Pioneering Rare Disease Diagnostics in China—An Interview with Fudan Children’s Hospital Clinicians at ASHG17

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The first year of WuXi NextCODE’s partnership with Fudan Children’s Hospital has delivered 11,000 clinical reports and a diagnosis rate of 33%, matching the throughput and success rate of the world’s leading laboratories.

One year ago, WuXi NextCODE (WXNC) and the Children’s Hospital of Fudan University (CHFU) launched a joint laboratory to put the global gold standard in sequence-based rare disease diagnostics at the service of patients in China. In the first year of that joint effort, the partnership delivered some 11,000 clinical reports—with more than 1,000 new reports now being generated each month—and a diagnosis rate of 33%. This matches the throughput and success rate of the leading laboratories in the world.

Dr Lin Yang of CHFU presented a summary of this remarkable progress at WXNC’s breakfast session on rare disease at the ASHG17 meeting held recently in Orlando. Afterwards, WXNC’s global communications lead, Edward Farmer, sat down to talk about this collaboration and what it means for patients, with Associate Professor and Laboratory Director Dr. Huijin Wang from the clinical team; Dr. Bing Bing Wu, director of the medical diagnostics laboratory; and Assistant Professor Dr Xinran Dong, who leads the bioinformatics team, as well as WXNC Chief Scientific Officer, Jeff Gulcher.

Edward Farmer: It’s a real pleasure to have with us our colleagues from Fudan and to be able to hear about this collaboration in rare disease diagnostics and genome-based testing in the neonatal unit. To start us off, Jeff, can you tell us how this partnership came about and how you see its importance to rare disease diagnostics in China and worldwide?

Jeff Gulcher: It’s been a fantastic partnership that started about two-and-a-half years ago, when we began discussing the possibility of creating a joint laboratory. The aim was to take advantage of WXNC’s technology and sequencing expertise together with Fudan’s expertise, both on the medical side and the interpretation side. The goal was to enable whole exome or medical exome sequencing of very sick children. In parallel, we decided to see if sequencing is useful in the neonatal ICU setting.

Through this partnership, we’ve now sequenced a large number of children and worked together to make diagnoses. Our medical genetics teams have worked closely together to interpret these cases, and in about one-third of the cases, we’ve been able to deliver diagnoses that were not suspected by the treating physician. In many cases, that has led to different treatments, with better outcomes for the children.

Together, we have now sequenced over 11,000 pediatric cases, including some 2,500 neonatal ICU cases, and we are very pleased with this partnership.

Edward Farmer: We have with us several senior people from Fudan. Huijin, let’s begin with you, as director of our joint laboratory. Can you share with us your impressions of this partnership so far and some of your results?

Huijin Wang: We have had a very good experience with this collaboration. We have many cases and, each week, we have a case meeting with the Cambridge WXNC team and we discuss the data and variant curation for the more difficult ones. The results have been impactful for the patients. In many cases, we can deliver a clinical diagnosis, and some of these offer real treatment options.

I remember one case that first came to the neurological clinic with seizures and hypoglycemia. This child had presented with recurrent hypoglycemia at a very early age and was in the NICU. We sequenced the family and found a recessive variant in the FBP1 gene, which the patient had inherited from both parents.

After this diagnosis, the doctor was able to discuss the problem with the family and advise them on how to limit the child’s diet to avoid hypoglycemia. The child is now doing well and no longer experiencing hypoglycemic episodes. And his family came back later and planned to have another child, and we referred them for prenatal diagnosis, and they were able to have another child who is healthy. This was a very successful case and is the sort of story that encourages us and shows us the value of the work we are doing.

Edward Farmer: That is an encouraging result. Lin, as an attending physician, how do you see the impact of introducing this technology into China at scale?

Lin Yang: We have more and more children at our hospital with birth defects or congenital malformations, so we really want to get a diagnosis and whatever possible treatment for them, including new treatments when available.

The collaboration between our hospital and WXNC starts with us deciding whether the case is likely to be the result of a genetic disorder. If it is, we do pre-testing counseling for the whole family before taking DNA samples. We then use WXNC’s capabilities for the sequencing and analysis of the results. Finally, we need to interpret the sequencing results and report them to the parents. It is often very difficult for parents to understand “what is a gene,” “what is a mutation,” “what is the disorder,” and “how can your child benefit from a molecular diagnosis?” So that is a critical part of our work.

But more and more patients are choosing molecular diagnosis and, if they get a correct diagnosis early, they may find a useful and more targeted treatment earlier.

In the NICU, we have some patients that have immune deficiency disorders. These can be very serious conditions, as the children suffer from repeated infections. It is very hard on the whole family. For such cases, if you have a specific diagnosis, there is often a cure. This is very good news for these families in the NICU, as they now have the possibility of getting a molecular diagnosis and then a treatment.

Edward Farmer: Are there any specific examples or cases that you can share with us?

Lin Yang: I had a newborn patient who had very low platelet counts and petachiae (red spots from small bleeds) on his face and body. We found that he has a mutation in the WAS gene, inherited from his mother’s side of the family, which means that his bone marrow is not producing enough platelets. But with a hematopoietic cell transplantation [HCT, which can include bone marrow] from a relative or closely matched donor, he has every chance of being cured of the disease and becoming a healthy boy. He is now waiting for a matched donor.

