Archive for the 'General' Category


Mar 09 2017

An injection of optimism into biomedical research – Part 5: Millions of babies

by at 3:59 am

This is the fifth and last part of my Injection of Optimism into Biomedical Research Series. I’m getting back to the babies on this one! In Part 1, I talked about the success of newborn screening programs, here I will be discussing a prenatal public health intervention that has saved and helped millions of babies worldwide.

The Rh protein complex is embedded in the membranes of red blood cells. Most individuals are Rh positive (Rh+), which means that their Rh complex contains a specific protein (the RhD antigen); individuals without that protein are Rh negative (Rh-). Approximately 15% of Caucasians, 7% of blacks, and 1% of Asians are estimated to be Rh-. Blood types are generally denoted by a shorthand reporting the ABO blood group and Rh status.  For example, an individual who has an ABO blood group of B and is Rh- is often denoted as “B-.” The Rh type is inherited in a recessive manner, so that a child who is Rh- must have two Rh- parents, but a child who is Rh+ may have two Rh+ parents or one Rh+ and one Rh- parent.

Problems can result if an Rh- woman is pregnant and carrying an Rh+ baby. In that case, the woman’s body may create antibodies to the RhD protein in the baby’s blood. These antibodies can destroy the baby’s red blood cells, leading to severe anemia or even death. This is called “Rh incompatibility” and generally occurs after the first pregnancy, since the first baby is usually born before the development of too many antibodies. In 1960, Rh incompatibility and the resulting hemolytic disease of the newborn (erythoblastosis fetalis) was estimated to result in 10,000 stillborn babies and even more babies who were affected and generally expected to recover after blood transfusions. In 1968, two clinical trials showed that injection of the anti-Rh gamma globulin (RhoGAM) after the delivery of an Rh+ baby by an Rh- woman will prevent problems with later pregnancies. Women who are at risk of Rh incompatibility now generally receive the RhoGAM shot at 7 months and within 72 hours of delivery, as well as in the case of miscarriage or bleeding during pregnancy.

Given that Rh incompatibility used to lead to many cases of perinatal death and illness and is now a rare concern if the RhoGAM shot is appropriately administered, this is a major public health victory. I hope this series as a whole will help renew your optimism and sense of wonder in biomedical research and science in general. Now let me get back to writing that grant proposal…

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Mar 06 2017

An injection of optimism into biomedical research – Part 4: Cancer prevention and early detection

by at 4:13 pm

This is the fourth part  of my Injection of Optimism into Biomedical Research Series. Since I am faculty at the Lombardi Comprehensive Cancer Center, I wanted to have a cancer-related post!

The use of Papanicolaou (Pap) tests for cervical cancer prevention and early detection has been an essential aspect of gynecological care in the United States since the 1950s. Recently Pap tests have been supplemented by the use of viral genotyping tests for the types of human papilloma virus (HPV) which cause essentially all cervical cancers as well as by the HPV vaccine (co-invented by Georgetown’s own Dr. Schlegel!). Given the huge decrease in cervical cancers due to the introduction of the Pap test, it is hard to remember that in the 1940s cervical cancer was a major cause of mortality for young women in the US – it is now only the 14th most frequent cancer in American women while still being a major driver of mortality in many parts of the world – globally it is the 4th most common female cancer and the 2nd most common in the developing world. Improved adoption of screening and vaccination practices are on their way to changing this picture. Since HPV also causes certain types of head and neck cancers in both men and women, HPV vaccines may play an even larger role in cancer prevention in the future.

An important note about cervical cancer: Recent work has shown that both the incidence and mortality rates and the disparities between these outcomes for black and white women are higher than had been previously estimated, particularly for older women, due to the inclusion of women who had had hysterectomies – which generally include removal of the cervix – in the denominator. There is still much work to be done, but the type of tools available for cervical cancer prevention and early detection would be a dream to researchers in other cancer fields!

