The value in NGS: Turning raw data into insights
06/05/2014 // Feature // Text: Richard Johnson // Photo: Andreas Fechner // Video Editing: Jan-David Bürger

Shortly after birth, a baby struggles. The doctor labels the symptoms as failure to thrive or developmental delay, but physical examinations do not reveal any known disease. When initial treatments do not help, the child and parents are sent to a specialist – and embark on what will turn into a “diagnostic odyssey.”

The first specialist orders tests seeking to discover the cause, to no avail, and tries a new therapeutic regime, but that, too, fails. On to the next specialist, who takes a new approach but with similar results. Like thousands of other babies born each year, this child suffers from a rare congenital disorder. In each case the medical mystery can elude answers and the family’s frustrating odyssey can drag on for years.

Only now is this pattern beginning to change, giving way to a new era: genomic medicine.

Advances in understanding of molecular biology – and new sequencing technologies – are transforming healthcare. In the near future, doctors are expected to routinely order laboratories to analyze a patient’s genome or the relevant parts, identify suspicious variations, and compare the red flags against a world of genomic knowledge. The promised result will be faster, more precise diagnosis – and improving outcomes for patients.

QIAGEN technologies are playing a leading role in this transformational change in healthcare.

Genomic medicine: the promise

That child with a rare disease finds no definitive answers – until caregivers look into her genome. While the physical manifestations of her disorder may look like one syndrome or another, they don’t entirely match up. But searching her genetic material holds the promise of identifying specific markers that, even though rare or unique, may be causing her ill health – and may suggest the best treatment.

Doctors already are accustomed to ordering targeted genetic tests to guide treatment. Molecular testing is benefiting millions of patients with cancers including colorectal, lung, breast, melanoma, leukemia and lymphoma; certain cardiovascular diseases; hepatitis; HIV; and some neurological disorders. Patients also have begun to request genomic testing for predictive medicine, for example to identify genetic predisposition to especially aggressive cancers and evaluate preventive measures.

The recent emergence of NGS technologies makes it possible to generate large volumes of biological data quickly and economically, paving the way for many new applications in clinical research and diagnostics.

The trend of genomic medicine is accelerating as next-generation sequencing (NGS) moves from research labs into clinical care. The recent emergence of NGS makes it possible to explore a patient’s DNA and other genetic material quickly and economically, gathering data ranging from individual gene mutations to comparisons of whole genomes. And the applications are just beginning to take hold.

“Rare diseases are one of the areas where the uptake of NGS has been dramatic, because there are several well-documented cases where sequencing of exomes (parts of a person’s DNA carrying genetic information) has turned up remarkable findings that either established what’s wrong or, in some cases, even identified a therapy that would alleviate the symptoms. That’s pretty powerful,” says Dr. Elaine Mardis, Co-director of The Genome Institute at Washington University in St. Louis.

“In cancer, it’s a rapidly changing landscape,” she says. “We’re getting away from just applying broad-spectrum cytotoxic chemotherapies. We’re beginning to understand through lots of discovery sequencing that there are genes that are often mutated in cancer, and if there’s not a drug already available to target those mutations, there probably soon will be.”

Because variations in genes and their interactions with the body influence many diseases, detecting genomic differences can guide physicians to the best treatment for each patient – and this kind of personalized healthcare promises to transform the practice of medicine in our lifetimes.

The challenge: ‘Big Data’

Moving genomic medicine into routine clinical care, however, isn’t an easy task. The amount of biological data being generated through NGS and other technologies already is vast, the information is highly complex, and the task of analyzing the data to determine the best course of action for patients is a huge challenge.

“The data deluge from next-generation sequencing is of little value without analysis and interpretation. Either you have to spend a lot of money for programmers to sort it all out – or you buy software to do the job. If you don’t have bioinformatics, none of this happens."
Dr. Elaine Mardis, The Genome Institute of Washington University, St. Louis, U.S.

Experts say more genomic information was generated during 2013 than in all of mankind’s previous history – and it is growing exponentially. The world has now collected nearly one billion billion “bases,” or individual items of genomic data, one study indicates. In cancer alone, roughly 5,000 associations between specific gene variants and different forms of cancer have been published in the literature.

