. October 2013.

http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PersonalizedMedicine/UCM372421.pdf

Selecting Studies for Meta-Analysis: Publication Bias

Meta-analysis is a statistical method of combining the results of individual studies. Meta-analysis may allow a more precise estimate of treatment effects, and may explain differences between the results of individual studies. Although meta-analysis can be a powerful and useful technique, they must be designed carefully to ensure that the results are not misleading.
The identification and selection of individual studies used in a meta-analysis is critical. Publication bias has a direct impact on this selection.
Publication bias refers to the greater likelihood of papers showing positive results to be published than negative results. If the sample of studies selected for meta-analysis is biased, the conclusions drawn from the analysis may be invalid. Turner(2) analyzed the publication status of antidepressant drugs. He found that 97% of the positive studies were published versus only 12% of negative studies. The inclusion of negative studies in the analysis reduced the positive effects of the drugs.
Statistical tests have been developed to identify and assess the impact of publication bias in meta-analysis.
Attempting to locate unpublished studies is time consuming, difficult, and can use methodology hard to assess.(1)
In evaluating the results of meta-analyses (as well as for individual studies) it is important to be aware of who is sponsoring the studies and whether the authors have any vested interests.
Is it possible to overcome the problem of publication bias? The National Institutes of Health keeps a registry of all studies it supports, and the FDA keeps a registry and database in which drug companies must resister all trials they intend to use in applying for marketing approval or for changes in labeling.
Prospective meta-analysis looks forward to meta-analysis in the planning stage of individual trials. Researchers of these trials agree, prior to knowing the results of their studies, to combine their findings when the trials are complete.(3) The researchers agree on trial design as well as outcome measures which facilitates the analysis of results.

References
1. Rothstein, Hannah, Alexander Sutton & Michael Borenstein, eds. Publication Bias in Meta-Analysis: Prevention, Assessment and Adjustments. 2005. John Wiley & Sons

http://www.wiley.com/WileyCDA/WileyTitle/productCd-0470870141.html
2. Turner, Erick, et al. Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy. N Engl J Med. 2008; 358: 252-60. Trials (BioMed Central) 2011;12:104

http://www.nejm.org/doi/full/10.1056/NEJMsa065779
3. Turok, David et al. The methodology for developing a prospective meta-analysis in the family planning community.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103448/
4. Walker, Esteban, et al. Meta-analysis: Its strengths and limitations. Clev Clin J Med. June 2008; 75(6): 431-439.

http://www.ccjm.org/index.php?id=107937&tx_ttnews[tt_news]=360745&cHash=c4f41096946e87f82f539928262b817f

DNA molecule

Big Data Advances Personalized Medicine

Personalized medicine is much in the news today. What is it and why is it important?

Until recently, patient treatment has been characterized by a one size fits all approach. Patients with a given condition are given a set medication; many respond as expected, while others either do not respond or react unfavorably.

An important factor in variability in response to treatment is the underlying genetic makeup of individuals. Drug response is affected by the extent (variability) of drug delivery to the sites of drug action as well as by the effectiveness with which the drug interacts with specialized receptors or enzymes. The activity of these processes are influenced by genetics.

Roden, Dan & Alfred George. The Genetic Basis of Variability in Drug Responses. Nature Reviews Drug Discovery, Vol. 1, Jan. 2002, pp. 37-44.

http://www.nature.com/nrd/journal/v1/n1/full/nrd705.html

Dramatic reductions in costs of genomic analyses have resulted in real advances in personalized medicine applications. A profile of each individual can be made by associating their unique genetic makeup with treatments that are most likely to respond favorably to that makeup. These personalized treatments (known as targeted therapies) result in more effective treatments at lower cost and time.

A Personalized Medicine World Conference is held each year providing the latest developments in the field. Past speaker videos can be viewed at:

http://pmwcintl.com/conferences.php

Although the healthcare community recognizes that Big Data could aid in improving patient care, they often do not have the means to use it. This is where information technologies come into the picture. GNS Healthcare is an example.

http://ebdgroup.com/partneringnews/2013/07/big-data-delivers-promise-of-personalized-medicine/

their computational engine uses “ supercomputers to analyze relationships among multiple types of patient data, including patient population information, electronic medical records, images, clinical outcomes, and other data, learning as it goes.”  Personalized medicine, therefore, is going beyond application of genome analyses to include “real life” data.

Personalized medicine improves diagnostic capability and predictions of outcomes. It can aid investigators to select patients for clinical trials who are most likely to respond to the treatments. For trials in progress, biomarkers can be identified using genotype, gene expression, and patient outcome data. Big Data analytics can identify hidden drug interactions as well as patient characteristics and care processes that affect safety and efficacy.