Hepatocellular carcinoma (HCC) – the most common type of liver cancer – is generally the result of chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV); a 2006 study led by the CDC estimated that 78% of cases worldwide can be attributed to these two viruses, which can also lead to a variety of other problems such as cirrhosis. Over the past couple of decades, the incidence of HCC has been increasing in the US, with approximately half of the extra cases between 1975 and 2007 being due to the increase of older individuals with chronic HCV. HCV was only discovered in 1989 and screening of donated blood and organs for this virus only became available in 1992. Since infected blood was a common source for HCV transmission before that time, the CDC recommends that all adults born between 1945 and 1965 be tested for HCV regardless of other risk factors, given that those individuals are five times as likely to be infected compared to other adults and an estimated 45%-85% of HCV-positive individuals are not aware of their status. A number of highly effective treatments for HCV now exist; the primary challenge right now is the high price of the drugs, which often leads to their use being limited to a subset of infected individuals, such as those who already have advanced liver disease.

The situation is somewhat simpler for HBV compared to HCV, as an effective vaccine exists, which is now part of the standard childhood vaccine schedule recommended by the CDC. Consequently the incidence of HCC can be expected to have a substantial drop over the next few decades. I mentioned in Part 1 of this series that I would not discuss the prevention of infectious diseases via vaccination in this series. When talking about cancer prevention though, I could not help but highlight the astounding fact that yes, there are vaccines against specific cancers!

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Jan 10 2017

An injection of optimism into biomedical research – Part 3: From deadly to chronic

by at 11:09 am

The first two parts of my Injection of Optimism into Biomedical Research series can be found here and here.

This part concerns a disease that was once considered deadly and is now considered generally chronic, Addision’s disease. Though somewhat obscure, this disease has affected many, including several noteworthy individuals. A more recent example of the deadly to chronic improvement process is HIV/AIDS, as increasing evidence is accumulating that the life expectancy for infected individuals in the developed world is approaching that of uninfected individuals – for example, see here and here.

Addison’s disease, first discovered in 1849, refers to reduced levels of adrenal hormones – such as cortisol – due to damage of the adrenal glands, usually of autoimmune origin, but also possibly due to a variety of other ailments such as tuberculosis and cancer. It is estimated to affect slightly more than 1 in 10,000 individuals. It can lead to low blood pressure, fatigue, weakness, and pain, with loss of consciousness and death possibly occurring during the severe “adrenal crises.” Before the introduction of glucocorticoid replacement therapy in 1938, this disease had a 2 year mortality rate of 80% and a 5 year mortality rate of 100% from the time of diagnosis. After the synthesis of hydrocortisone in the late 1940s, outcomes truly started turning around, although morbidity and mortality are still higher than in the general population, partly due to the side effects of chronic glucocorticoid use.

As an example of how the course of this once deadly disease was changed, consider two famous sufferers: Elizabeth Catez, a young French Carmelite nun and mystic, recently canonized as Saint Elizabeth of the Trinity, and President John F. Kennedy. Elizabeth died in 1906 at the age of 26 after being diagnosed with Addison’s three years prior. Her experience with the disease, especially the later stages, was so excruciating that it led her to develop a “mystical theology of suffering” and to write that Christ “wishes me to be the surrogate human being in whom he can suffer again for the glory of the Father and the salvation of the Church. This thought makes me so happy.”

The improvements made in disease management in the decades after Elizabeth’s death enabled JFK to keep his disease under control via the use of glucocorticoid treatment. There was much speculation during his life and his physicians always failed to either confirm or deny that he suffered from Addison’s disease. In 1967, after the president’s tragic 1963 assassination, Dr. John Nichols of the University of Kansas Medical Center provided evidence for the conclusion that JFK not only probably suffered from Addison’s, but had in fact also been case No. 3 in a 1955 study on the management of Addison’s disease during surgery. This was confirmed in 1992 when JAMA was able to establish this on the record with both hospital officials and the lead author of the 1955 paper.

Current treatment for Addison’s still relies on replacing the missing hormones, for example by substituting cortisol by hydrocortisone, prednisone, or dexamethasone, along with possible dietary interventions and the management of potential side effects of corticosteroid treatment, such as osteoporosis. Adrenal crises require immediate intervention and often involve giving the hormones as injections. Guidelines also exist for managing specific problems, such as surgery, illness or injury, and pregnancy, enabling those affected to live a much fuller life than was ever possible before.