Edward Farmer: Huijin, you’ve done amazing work so far, and I know you are only getting started, but I wonder what proportion of the patients you see are able to benefit from the work of your lab and the collaboration with WXNC?

Huijin Wang: Currently, we are delivering a diagnosis to about 30% of patients, and we are able to recommend specific clinical treatment for about 20% of our patients.

And very often, we can give some guidance, if not a cure. Sometimes just knowing exactly what the diagnosis is gives patients peace of mind and new options. For example, many can go to a specialty clinic. But just knowing the diagnosis is often a comfort.

There is also a big need, and as a national center of excellence our diagnostics can help people across the country. About 80% of our patients come from outside of Shanghai, so with a diagnosis, they can go back to where they live and take some action there.

Lin Yang: There is also a difference among different diseases. I think we are now able to provide actionable results to about 50% of patients with neuromuscular disorders, and for respiratory maybe something less than that. For NICU, it’s maybe 15% that get a diagnosis, but we want to boost all of these.

We can benefit many more patients with this technology. In our hospital and with the WXNC collaboration, we can see an increasing number of patients. But there are a lot of undiagnosed patients, and in many places, there is not yet access to molecular diagnostics, so we hope this capability spreads to other parts of the country as well.

Edward Farmer: And Xinran, as we’re talking about building the scale and reach of molecular diagnostics, perhaps you can tell us a bit about how you are dealing with all of this data.

Xinran Dong: We have collected a lot of data. And from my bioinformatics perspective, one of the things that the WXNC collaboration is helping us to do is to make good use of the data, both for our clinical cases and for research.

I see part of my job as helping to build this into one of the biggest databases on rare disease in China and maybe the world. This is going to help patients today and advance the discovery of new genes.

Edward Farmer: Clearly there is no lack of ambition here. I want to thank you all for your time, and we look forward to sharing more stories of our work together.

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From Rare to Common: How Rare Diseases Could Advance Schizophrenia Treatment

Rapidly advancing our understanding of rare diseases is a key area of focus for us at WuXiNextCODE. We believe genomics can both transform our ability to understand and diagnose rare conditions, and that this is going to point us is the direction of developing new treatments. At the same time, there is a growing body of evidence and even approved new therapies that show that an understanding of rare diseases can also shed new light on the genetics of complex diseases, such as heart disease, arthritis, and schizophrenia.

Understanding complex diseases is a mammoth challenge because multiple genes are usually involved as well as environmental factors. It’s particularly hard with neurologic conditions. No animal models can really mimic what happens in people’s brains, and human studies usually only provide hints of the information needed to identify potential treatments.

But rare diseases are often caused by single variants that perturb specific and identifiable biological pathways. That’s why recent genetic studies of rare types of early-onset psychosis have inspired so much interest among researchers studying schizophrenia. This disease affects more than 50 million people worldwide, but early-onset cases are very rare, suggesting they may be extreme manifestations.

A new line of inquiry into this condition emerged after a group of our close collaborators at Boston Children’s Hospital, including a scientist now at WuXi NextCODE, used chromosomal microarray analysis and whole exome sequencing in a six-year-old with profound symptoms of psychosis. They discovered this patient had a variation in the ATP1A3 gene, which was not previously associated with schizophrenic symptoms. The team wondered: was that mutation helping cause his symptoms? Would the same mutation be found in other children with early-onset schizophrenia? Could this new lead point to a biological pathway common to many people, young and old, with these same symptoms?

That would be a real breakthrough, both for this child and potentially for many other people.

The Puzzle of Schizophrenia Genetics

Schizophrenia is one of the most serious and common mental illnesses. It is often very difficult to treat, in part because of available drugs’ side effects. There are already about a dozen anti-psychotics on the market for this condition. Besides causing serious side effects, treatment must also usually be life-long. Doctors often have to try different drugs until they find something that works and which the patient can tolerate. Even then, the patient’s response can change over time.

The genetics of the disease are still not well understood. Studies of families and populations show it is heritable – the more affected close relatives someone has, the more likely that person will develop it. Many families are afflicted by both schizophrenia and bipolar disease, suggesting the two conditions are biologically related.  Both conditions seem to be associated with multiple mutations to possibly dozens of genes. Still, even in identical twins – who share exactly the same mutations – it’s not uncommon for only one twin to be affected.  Clearly, there is something other than genes afoot.

Scientists, notably including our colleagues at deCODE genetics, have put their fingers on a few genes and key pathways. Another large genomic study, with more than 30,000 cases and 100,000 controls, pointed to over 100 potential spots in the genome with mutations associated with schizophrenia. Both have found an association with mutations in a region called MHC (Major Histocompatibility Complex), a result that reinforced a then percolating idea that schizophrenia might be related to immune dysfunction.  And then just this week, Chinese researchers reported a new trove of suggestive genetic factors. But despite these massive gene hunts, we are still far from a complete picture of what genes cause this disease and how.

A Promising New Lead?

As described in the BCH blog Vector, The BCH team who found that ATp1A3 mutation in the six-year-old boy decided to do some more digging. The chromosomal microarray analysis showed that he was missing an entire chunk of DNA – one copy of the chromosomal region 16p13.11.  Next, they searched their database and found several other children with variations in that area.  One had a duplication of the 16p13.11 region, rather than a deletion. She had started experiencing hallucinations at the age of 4.  Those findings prompted the BCH researchers to launch a large-scale study, which has already enrolled at least 50 children with early-onset psychosis and will be able to leverage WuXi NextCODE’s informatics and global knowledgebase to find more cases, at BCH and beyond.