Personalized medicine has come of age through an explosion of electronically available medical data and advances in computing technology to analyze it.

 

Big Data Ready to Transform Healthcare

The problems of present-day healthcare are well known—gross inefficiencies, poor outcomes, and inadequate personalized care. A vast amount of information is out there, known as Big Data, that can aid greatly in solving these problems, if only the data could be efficiently accessed, analyzed, summarized, and applied to the healthcare system.

These advances are indeed rapidly taking place. The University of Pittsburgh Medical Center health system is partnering with several information technology companies to create a database that integrates financial, administrative, clinical and genomic information. Although the process is complex, it can lead to simplified solutions.

Another example is the use of IBM’s supercomputer, Watson. The supercomputer was loaded with vast amounts of patient records from the Memorial Sloan-Kettering Cancer Center, as well as from many medical journal publications. Platforms were developed that physicians can access to determine cancer treatment options.

Medicare is serving as an impetus to accelerate the process by requiring hospitals to improve care in three critical areas or to incur penalties: reduce readmission rate of patients, adopt electronic health record systems, and reduce hospital-acquired infections.

Analyses of Big Data promise applications that were not really available before, such as the prediction of disease onset so that interventions can be made before the disease manifests.

Not everyone in the healthcare field is happy about the application of big data analytics in an attempt to reduce costs. Some physicians fear that a change from the traditional fee-for-service system to performance metrics will limit their options in treating patients. The controversy relates to the types of tests or procedures that are ordered or performed and under what situations.

Big Data will be a great assist to advance “personalized medicine.” This will be a topic of another blog.

Sources

Bernard, Allen. Healthcare Industry Sees Big Data As More Than a Bandage. CIO, Aug. 5, 2013.

http://www.cio.com/article/737620/Healthcare_Industry_Sees_Big_Data_As_More_Than_a_Bandage?page=1&taxonomyId=3006

Cerrano, Paul. Why Physicians Don’t Like Big Data. Information Week, August 20, 2013.

http://www.informationweek.com/healthcare/policy/why-physicians-dont-like-big-data/240160189

Hagland, Mark. Thinking Really Big About Data. Healthcare Informatics

www.healthcare-informatics.com 

 

Big Data Applications

market analysis

“Big Data” is much in the news today. What is it, and what is its significance to the business and medical establishments? Big Data refers to the vast amount of information generated daily, but more specifically to the challenges involved in processing, analyzing, and using the data.

Big Data is being generated from advances in technology including the adoption of large numbers of sensors and smart devices. Big data can be very beneficial in solving business problems, often providing solutions previously inaccessible. To do so can require visionary thinking and talent.

A large amount of Big Data being generated is semi-structured or unstructured data. Quite a bit of this data is lost due to an inability in knowing how to use it.

IBM has developed a platform that addresses this problem. Based on the open-source Hadoop software, this system simplifies, manages, coordinates, and analyzes big Data.

Evaluating Big Data has led to the evolution of a new profession, the Data Scientist, with high levels of both quantitative skills and technical ability.

Virtually all industries can find valuable uses for Big Data, including retail, financial services, manufacturing, government, advertising, media, and energy. Its application for medicine and healthcare will be the topic of my next blog.

Sources

Davenport, Thomas & Jill Dyche. Big Data in Big Companies. SAS Institute, May 2013.

http://www.sas.com/en_us/offers/sem/big-data-2274228/register.html?gclid=CNCH24zB6bgCFRGg4AodelgAgg

Zikopoulos,Paul, et al. Understanding Big Data: Analytics for Enterprise Class Hadoop and Streaming Data. McGraw-Hill Companies, 2012.

http://www-01.ibm.com/software/data/bigdata/

Challenges to Open Access

As I mentioned in my previous blog, open access is a means of publication that allows free access to scientific journals for libraries, researchers, businesses, and the general public.

The publishing industry has contended that open access will lower the quality of publications by lack of adequate peer review.

Indeed, a few unfortunate recent incidences have occurred that seem to support this contention. Since financing open access often requires authors to pay for publication, some “predatory” online journals have appeared whose sole purpose is to prey on unsuspecting authors eager to publish. The Scholarly Kitchen

A scandal hit an open access journal published by Bentham Science Publishers. They accepted for publication a phony paper that was computer generated.

These incidences could serve as a wake-up call to the open access movement which is now well established. One of the measures of the impact and value of publications is the number of times an article is cited by other researchers. By this measure, open access articles are doing very well.

In 2012, a bill was introduced in Congress that would have repealed the current open access policy by the National Institutes of Health. This bill caused such a groundswell of protests by research organizations, universities, and even many publishers that it had to be withdrawn. (Online Searcher. Vol. 37, No. 2, March/April, 2013.)