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Dec 27 2016

An injection of optimism into biomedical research – Part 2: Improved management for two textbook diseases

by at 8:54 pm

This is Part 2 of my Injection of Optimism into Biomedical Research Series.  To read Part 1, click here.

Two diseases which have not (yet) been virtually eliminated – as phenylketonuria and congenital hypothyroidism have – but for which sufferers have seen huge benefits from early diagnosis and improved management are cystic fibrosis (CF) and sickle cell disease (SCD). Both of these diseases are caused by mutations in a single gene and inherited in an autosomal recessive manner. Though rare overall, they are among the most common genetic disorders in the world. As such, they are often “textbook examples” in introductory genetics classes. They are both now included in newborn screening programs in all 50 US states.

CF is present in 1 in between 2.500 and 3,500 births in Caucasians in the US, being the most common life-limiting genetic disorder amongst Caucasians. It leads to damage to multiple organ systems through the buildup of sticky mucus due to an abnormality in a chloride channel. In particular, it can result in severe nutritional and respiratory problems. While no curative treatment exists for this still-devastating disease, improved management has played a huge role in both quality of life and lifespan. This includes dietary recommendations to prevent malnutrition, therapeutic approaches to clear out the airways from thick secretions, and proactive use of antibiotics for treating airway infections. It is difficult to precisely understand the effect of this improved management on life expectancy, as when CF was first recognized as a stand-alone disorder in 1938 it was through autopsies of malnourished infants who had a life expectancy of 6 months. Less severe cases started being identified in the 1950s with the introduction of standardized “sweat tests” which led to comprehensive programs and improved survival. The responsible gene was finally identified in 1989. In the early 1970s the life expectancy for these “milder” cases was only in the teens, increasing to 25 years in 1985 and 37 years in 2008. There is increased hope that targeted gene therapy will provide a curative treatment, and the progress obtained in the last few decades must still not be overlooked.

SCD is a group of disorders which are characterized by hemoglobin – the protein in red blood cells that carries oxygen from the lungs throughout the body and returns carbon dioxide back to the lungs – having an abnormal and stiff shape. This leads to red blood cells (RBCs) which are sickle shaped instead of the usual flexible disc shape. The abnormal RBCs can stick to the vessel walls, leading to a lack of oxygen in surrounding tissues. This can result in severe “pain crises,” as well as anemia, increased susceptibility and impaired response to infections, and progressive organ damage.  SCD is the most common inherited blood disorder in the US and occurs in 1 in 365500 African Americans. The use of screening and other management strategies in early childhood, including penicillin prophylaxis and pneumococcal vaccines have led to an increase in life expectancy from < 20 years in the 1970s to the 30s or 40s since the early 1990s. Adult patients may also be prescribed hydroxyurea, which may reduce the frequency of the pain crises and the need of blood transfusions – this medication was initially approved in 1967 by the FDA to treat cancer and received a new indication for SCD in 1998 and is thus a great example of drug repurposing.

As the sickle cell trait is associated with protection against malaria when the disease-causing allele is present in a single copy, SCD is also very common in sub-Saharan Africa, estimated to affect 3% of all births in some regions. Indeed, it appears to be a major but often ignored cause of early childhood mortality, with some estimates ranging from 50-90% of individuals with SCD dying in early childhood and SCD accounting for 5-16% of under-5 mortality in certain regions. Similarly to CF, there is hope in using modern targeted approaches, including CRISPR, however the impact of improved management has been tremendous and indeed, its adoption in sub-Saharan Africa could substantially lower childhood mortality. Even in the US, there are limitations in terms of access to care for many SCD patients, meaning that improving overall management could improve outcomes even further.

Acknowledgment: Dr. Jacob Corn from UC Berkeley, the senior author of this paper on using CRISPR for SCD, was a keynote speaker at the 2016 ICBI Symposium. I learned a lot about SCD from talking to him, which made it very easy for me to look up the references for the second part of this post.


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Dec 16 2016

An injection of optimism into biomedical research – Part 1: Newborn screening success!

by at 1:03 pm

With headlines questioning whether science is broken, the skyrocketing costs of drug development, the high rates of obesity, and the recent decrease (though by only 0.1 years!) in life expectancy in the US, it can be tough to be an optimist in biomedical research – gloom and doom lurk just about everywhere. This is doubly so for someone like myself who is both an innate and a trained pessimist, what with my training in Biostatistics. However, I have been coming across numerous examples of successes in biomedical research and public health implementation from the past 60 years, and therefore want to share them in a multipart series here – my first foray into blogging – in order to spread cheer and hope in time for the holidays.