The researchers hope that ultimately their studies will not only help children with early-onset schizophrenia but also point to the biological pathways that cause the more prevalent form of the disease, which usually strikes adolescents and young adults.

Such research will hopefully provide firm leads on novel pathways that can be used to identify new drug targets. There is a tremendous need for new medicines. Most of the antipsychotic drugs we have today were developed back in the 1950s and act on the dopamine and/or serotonin receptors. They don’t improve all of patients’ symptoms, and as noted earlier, they can have serious side effects.

By uncovering new biological pathways, groups like the researchers at BCH, able to leverage massive global genomic data like that we are able to provide, aim to uncover such targets and begin the journey to providing better options for patients with rare and common diseases alike.

If you are attending ASHG this month, join us to hear more about how rare disease studies can inform our understanding of common diseases at two of our “Genomes for Breakfast” events:  Using Population Genomics to Understand Common and Rare Disease (Oct. 18), and Using NGS to Diagnose Rare Disease – Experiences from three continents (Oct. 19).

 

 

 

New Breast Cancer Study Underscores the Need for More Sequencing

Gene sequencing for breast cancer. More than the usual suspects at play.

Ever since actress Angelina Jolie’s highly publicized preventive mastectomy ignited discussion about BRCA 1 and BRCA2, almost everyone has heard about these genes and how they can increase risk of breast cancer.  Some people even refer to them as “the breast cancer genes.” But how genes cause this disease is much more complicated than just through the most well known BRCA mutations, as a recent study in JAMA of Ashkenazi Jewish women has demonstrated. http://jamanetwork.com/journals/jamaoncology/fullarticle/2644652

This intriguing study raises a crucial question: How much sequencing is enough when diagnosing breast cancer in the age of targeted therapies? The number of these therapies keeps growing, as does our knowledge of the links between what drugs work for women with particular mutations. But at what point should we say we have uncovered enough mutations to make a proper diagnosis? And in a field in which we know there’s a lot we don’t know, is there such a thing as enough?

The good thing is that sequencing costs are going down. “It used to be that just testing for a single gene cost several thousand dollars,” says Jim Lund, Director of Tumor Product Development at WuXi NextCODE.  “Now a panel of genes costs that and whole exome sequencing is slightly more.” At the same time, the number of mutations that are discovered and studied is increasing – in the genomes of patients and the genomes of their tumors.

The data here has a message about data itself: in principle, we should be generating as much sequencing data as possible. By generating it, storing it for vast numbers of patients and their healthy relatives, creating more comprehensive databases of all disease-linked variants, and then reanalyzing patient and tumor samples as more is learned, we can improve the risk assessment and the speed and accuracy of diagnosis for patients everywhere. Since we can do this, the question isn’t whether we can afford to do more sequencing, but why anyone would argue that we can afford not to.

The researchers who led the recent JAMA study used multiplex genomic sequencing on breast tumor samples from 1007 patients. They tested for a total of 23 known and candidate genes.  It has been well documented that women of Ashkenazi descent have a higher risk of breast and ovarian cancer, and that is at least in part because of three particular BRCA1 and BRCA2 mutations. These are called founder mutations, because they probably originated among some of the earliest members of this ethnic group, and have been propagated because of a strong history of marriage within the same community.

But the researchers working on this study wanted to know if there were mutations in other genes besides BRCA that made it more likely these particular women would develop breast cancer. The patients were from 12 major cancer centers; had a first diagnosis of invasive breast cancer; self-identified as having Ashkenazi Jewish ancestry; and had all participated in the New York Breast Cancer Study (NYBCS).

Surprisingly, only 104 of the patients were carrying one of the infamous founder alleles. Seven patients had non-founder mutations in BRCA1 or BRCA2, and 31 had mutations in other genes linked to increased risk of breast cancer, including CHEK2. The vast majority of these women carried none of the mutations that are “obvious suspects” for breast cancer. “We do not know why those women got breast cancer,” says Shannon T. Bailey, Associate Director of Cancer Genetics at WuXi NextCODE.

It’s important to note that thousands of different cancer-predisposing mutations have been found in BRCA1 and BRCA2 alone. Every population studied to date includes people with such mutations.  The three founder mutations that have been established as being common among Ashkenazis are estimated to account for about 10% of breast cancers in this group. The rest of BRCA1 and BRCA2 mutations are considered extremely rare under any circumstances.

“If you look at the genes on the panel used in this study, it looks as if they are mostly associated with DNA damage and there are no cell cycle regulating genes included,” says Bailey. “But there are all kinds of mutations that cause breast cancer, even in noncoding regulatory zones.” As a result, even the best designed panel may fall short.

That’s why this study is so important. It tells us that even with founder mutations, family history matters but it doesn’t yet always tell you everything you’d like to know. Of the women with the founder BRCA mutations, only about half had a mother or sister with breast or ovarian cancer.  It’s also already well known that just carrying a BRCA1 or BRCA2 mutation is no guarantee the patient will get cancer. For reasons we don’t yet understand, these mutations raise overall risk, but not everyone who carries one will develop the disease. So while BRCA mutations are important, we need lots more information about other genes too.

The authors of this JAMA report suggest that Ashkenazi patients with breast cancers should have “comprehensive sequencing,” including, perhaps, complete sequencing of BRCA1 and BRCA2 and possibly testing for other breast cancer genes as well.