The challenge for physicians and clinical laboratories is how to make use of this flood of information.

“The data deluge from next-generation sequencing is of little value without analysis and interpretation. Either you have to spend a lot of money for programmers to sort it all out – or you buy software to do the job. If you don’t have bioinformatics, none of this happens,” Dr. Mardis says.

The Genome Institute, which played a pioneering role in the Human Genome Project and remains one of the world’s leading genome centers has been Dr. Mardis’ place of work for 20 years. A Ph.D. in chemistry and biochemistry, she works in the forefront of NGS research – and knows the data deluge first-hand.

Until 2008 the Institute’s computers were on the fifth floor of its building on Washington University’s medical school campus. But when Institute scientists set out to sequence the first whole human genome, staff members began to fear the growing weight of servers and disc arrays handling the data might literally collapse from the fifth floor down into the fourth floor – as it would happen, into Dr. Mardis’ office.

Of course, the research had to go on, so the Institute razed an adjacent building and built a state-of-the-art data center in 2008. Two years ago, the center was revamped to double its capacity. Now, seven long rows of servers and disc arrays in a secure 13,000-square foot space process and store about 20 petabytes of genomic data (1 petabyte is 1 million billion bytes, or individual units of data), a total capacity that is equivalent to the storage on more than four million DVDs.

In the healthcare setting, most clinical laboratories do not have the resources to deal with these quantities of data. Dr. Mardis is one of several top genomic experts advising QIAGEN on the coming transition of bioinformatics to clinical use.

The clinical community is aware of the challenge. A recent survey of more than 900 sequencing users cited analysis of complex data as the No.1 bottleneck inhibiting clinical adoption of NGS.

“It’s sort of a perfect storm,” Dr. Mardis says. “We’ve got new targeted drugs, a new understanding of many of the genes that are mutated or otherwise altered in cancer that may respond to these drugs, and the ability to do rapid, very precise testing using DNA or RNA. The sequencing is straightforward. Getting the data is very easy. Data analysis is the hardest part, the bioinformatics. And the bigger the data set, the harder the analysis.”

Solutions for clinical workflows

With information driving the healthcare of the future, the market for tools to handle the growing volume of data is expanding rapidly – and QIAGEN has taken strategic action to achieve global leadership in this emerging sector by acquiring two respected bioinformatics companies, Ingenuity Systems and CLC bio.

“We view bioinformatics as a major need for healthcare – and a major growth driver for QIAGEN. Our vision is to deliver workflows for clinical research and diagnostics that provide evidence-based clinical decision support, enabling laboratories to transform genomic information into actionable insights”, says Dr. Dietrich Hauffe, Senior Vice President and QIAGEN’s Head of the Life Science Business Area.

QIAGEN already is helping a broad range of customers turn data into insights. Full-year 2013 adjusted sales of Ingenuity and CLC software were more than $30 million, growing at strong double-digit rates. “We are integrating these industry-leading tools with our innovative Sample & Assay Technologies to deliver complete and seamless workflows – a major value driver for our emerging presence in the NGS market”, explains Dr. Hauffe.

These bioinformatics solutions focus on two steps in transforming data into insights: analysis and interpretation. Analysis involves sorting and focusing on the right genomic data, while interpretation goes to the next step of comparing results with other medical knowledge to come to conclusions.

“When the data comes off the sequencer, a lot of work has to be done to focus on the important parts of the information. That’s what CLC analysis software does, to get from terabytes of data down to a short list, maybe five things the scientist or laboratory needs to focus on,” says Thomas Knudsen, Head of QIAGEN Aarhus and former CEO of CLC bio, the Danish bioinformatics firm QIAGEN acquired in 2013..

Ingenuity bioinformatics software then comes into play. Based on a vast database linking information from all of the clinical sources in the world’s medical and scientific literature, the system performs the interpretation to apply what the sequencer has found to identifying and profiling a specific disease.

Analysis to cut through complexity

As start-up entrepreneurs in 2004, Thomas and Bjarne Knudsen set out to solve the problem of analyzing sequencing data by developing software “to create the Microsoft Office of molecular biology”, as the both brothers put it. The resulting company – CLC bio – focused on easy-to-use, standardized software for genomic labs.