Research is hard and the only problems we tackle are those for which no solutions have yet been found. There are reasons why no longer look for cures for smallpox and polio! The prevention of many infectious diseases is well recognized as a huge public health success. I want to shed a bit more light on quieter success stories – There are many other examples which, though not as dramatic, show that science works and for many lesser known diseases that nonetheless affect many people in total, there is less suffering and more hope. I will be focusing on US examples, because these are the ones I am most familiar with, and welcome other examples in the comments.

Newborn screening programs for congenital diseases are valuable public health interventions, currently implemented in every state in the US – though the exact diseases considered are different in each state – and many other countries around the world via a blood test performed shortly after birth. In case of a positive result for one of the screened diseases, follow-up testing is performed to confirm the presence of the disease. The “poster diseases” for screening are phenylketonuria (PKU) – a recessive disease affecting 1 in 13,000 births – and congenital hypothyroidism (CH) – affecting 1 in 4000 births – for which screening has existed since the 1960s, respectively 1970s. In the absence of management, they both generally result in severe intellectual disabilities along with other potential health issues. The impact of these diseases can now be functionally eliminated via, respectively, a restricted diet, and a hormone supplement, both of which must be started shortly after birth. To give an idea of the human cost, consider the writer Pearl Buck, a novelist who won the Pulitzer prize in 1932 and became the first American woman to win the Nobel Prize for Literature in 1938. Her daughter Carol, born in 1920, had PKU and was institutionalized for most of her life. Part of the reason why she wrote her famous novel “The Good Earth” was to help pay for her daughter’s care. She would also write to her friend Polly Small “I would gladly have written nothing if I could have just an average child in Carol. Average children seem such a wonderful joy to me – I wouldn’t ask for a clever, bright child if I could have had her just average.” Buck would later publish the book “The Child Who Never Grew” in 1950, which is considered one of the first books to openly discuss intellectual disability.

Newborn screening panels are actively evolving, with a Recommended Uniform Screening Panel developed by the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) of the Department of Health and Human Services currently encompassing 34 core conditions. In general, diseases are included only if a treatment or management plan is expected to substantially alter the disease course if started before symptoms appear – this can be a difficult evidence-based medicine question and as such there is not always complete agreement. Other biomedical and ethical concerns – also see here and here – including issues such as:

  • Does the screening test have good performance in terms of false positives and false negatives? What are the costs of a false positive?
  • Should screening be performed for diseases without treatment or for carrier status so that families could be informed of risk to future pregnancies or be prepared for caring for a special-needs child?

While more work needs to be done in this area (I wouldn’t be a researcher if I didn’t end on this note), it is important to keep in mind that many children are already being substantially helped by this screening. In 2014, 3,988,076 babies were born in the US, which means that approximately 1,300 lives were fundamentally transformed by CH and PKU screening alone.


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Jan 15 2015

Empowering Researchers in NGS Data Analysis on the Cloud

by at 5:17 pm

Next generation sequencing (NGS) has grown exponentially since 2007 due to faster, more accurate and affordable sequencing. The potential of NGS is now being tapped in a wide variety of applications including re-sequencing, functional genomics, translational research, and clinical genomics enabling scientists to find new insights in the genome, transcriptome, epigenome and microbiome. These technologies produce massive amounts of data, and their processing and analysis is non-trivial; requiring a powerful computational infrastructure, high quality bioinformatics software, and skilled personnel to operate the tools.

Cloud computing has been synonymous with NGS data processing, since it leverages virtual technology to provide computational resources to users and helps better utilize resources. Its shared computing environment and pay-as-you-go storage can greatly benefit geographically dispersed teams working on the same data.