And what about other patients?  WuXi NextCODE’s Lund points out that even the most highly regarded recommendations for breast cancer testing do not cite specific panels. Those recommendations come from the U.S. Government Task Force [https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing] and the NCCN Clinical Practice Guidelines. Women with a family history will likely get more comprehensive testing, but beyond that it is not clear exactly how to proceed in every case.

At WuXi NextCODE we believe that this is clear evidence pointing to the value of doing more sequencing across all ethnic groups – for healthy individuals, patients, and their tumors, and pushing towards sequencing as standard of care. This would expand our knowledge of the genetic risk factors for breast and other cancers; provide vast new cohorts for research; and deliver the most actionable insights to patients, from risk assessment through diagnosis and then ongoing as new discoveries are made.

All of the participants in this JAMA study consented to have their sequence data used to advance research. They are already helping to do that, and this is just one study of thousands that are now underway and that are helping us to expand our data- and knowledgebases with the ultimate aim of delivering even better outcomes for all people and patients everywhere.

Speeding Diagnosis of Rare Diseases

WuXi NextCODE Claritas

Claritas Genomics combines physician experience with next-generation sequencing and WuXi NextCODE’s analytics to accelerate rare disease diagnosis.

It’s one of the most heartbreaking and frustrating things for parents and pediatricians. When a child presents with a constellation of symptoms that doesn’t point to a known disease, what do you do?

Typically, these kids undergo a battery of tests, some of which will eventually be for single genes suspected to play a role in their health problems. But what if those tests come up negative? That leaves the families and doctors wringing their hands as they wonder what to do next.

That was the case with a patient at Boston Children’s Hospital (BCH). He was a boy who, at six months, wasn’t sitting up, smiling, or doing most of the things babies his age typically do. Instead, he seemed “rigid” to his mom, and then he developed a severe respiratory virus and was hospitalized. He also had repeated seizures and eventually needed a tracheotomy—a tube placed through an incision in his throat to help him breath.

Usually, such kids then begin going through what is known as a “diagnostic odyssey”—a long and arduous journey from doctor to doctor and lab to lab.

BCH doctors are trying a new approach. In 2013, the hospital spun out Claritas Genomics, a specialized genetics diagnostics business that combines the experience of the hospital’s physicians with the power of next-generation sequencing and WuXi NextCODE’s advanced analytics. Timothy Yu, a neurologist and researcher at BCH, helped found Claritas to provide a more holistic approach to rare disease.

WuXi NextCODE’s advanced analytics play a key role in improving the speed and efficiency of such diagnostics. Reading the genome isn’t the major challenge anymore—now the issue is finding the relevant mutations in those three billion base pairs.

The data from a single genome can comprise more than 100 gigabytes, which is enough to fill the hard drive on a good laptop computer. Even the exome, which comprises the parts of the genome that encode proteins, can be 15 gigabytes. To diagnose a rare disease, doctors need to find sequence variations and then scour the research to find out what those actually do. That used to take months to years, and many of the variants were simply classified as being of “unknown significance,” without any further information or the ability to check again as the field of knowledge grew.

WuXi NextCODE’s system has begun to make this a click-and-search task. Our knowledgebase can mine all publicly available global reference datasets simultaneously and in real time to show all there is to know about any given variant and its likely biological impact. By keeping the data in a WuXi NextCODE research database, such as the one BCH is growing every day, our system can also quickly rerun the analysis and provide new information as soon as it becomes known.

Claritas is continually expanding the range of its services. Most recently, the group received conditional approval from the New York Department of Health for three new “region of interest assays” as well as one for mitochondrial DNA. That brings the number of Claritas’s approved tests in that state up to six and means more patients in New York will benefit from this new technology.

Children at BCH with ambiguous diagnoses now regularly undergo a whole exome scan early in their clinical journey. The data is then triaged. It is examined first for the most obvious mutations and then more data is progressively analyzed as necessary. With the consent of parents and security measures for privacy, that data can also become part of research datasets at BCH and other major hospitals around the world, so that the growing data pool can benefit that child and others.

This combination of expertise and technology helped Claritas Genomics find an answer for that baby boy and his family mentioned earlier. Heather Olson, the boy’s treating neurologist, had the boy’s exome scanned through Claritas Genomics, and 130 genetic variations were identified that could have caused one or more of the symptoms. WuXi NextCODE’s system helped narrow that down to only six variants that could have possibly been passed on by the boy’s parents. Olson and Yu finally focused on one, a mutation of the BRAT1 gene, which served as a diagnosis. A paper published by Yu, Olson, and colleagues, which describes this mutation and children affected by it, should help other physicians make this diagnosis more quickly in the future.

Yu presented more on Claritas’s novel platform recently at Boston’s Bio-IT World meeting. He explained how the platform helps doctors to much more quickly and accurately diagnose kids with diseases not previously described.

“Thanks to the speed of the platform, we can get a whole clinical exome completed in as little as two weeks,” he said.

The growing database of genetic variants and their effects also means more patients will get an actual diagnosis, rather than walking away still wondering what could be going on.

The ability to diagnose more cases is a start to unravelling the causes of the estimated 7,000 different rare diseases estimated to exist. And it’s a necessary first step towards developing new therapies for those conditions, too.