“When the data comes off the sequencer, a lot of work has to be done to focus on the important parts of the information. That’s what our software does, to get from terabytes of data down to a short list." 
Thomas Knudsen, QIAGEN Aarhus, Denmark

The timing was good: Next-generation sequencing emerged from 2005 to 2008 and the amount of data generated began to grow exponentially. CLC quickly became the leading provider of commercial data analysis solutions and workbenches for NGS, serving leading institutions and top pharmaceutical companies worldwide. In 2013, QIAGEN acquired CLC bio and began integrating these solutions into the company’s existing sample-to-insight workflows.

CLC software applies algorithms to take data from sequencers through a series of stages of analysis, whether in healthcare or other research fields. Top products are CLC Genomics Workbench, a user-friendly package for analyzing, comparing and visualizing NGS data; and CLC Genomics Server, a flexible enterprise-level infrastructure and analysis backbone for NGS data analysis. In 2014, QIAGEN has also launched CLC Cancer Research Workbench, the world's first comprehensive, user-friendly and customizable bioinformatics solution focused on cancer.

Interpretation to guide actions

When a group of Stanford University graduate students formed Ingenuity Systems to tackle bioinformatics, their focus was on interpretation – connecting genomic results with the universe of scientific and medical knowledge to support decision-making. Ingenuity introduced a scalable database for matching clinical and genomic data in 2003 and now serves thousands of leading research institutions.

“The Ingenuity Knowledge Base is the starting point,” says Ingenuity co-founder Dr. Dan Richards, now Vice President of Biomedical Informatics, QIAGEN Silicon Valley. “We are curating all of the available biomedical literature worldwide, including the gene variants implicated in human disease and thousands of disease models, with rules-based structuring of the data. Manually curating all literature is a huge job, and there’s so much coming out that a lab director can’t possibly keep up.”

The software that taps into the Knowledge Base enables users to accurately interpret biological data, connecting gene variants to specific diseases to guide scientific experiments and treatment decisions.

QIAGEN acquired Ingenuity in 2013. While continuing to empower research – for example, integrating the GeneGlobe online portal for disease pathway analysis with the Ingenuity Knowledge Base – the company is also applying Ingenuity software to the growing use of NGS in clinical research and diagnostics.

In 2014 QIAGEN will offer expanded beta testing of Ingenuity Clinical, a web-based solution to deliver faster, easier-to-use and high-confidence clinical interpretation and reporting of insights from NGS-based tests. Currently, more than 20 clinical laboratories are involved in the development of this exciting new product, the first bioinformatics solution specifically designed to address challenges of scale, speed and decision support that healthcare laboratories face in the adoption of NGS.

"You can see the results, sometimes in dramatic ways, as the diagnosis can change the course of their disease and their life. So it's pretty exciting."
Dr. Elaine Mardis, The Genome Institute at Washington University, St. Louis, U.S.

“As we take bioinformatics into healthcare, Ingenuity Clinical will provide the ‘review of evidence’ that labs cannot perform because of the mass of data out there,” Dr. Richards said in regards to supporting physician’s decisions. “It’s about better diagnosis and better treatment decisions – earlier diagnosis of the precise disease that a patient is suffering from and, especially in the case of cancer, what drugs may or may not be effective in treating that patient.”

Insights for the future of medicine

For many cancers, rare disorders and a growing number of other diseases, bioinformatics can deliver not just data, but actionable insights to enhance outcomes for patients and healthcare providers. 

QIAGEN is well positioned to lead the coming wave of genomic medicine, which fits the company’s mission of making improvements in life possible. By linking individual genetic variations to a world of clinical experience, the bioinformatics software QIAGEN is commercializing will offer doctors and patients conclusions on diagnosis, prognosis and potential treatments – personalized healthcare. 

Genomic medicine demands effective, easy-to-use tools for analysis and interpretation, integrated into the higher-throughput, standardized workflows of healthcare laboratories. Already, research institutions like Washington University have demonstrated the potential for benefiting patients.

“With the right combination of tests – and the right data interpretation – you can actually come up with the right answers for these patients,” says Dr. Mardis. “You can see the results, sometimes in dramatic ways, as the diagnosis can change the course of their disease and their life. So it’s pretty exciting.”

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