As we move into this new era of big data, many basic scientists’ and genomic core labs currently rely on third party vendors or bioinformaticians to help with the processing and handling of this big data. Many researchers, who prefer to do the processing on their own, are having to learn how to run command line tools; and like learning any new language, this can pose many challenges, not to mention time consuming. There are many commercial systems that offer solutions through user interfaces including DNA Nexus, Maverix Biomics, Seven Bridges and others. The Innovation Center for Biomedical informatics (ICBI) at Georgetown faced this challenge as well a few years ago; at that time we explored various cloud based solutions, and found the commercial options to be too expensive for an academic center like us to adopt. We hence looked for other options that offered a practical solution to the data management and analysis challenge of NGS data, and found the “Globus Genomics” to be a solution that can save significant time and cost.

We chose the “Globus Genomics” system for a case study due to its scalability, availability of tools, and user-friendliness at an affordable cost. The Globus Genomics system was developed at the Computation Institute, University of Chicago. ICBI collaborated with the Globus Genomics team on a pilot project to develop and test several NGS workflows and have summarized our experiences from the case study in a recently published paper.

The “Globus Genomics” system simplifies terabyte scale data handling and provides advanced tools for NGS data analysis on the cloud. It offers users the capability to process and transfer data easily, reliably and quickly to address end-to-end NGS analysis requirements. The system is built on Amazon’s cloud computing infrastructure and takes advantage of elastic scaling (i.e., increasing and decreasing compute capacity in response to changing demand) of compute resources to run multiple workflows in parallel to help meet the scale-out analysis needs of modern translational genomics research. It is offered as a service that eliminates the need to install and maintain the software, and allows users to run high performance compute (HPC) workflows on the cloud through graphical interfaces; so users don’t have to worry about any operating complexities.

In the case study, we presented three NGS workflows to illustrate the data management and sharing capabilities of the Globus Genomics system. The NGS workflows were for whole genome (WGS), whole exome (WES) and whole transcriptome (RNA-seq) sequencing data. The workflows involved medium scale data presented through the Globus Genomics architecture; providing a fast and scalable solution for pre-processing, analysis, and sharing of large NGS data sets typical for translational genomics projects. The paper also provided guidance to the users of NGS analysis software on how to address the scalability and reproducibility issues with the existing NGS pipelines when dealing with large volumes of data.

The Globus Genomics system allowed efficient data transfer of large number of samples as a batch; and was able to process 21 RNA-seq samples in parallel (average input size 13.5 GB each paired-end set compressed) in about 20-22 hours generating about 3.2 TB of data. The system also processed 78 WES samples (average input size 5.5 GB each paired-end set compressed) and completed execution on about 12 hours and generated about 3.1 TB of data. This will hopefully allow users to roughly predict the time required to complete processing of raw data given the workflow and size of data. The variant calls or the gene/isoform expression data output from the workflows can be exported from the Globus system and further analyzed at the level of gene, pathways and biological processes relevant to disease outcome.

At the end of the case study, we found the system to be user friendly; we believe its user-interface is suitable for scientists who don’t have programming experience. The system is especially suited for genomics cores that need to process increasing amount of NGS data in a short amount of time, and have to share the processed results with their respective clients.

We hope that the Globus Genomics system and our case study will empower genetic researchers to be able to re-use well known publicly available pipelines or build their own and perform rapid analysis of terabyte scale NGS data using just a web browser in a fully automated manner, with no software installation. The power is now in your hands!

Our case study has enabled an implementation of the Globus Genomics system at the Genomics shared resource at Georgetown. This six-month pilot project that will start beginning of 2015 is a big step for the Georgetown community, and will allow for end-to-end processing of NGS data in-house.

ICBI has come a long way in its NGS data processing and analysis capabilities. Apart from WGS, WES and RNASeq pipelines inside the Globus Genomics system, we also have in-house command line pipelines that have been used in G-DOC Plus, and are continuing our efforts to improve our standing in the NGS community. If you are interested in partnering with us, feel free to contact us at:

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May 16 2014

Highlights from TCGA 3rd Annual Symposium

by at 4:54 pm

The Cancer Genome Atlas’ 3rd annual scientific symposium – a report

Earlier this month, I had the opportunity to attend the 3rd annual TCGA symposium at NIH, Bethesda. The TCGA symposium is an open scientific meeting that invites all scientists, who use or wish to use TCGA data, to share and discuss their novel research findings using this data. Although a frequent user of TCGA data, this was my first visit to the symposium and I was excited to see so many other researchers using these datasets to create new knowledge in cancer research. Here I have highlighted a few talks from the symposium.