Genomics: Forging Patient-Centric Communities

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Genomics has become a foundation for virtual patient-centric communities involving patients, caregivers, clinicians, and researchers worldwide.

In recent years, genomics has become a foundation for virtual patient-centric communities – communities built on the Internet and through social media that:

  • Connect people touched by a disease or disorder; or
  • Reach out to broad populations affected by rare diseases, many of whom are undiagnosed.

These patient-centric communities are dedicated to sharing information and providing support in order to break down the barriers of isolation and uncertainty that can compromise care and adversely affect quality of life for patients and their families.  As we learn more about the genetic variations that contribute to diverse conditions, virtual communities that are fueled by genomics contribute an ever-expanding resource.

Virtual communities have greatly affected patients and caregivers worldwide, and the relationships forged through genomics are essential to clinicians and researchers as well.  Genomics not only serves to link patients to each other but also to connect those patients to research initiatives that use genetic sequencing to diagnose conditions and guide treatment, thus improving patient outcomes today while influencing research for better therapies tomorrow.

RareConnect, for example, is an online platform that connects patients, caregivers, clinicians, and researchers in more than eighty disease-specific communities.  Another leader in this arena is PatientsLikeMe, which has activities that encompass more than 400,000 members with over 2,500 conditions.  Many diseases and conditions are identified by genetic abnormalities or characteristics.  Participants in RareConnect, PatientsLikeMe, and similar sites are drawn in part to the ways in which genomics could contribute to an accurate diagnosis, a novel treatment, and ultimately a cure.

The use of genomics to build communities has been especially important for rare diseases.  For patients and caregivers affected by the rarest of rare diseases – the disorders so rare that only a handful of known cases exist worldwide – the transformative role of genomics is that much more powerful.

An excellent article in The Atlantic tells the story of one young woman whose experience illustrates this phenomenon.  A genomic study identified the genetic mutation that underlies Lilly Grossman’s movement disorder.  The information provided by genomics has enabled the formation of a virtual community.

Lilly’s case has acted as a magnet for others with the same mutation. Families with the same problem read about Lilly’s case and contacted the Grossmans. Doctors and geneticists looked at their own patients and saw a new explanation behind puzzling symptoms. Before, there were isolated pockets of people around the world, dealing with their own problems, alone for all they knew. Now, there’s a community.

The connections forged through genomics are essential to patients, often children, and their caregivers, often families.  Genomics can provide the vital link, the piece of information that identifies individuals with similar experiences – the community of people who understand.  Patient-centric communities are one way in which the increasing availability of cost-effective genetic sequencing is transforming patient experiences, shortening diagnostic odysseys, and improving clinical care.

Many such communities are also critical for advocacy and fundraising.  Parent Project Muscular Dystrophy (PPMD), for instance, has worked effectively to promote Duchenne muscular dystrophy research and speed the discovery of potential treatments. PPMD has demonstrated how parents and caregivers can effect meaningful change, raising both awareness and financial resources – and even being a leading voice in support of FDA approval of therapeutics.

The intersection of genomics and social media increasingly drives progress, too. The Charlotte & Gwyneth Gray Foundation, for example, has raised an estimated $3.5 million to support CLN6-Batten disease research – through a crowdfunding initiative launched less than a year ago.

And coalitions of patient-centric communities can achieve significant advances through the power of numbers. Thus Genetic Alliance, a network of more than 10,000 organizations, was a key player in passage of the Genetic Information Nondiscrimination Act and in development of the National Patient-Centered Clinical Research Network.

Initiatives run the gamut from efforts to identify a handful of individuals with rare diseases to projects that aim to enroll thousands of participants.  Earlier this month, the University of Washington launched MyGene2, a site where families with rare conditions can publicly post their stories, establishing connections not only with those who share similar stories but also with clinicians and researchers.  At the other end of the spectrum, 23andMe has partnered with a number of Parkinson’s community groups on a project to gather genetic data from more than 11,000 individuals.

And, in the last year, the Simons Foundation Autism Research Initiative (SFARI) launched SPARK, a project to collect genomic information from 50,000 people with autism and their families.  At WuXi NextCODE we are delighted to participate in this endeavor by providing direct online access to the data.

Genomics has played a critical role in the evolution of patient-centric communities.  Groups that have developed resources and advice for patients and families are increasingly collaborating with clinicians and researchers.  Through voluntary contributions of personal knowledge – and genomic data – participants in patient communities are expanding the impact of genomics on medicine.  The growing power of virtual communities has facilitated numerous initiatives to improve patient outcomes through improved diagnosis, optimized standards of care, and new directions for promising research.

From rare diseases to disorders that affect millions, all stakeholders increasingly use genomics to translate individual experiences and expertise into meaningful improvements in the lives of patients and their caregivers.  Genomics sits at the powerful nexus between evidenced-based medicine and the empowered patient.  At WuXi NextCODE we are proud to advance the role of genomics not only in patient care but also in the evolution of strong, effective patient-centric communities.

Genomic Information and the Importance of Communication

Communicating clinically useful results both to doctors and patients will drive success

genomics-communications-hannes-smarasonAround the world, researchers and clinicians are taking on the challenge of integrating genomic analysis into medical practice. Physicians and patients are increasingly aware of the potential utility of genomic data. As genomics continues to become a more powerful tool in healthcare, there is a clear and compelling need for a commitment to excellence in communication.