Dr. Christopher C. Benz and team studied mutations across 12 different cancer types and found P1K3CA occurring in 8 types of cancer. Their analysis showed that breast and kidney cancers favor kinase domain mutations to enhance PI3K catalytic activity and drive cell proliferation, while lung and hand-and-neck squamous cancers favor helical domain mutations to preferentially enhance their malignant cell motility. It was interesting to see how different pathways are affected based on the domain of mutation, and such insights could help understand these mechanisms better.

Samir B. Amin and team profiled long intergenic non-coding RNA (lincRNA) interactions in cancer. The results of profiling show that cancer samples could be stratified/clustered according to cancer type and or cancer stage based on lincRNA expression data.

Another interesting talk was by Dr. Rehan Akbani whose team profiled proteomics data across multiple cancer types using reverse phase protein arrays (RPPA) to analyze more than 3000 patients from 11 TCGA diseases using 181 antibodies that target a panel of known cancer related proteins. Their findings identify several novel and potentially actionable single-tumor and cross-tumor targets and pathways. Their analyses also show that tumor samples demonstrate a much more complex regulation of protein expression than cell lines, most likely due to microenvironment i.e. stroma-tumor interactions and or immune cells – tumor interactions.

Gastric cancer (GC) is the third leading cause of death worldwide, after lung and liver cancers, respectively. Most clinical trials currently recruit patients with stomach cancer and find that all patients do not respond the same way to treatment, implying an underlying heterogeneity in the tumors.  Adam Bass’s group at Dana Farber Cancer Institute did a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas. Using a cluster of clusters and iCluster methods, they have separated GC into four subtypes:

  1. Tumors positive for Epstein-Barr virus – displaying recurrent PIK3CA mutations and extreme DNA hypermethylation.
  2. Microsatellite unstable tumors – showing elevated mutation rates, including mutations of genes encoding targetable oncogenic signaling proteins.
  3. Genomically stable tumors – enriched for the diffuse histologic variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins.
  4. Tumors with chromosomal instability – showing marked aneuploidy and focal amplification of receptor tyrosine kinases.

They also found that tumor characteristics vary based on the tumor site in the stomach – tumors found in the middle of the stomach have more EBV positive and have strong methylation differences. Here’s hoping that understanding these tumor subtypes in GC will help develop treatments specific to each subtype and eventually improve gastric cancer survival in the future.

Even though the TCGA data analysis is synonymous with integrative analyses on multi-omics data, it was interesting to see in-depth analyses of single data types – including associations with viral DNA and yeast models; in-depth analysis of splicing, mRNA splicing mutations and copy number aberrations respectively. The TCGA data collection has not only compiled multi-omics data for various cancer types, but also imaging and pathology images for many samples that could be used for validation of results from ‘omics’ analyses.

Like a kid in a candy show, I was most surprised and excited to see a number of online portals and freely available software and tools showcased in the posters that take advantage of the TCGA big data collection. Some of them are highlighted below.

Online tools/portals:

  • CRAVAT 3.0 – predicts the functional effect of variant on their translated protein, predicts whether the submitted variants are cancer drivers or not.
  • MAGI – For mutation annotation and gene interpretation
  • SpliceSeq – Allows users to interactively explore splicing variation across TCGA tumor types
  • TCGA Compass – Allows users to explore clinical data, methylation, miRNA and mRNA seq data from TCGA

Online resources:

Downloadable tools from Github/R:

  • THetA – Program for tumor Heterogeneity Analysis
  • ABRA – Tool for improved indel detection
  • Hotnet2 algorithm – Identifies significantly mutated sub-networks in a PPI network
  • Switch plus – An R package in the making that uses segment copy number data on various cancer types to show differences in human and mouse models

It is energizing to see the collective efforts being taken to make this data collection more readable and parsable. I’m sure the biomedical informatics community will be more than pleased to know that it is becoming easier to explore and find what one is looking for within the TCGA data collection.

Comments by Krithika Bhuvaneshwar with contributions by Dr. Yuriy Gusev

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