At WuXi NextCODE, we are proud to provide sequencing and analysis resources that help doctors:

  • Shorten diagnostic odysseys, as I have discussed here; and
  • Improve treatment choices, as I have discussed here.

Maximizing the opportunities afforded by the ‘big data’ of genomics necessitates collaboration and communication, which I discuss in more detail here. As part of our genomics business, we are dedicated to the highest standards of communication – indeed, we view effective communication as central to how our technologies will improve health in both the near and the long term.

The task of harnessing the vast and expanding quantity of genomic data to improve clinical care requires interpretation and discovery powered to translate the data into clinically useful information. Leveraging that information to improve patient outcomes also requires clear and accurate communication:

  • Between researchers and clinicians;
  • Between specialists in different medical fields;

And, increasingly,

  • Between doctors and patients.

As the recent CLARITY Undiagnosed competition highlighted, applying genomic data to medical practice involves interpreting the sequenced genomes and identifying molecular diagnoses – and a third step: communicating clinically useful results both to doctors and to patients.

The CLARITY challenge winners, including WuXi NextCODE, were explicitly recognized for the quality and clinical utility of their reports.

Studies and surveys have shown that many people favor greater access to genetic information. Individuals want analysis of their genomes in order to:

  • Reveal their unique risk factors for inherited diseases;
  • Pinpoint a diagnosis if they are ill; and
  • Guide their decisions if they are seeking treatment.

Genomics is helping to inform patients in all these ways.

In addition, genomics demonstrates enormous potential to empower individuals.

The hundreds of thousands of people who purchase genomic testing through direct-to-consumer businesses like 23andMe are demonstrating a robust enthusiasm for gathering genomic information. And patients enrolled in clinical trials and donors participating in population-wide genomic studies express a desire to be more informed. Patients and consumers consistently seek resources that transform their personal genomic signatures into information they can use to make better healthcare and lifestyle decisions.

And most patients and consumers are willing – often eager – to share their genomic information to aid medical research and discovery. 23andMe reports, for example, that 80% of its customers consent to share their genomes for research.

It is unmistakably clear that, in the not-too-distant future, every individual in many countries around the world will have their genome sequenced. Throughout a person’s life, medical professionals will be able to access genomic information to guide health decisions – from identifying inherited conditions to assessing risk for complex diseases to calculating appropriate treatments, drugs, and even dosages for truly personalized healthcare.

The more effectively we communicate – the more we share information within the research community and parlay that into clinically useful information for patients – the greater the benefit to all.

As much as people understandably prefer simple, definitive answers to questions about their personal health, the information that genomics provides can be complex and even ambiguous. A genetic variant might be identified, for example, that can be tied to family medical history and translated into a probability or likelihood. This was the case for Angelina Jolie Pitt, who noted in her New York Times piece that her genomic analyses “gave [her] an estimated 87 percent risk of breast cancer and a 50 percent risk of ovarian cancer.” Percentage risks are nuanced, and individual perceptions of acceptable risk vary considerably. It is therefore difficult to define precisely the circumstances under which a genetic variant becomes clinically actionable.

Or a genetic variant might be identified which gives physicians clues but does not explicitly identify a specific disease. For example, a patient seeking a diagnosis may have a genetic variant that correlates to a number of diseases involving dysregulation of lipid metabolism. Identifying the variant provides physicians and caregivers with a clear direction for further analysis and treatment, but does not yield a conclusive diagnosis or prognosis.

Or a genetic variant might be identified which has yet to be understood as causing or playing a role in disease. Such a variant may occur by chance and have no medical relevance, or its meaning may be uncovered as science in the field advances. But for the person who is having the genomic information analyzed today, it offers no actionable information.

As all of these examples illustrate, effective communication about genomic information can be a significant challenge. There is a risk that poor communication will be a barrier to the adoption of genomic medicine, but if we strive to communicate clearly with patients and the public, our successes will likely accelerate more widespread use of genomics. The role of genomics in transforming health care will grow exponentially as we all endeavor to improve communication with patients, their families, and the public at large.

Our work at WuXi NextCODE is advancing the transformation of medical practice through genomics. As part of that vision, we recognize the critical importance of facilitating effective communication among all stakeholders. We provide the resources that enable researchers and clinicians to identify disease and inform treatment decisions. And we strive to add additional value by communicating about genomic information accurately and proactively, all with the ultimate goal of meaningfully improving patient outcomes.

FDA Approval Moves DTC Genetic Testing Forward

DTC genetic testing, Hannes Smarason

23andMe is relaunching its direct-to-consumer genetic tests in the U.S. with the approval of the FDA to provide consumers “carrier status” information on 36 genes that can cause rare diseases. I am optimistic that DTC genetic testing will expand its impact over time, ultimately having a tremendous impact on human health globally.

Today, genomics industry maverick, 23andMe, is relaunching its direct-to-consumer (DTC) genetic testing in the U.S., with the approval of the FDA to inform consumers whether they carry a genetic variant for one of 36 rare diseases that could potentially be passed on to their children. In addition to this carrier status information that now meets FDA standards, reports from the newly launched 23andMe test will include information on wellness, traits, and ancestry.

A big positive step forward

For the genomics industry as a whole, this is a significant step forward as the FDA’s decisions have global influence. Indeed, this is a landmark FDA decision, as it is the first time ever that the FDA has allowed such a broad spectrum of medically relevant genetic information to be provided directly to consumers. Both the FDA and 23andMe deserve credit for working through the challenges that, less than two years ago, resulted in the FDA ordering 23andMe to stop marketing its genetic testing kits in the U.S. That the FDA—one of the world’s most thoughtful medical regulatory agencies—has come so far so fast is indicative of the potential it likely sees in DTC genetic testing improving the health of U.S citizens.

A larger journey ahead for direct-to-consumer genetic testing

Moving forward, there are at least two important directions that—in collaboration with the appropriate regulatory agencies, such as the FDA—I think DTC genetic testing will advance:

• DTC genetic testing will expand its reach globally; and
• DTC genetic testing will likely expand the medical impact of its reported results.

DTC genetic testing will expand its reach globally.

Catalyzed by demand for improved health, DTC genetic testing services will inevitably become accessible to much of the world’s population over the decades to come. To be successful, these services will need to be customized by geography and culture and approved by the appropriate local governmental agencies. While the genome is shared by all humans, it is naïve to think that DTC genetic testing services will be the same across all people living anywhere. It is incumbent on industry participants to align their DTC reports and services to best meet the needs of the specific customers in specific countries and geographies—and to do so in a spirit of cooperation with the appropriate governmental health regulators.

DTC genetic testing will likely expand the medical impact of its reported results.

As noted, today’s FDA approval for 23andMe to be able report on carrier status is a significant step forward, but more health data remains to be gleaned—and reported—from an individual’s genomic data. From 23andMe’s announcement, you can see the foreshadowing of what may ultimately be possible:

About [23andMe’s] Carrier Status Tests
[23andMe’s tests] can be used to determine carrier status in adults from saliva collected using an FDA-cleared collection device (Oragene DX model OGD.500.001), but cannot determine if you have two copies of the genetic variant. Each test is most relevant for people of certain ethnicities. The tests are not intended to diagnose a disease, or tell you anything about your risk for developing a disease in the future. On their own, carrier status tests are not intended to tell you anything about the health of your fetus, or your newborn child’s risk of developing a particular disease later in life.

Clearly, working with regulators such as the FDA, and others, such as thoughtful genetic counselors, there is a future potential for the right service to be able to report on people’s risk for developing specific diseases. Informed, health-conscious consumers are very likely to demand access to this information—and millions of individuals have already paid significant sums out of their own pockets to have their genomes sequenced and analyzed. Indeed, from news reports covering 23andMe, we know that when ordered by the FDA to stop providing health information such as the disease risk, their rate of new customer sign-ups dropped by more than half.

I am very optimistic that DTC genetic testing will expand its impact over time, overcoming skepticism and ultimately having a tremendous impact on human health globally. I am proud that our team at WuXi NextCODE will be a part of making this exciting future happen, and today I am especially proud that WuXi Ventures recently invested in 23andMe, making us active supporters of its current and noteworthy success.

Genomics in Cancer: Continuing to Push the Leading Edge

genomics in cancer - hannes smarason

Genomics is helping to prevent and treat cancer at an accelerating rate, supporting the goal of oncologists to dramatically improve cancer patient outcomes.

The progress in the use of genomics to help prevent and treat cancer continues to grow at a pace that is impressive. Indeed, there is expanded use of genomics to drive patient care and improve outcomes across an ever-expanding number of cancers by a growing number of oncologists.

Genomic Knowledge Can Clearly Drive Better Care

Applying genomics to cancer treatment is a powerful clinical application, as genomics can provide a window into how to best treat a patient’s particular cancer as it:

  1. may help better understand the genetics of the tumor itself, and
  2. can provide insight into how cancerous tumors may grow and spread over time.

With a genomic-based approach to cancer care, oncologists can more personally tailor anti-cancer treatments to an individual tumor’s mutations, thus molecularly targeting the specific cancer’s Achilles heel. Already, there are well-documented successes of molecularly targeted anti-cancer agents, such as cancer drugs that target certain genes—HER2, EFGR, ALK, and others.

In 2015, the pace of adoption of genomics in clinical oncology has advanced significantly. Recent evidence of the accelerating use of genomics to help fight cancer includes:

  • Evolving from ‘why’ to ‘how’ to use genomics at leading cancer centers. At the top cancer care facilities, genomics has become part of the programmatic approach to provide certain cancer patients with optimal care—care that is fundamentally designed to lead to the best outcomes. The question for leading medical centers globally has evolved over the last few years from “do we need genomics?” to “for which cancer types and at what stages of cancer treatment and diagnosis can we best use genomic sequencing and analysis?”—an evolution from “why?” to “how?” at a very fundamental level. The accelerating use and deployment of genomics by leading medical facilities validates that they are deriving significant value from genomics, and that value is resulting ultimately in meaningfully advancing better care for cancer patients.
  • Expanding potential applications of genomics within different types of cancers, broadening the types of cancers and tumors that can potentially benefit from genomics. Researchers and clinicians continue to publish a wealth of information validating the potential of genomics to improve outcomes in certain types of cancer patients. In 2015 alone, highlights of these advancements include certain prostate cancers, brain cancers, rare types of pediatric kidney cancers, and even potential targets in certain non-small cell lung cancers.
  • Broadening acceptance in cancer prevention. Driven in part by the education of oncologists and physicians generally and in part by the empowerment of knowledgeable patients, people are seeking and benefiting from genetic tests that reveal their personal risk for certain tumors (such as BRCA for breast or ovarian cancers). The idea of using genomic analysis to predict an individual’s cancer risk by comparing their genome with databases of confirmed genetic mutations linked to disease is—for certain individuals with specific family histories and genetics—driving appropriate medical decisions for patients who may be at high risk for certain cancers.
  • Powering clinical trials with genomics. The use of genomics in cancer clinical trials – whether for inclusion in data-gathering or even screening of patients—has gone from rare to commonplace over recent years, and is improving knowledge around the safety and efficacy of drugs in cancer and beyond. Two large-scale cancer trials have been initiated in 2015 with the bold goal of substantially advancing the understanding and use of genomics in cancer care. The anti-cancer treatments being tested in both trials were selected for their activity on a specific molecular target, independent of tumor location and histology. The two trials are actively enrolling and are (1) an American Society of Clinical Oncology (ASCO)-sponsored study, called TAPUR (Targeted Agent and Profiling Utilization Registry) and National Cancer Institute (NCI) and is called NCI-MATCH (Molecular Analysis for Therapy Choice). These trials and any subsequent follow-on trials will doubtless provide insightful information to drive the growing use of genomics in improving cancer care.

In summary, genomics is helping to prevent and treat cancer at an accelerating rate, supporting the goal of oncologists to dramatically improve cancer patient outcomes. There are at least four frontiers where we can see substantial progress in the use of genomics in cancer care, including expanded use in leading medical centers, increased potential applications within cancer, widespread acceptance in cancer prevention, and an increase in the use of genomics within clinical trials. I am personally committed to continue to drive and accelerate this genomic revolution to continue to bring true progress in improving cancer care to patients in need globally.

Genomics for Rare Diseases: Going Global and Shifting the Care Paradigm

The use of genomics in rare disease diagnosis and treatment is going global

The benefits of genomics in rare diseases are increasingly making a difference to patients, their families, and their physicians, and they are being scaled globally.

The trend of accelerating the use of genomics in rare disease diagnosis and treatment is going global, driven by the important goal of reaching all people around the world, no matter where they live.

Active programs have now been deployed and exist in many populous countries around the world.

For instance, WuXi NextCODE has established active collaborative efforts in three continents, most recently adding Fudan Children’s Hospital as a partner in its efforts to lead whole genome diagnostics for rare diseases in China.

Over the coming weeks, I expect WuXi NextCODE to continue have news of its dedicated efforts to spread the application of genomics for rare diseases to all geographies.

Diagnosing Rare Diseases: Genomics Shifts the Paradigm

Rare diseases are an area of significant advancement for genomics, as the opportunity for improved diagnosis and treatment through the use of genomics is truly remarkable.

According to the National Institutes of Health (NIH), there are over 7,000 rare diseases affecting between 25 and 30 million Americans, which is nearly 1 in 10 people, making the overall prevalence of rare diseases significant. Since NIH believes that approximately 80 percent of rare diseases have genetic origins, the potential for genomic sequencing, interpretation, and analysis to offer a solution here is truly game-changing.

Every day there are new cases of children with “unknown” diseases, many of which are likely related to a hereditary genetic disorder. Sadly, these children and their families often spend years undergoing testing and experimental treatments for a wide range of diseases in an attempt to properly diagnose and treat them; usually, this so-called “diagnostic odyssey” is accompanied by a very high financial and emotional burden.

Genomics offers the potential to deliver a correct and precise diagnosis for rare diseases that have identifiable genetic causes. Indeed, case studies are rapidly accumulating that show that, by offering genomic sequencing and analysis services to patients with a suspected rare genetic disease, mutations that might be causing the disease may be identified, and thus correct treatment can be employed much earlier to eliminate the burden of a long-term diagnostic and treatment odyssey.  A recent article in Bloomberg BusinessWeek highlighted medical histories of two patients who recently received a diagnosis informed by genomics. In both these representative examples, genomic analyses provided an end to the burden, cost, and stress of their multidecade-long diagnostic odyssey:

  • Jackie Smith, 35, spent the 32 years from age 3 unable to receive a correct diagnosis that could account for her weak limbs and turned-in ankles, despite seeing many doctors on numerous occasions. Indeed, Jackie’s parents were told to “take the 3-year-old girl home and enjoy her while they could” …”[her disease] would probably kill her before she was old enough to drive.”  This past February, using genomic interpretation and analyses from Wuxi NextCODE, Claritas Genomics definitively identified her condition as centronuclear myopathy in less than three weeks.
  • Dustin Bennett, 24, would tremble and violently jerk for hours or days at a time and had been developmentally delayed since childhood. After dozens of doctor visits and incorrect diagnoses—seizures, muscle disorders, mental health problems—a Mayo Clinic genomic-based analysis showed he has episodic ataxia type I, a neurological disease characterized by hours-long attacks with no clear trigger. Dustin, a 24-year-old who functions at a first-grade level, is now on the second round of a medication doctors say should help reduce the frequency and severity of his episodes.

The benefits of genomics in rare diseases – to individuals, their families, and their physicians – are increasingly making a difference to patients.  These benefits are being seen in case after case – and they are being scaled globally, as leading medical centers in many countries around the world are using genomics to support their efforts in diagnosing and treating rare diseases.  I believe passionately in the game-changing potential of genomics to help rare disease patients and I am dedicated to advancing world-leading genomics globally to uncover new solutions for patients.