My BRCA Journey

1 Oct

Screen Shot 2014-10-01 at 1.57.45 PMAs a little girl, all I really knew about my paternal grandmother, Irma Saklad, was that she died of breast cancer in 1985. I was a toddler at the time of her passing and knew her only from pictures and stories. To me, that’s what cancer was – pictures and stories. However, what I learned later changed my perspective, and my life, forever.

In late 2008, I learned I had inherited a BRCA1 gene mutation from my father, Elliot Schnier, who had inherited it from his mother, Irma. It turns out that my great-grandfather was one of thirteen children, and sadly all seven of his sisters died from breast cancer.

At the time I found out about my BRCA1 results, I was 26 years old, engaged to be married, and living a very healthy lifestyle. It never occurred to me that I needed to worry about developing a cancer. I associated breast cancer with older women…my grandmother was old. I never thought in a million years that the threat of breast cancer would affect me at such a young age. My genetic counselor explained that my lifetime risk was up to 87% for breast cancer. This information turned the world as I knew it upside down. I went from interviewing wedding photographers and caterers to interviewing oncologists and surgeons. In a matter of hours, wedding planning became a trivial endeavor.

Every woman deals with risk in their own way. I started with extensive screening, but every time I went for a mammogram or MRI — which often lead to a biopsy or an ultrasound — I felt an overwhelming sense of fear. I would often think…is today the day my results come back positive with cancer? That burden was just too heavy for me to bear.

After a year of researching and obtaining valuable medical opinions, I made the difficult decision to reduce my breast cancer risk through surgery. In January 2010, at 27 years old, I underwent a prophylactic bilateral mastectomy. It’s now over three years later, and every time I look at myself in the mirror, I feel a complete sense of relief. With the support from my loving parents, and incredible husband, friends and family, I feel grateful for having learned this life-saving information with sufficient time to act upon it. They would often remind me how lucky am I that I had a choice, and what a brave decision I made.

Learning of my BRCA1 gene mutation has empowered me to be an advocate for my health and not a victim of a disease. Unlike our mother’s and grandmother’s generation, young women like me can develop a strategy to reduce our risks or detect cancer early, while it is still treatable. The bottom line is this: identifying your risk and alerting your loved ones allows you to play a critical role in possibly preventing breast cancer.

I credit my father for giving me the incredible gift to take charge of my health, to know my risk, and to be spared the disease that claimed his own mother. The most important message I can spread is that hereditary cancer risk can be passed down from fathers to daughters, and your father’s family health history is just as important as your mother’s history in determining risk. I’m living proof of this fact.

Pretty soon, we’ll be planning my beautiful daughter’s 3rd birthday. As Dylan blows out her candles, I’ll be celebrating the gift of health and life, ever mindful of the incredible journey I’ve taken so I can continue to celebrate many more birthdays with her.

Jodi lives in New York City with her husband, daughter, and recent addition, baby boy Austin. From 2010 – 2012, she served as the NYC ambassador for Bright Pink. Jodi plans to have her ovaries removed after she completes her family.

Software for flexible analysis and interpretation of genetic mutations

25 Sep

Advances in DNA sequencing technology are changing healthcare in many ways, including allowing us to determine a patient’s DNA sequence cheaper and faster than ever before. With modern technology, we can quickly discover if a patient has an unexpected change in the sequence of one of their genes. Depending on the field, you may see these changes referred to as “mutations”, “variants”, or “alleles”.

However, knowing which particular allele is present in a patient is not enough: we must also interpret it to determine whether that particular sequence will have a medical impact on a patient. This “interpretation problem” is an increasing challenge for many labs. At Counsyl, we have a growing variant curation team that researches every single new mutation we discover and determines its impact on a patient’s risk for disease. It turns out a lot of data is needed to do this, and I developed a tool to make this process better.

What does a mutation mean for a patient?

A mutation in the BRCA1 or BRCA2 genes can increase one’s risk of cancer. For example, in the general population, women have a 12% chance of developing breast cancer but those with a BRCA1 mutation may have as high as an 80% chance.

Suppose a patient has had both of their BRCA genes sequenced. A small part of the sequence might read like:

Patient's Gene:     ...ACGTGC...
Known Healthy Gene: ...ACGCGC...

If you look carefully, you’ll notice that the two sequences don’t quite match up. The patient has a T at a location where the known healthy gene has a C. Is the patient at a higher risk for cancer? Not necessarily. Answering this question is the job of the Counsyl curation team.

A geneticist on the curation team might start by looking for existing consensus on the effects of the allele. Databases such as ClinVar and HGMD contain published peer-reviewed studies on the effects of such alleles. If the allele has been studied thoroughly, the geneticist can confidently diagnose the allele as deleterious (harmful) or benign (not harmful).

If the allele has not been studied thoroughly, however, answering the question becomes more difficult. Before my project, geneticists would make this determination using qualitative information such as

  • medical histories of other patients known to have the allele
  • how often the allele occurs, compared to the disease it might cause
  • how the allele affects the cell’s ability to create the protein for which it codes
  • how the allele affects the structure of the protein for which it codes

Software to the Rescue

The geneticists at Counsyl aren’t alone on the curation team. Software Engineers work hand-in-hand with them to make the curation process more reliable and efficient, in part by providing tools that allow for quantitative analysis of alleles.

Computational scores establish a formal quantitative representation of some attribute of an allele, that might otherwise be evaluated qualitatively, such as predicting a mutation’s possible disruption of RNA splicing or detecting whether a mutation changes a site that has not changed for long evolutionary time periods.

The benefits of emphasizing quantitative analysis are twofold:

  • the curation process becomes more efficient. Geneticists on the curation team can make decisions more quickly because they do not have to manually process raw data.
  • the curation process becomes more reliable. The scores create a frame of reference on which consistent standards and processes can be built.

Diagnosing alleles via quantitative analysis is still a new idea in industry. Many of the software packages used to calculate quantitative scores for alleles are just emerging from academia; the challenges of distributing the software packages and integrating their outputs into a production workflow are largely unsolved. For example, some software packages are only made available upon request from the original authors. However, systematizing the installation of such algorithms and the computation of their scores promises to enable many new approaches. A hot area of research right now is the development of machine learning methods, such as CADD, which can consider a large variety of functional scores in order to automatically predict a mutation’s effect.

The Annotations Service

I spent my internship at Counsyl building the annotations service, which

  • manages all the third party allele-scoring software packages, dubbed annotators
  • calculates aggregate statistics on the annotations
  • caches annotations in a database
  • exposes an API and command line interface through which users and other software can query annotations for individual alleles and aggregate statistics

In turn, this service has allowed us to incorporate many scores into the Curation workflow. One use of the annotations service is generating visualizations, such as histograms of scores for known benign and deleterious alleles (Figure 1). For example, by comparing a novel allele against previously curated alleles, we see that the PhyloP score suggests a deleterious classification. Additionally, this service allows us to easily explore and visualize many more scores as well as various combinations of them.

PhyloP scores across Counsyl's deletrious and benign alleles.

Figure 1. Distribution of PhyloP scores across Counsyl’s known deleterious (red) and benign (green) alleles. The score of a novel allele is indicated by a thin blue line.

Hybrid Schema/Schemaless Database

One of the challenges of collecting annotations from a diverse collection of annotators is finding a useful way to store their output that is

  • flexible enough to support the output of all annotators
  • efficient at finding all annotations for a particular allele
  • efficient at executing arbitrary aggregate queries on the annotations
  • able to store billions of annotations
  • able to enforce uniqueness (there should only be one annotation per allele per annotator)

The annotations service satisfies all these requirements using a hybrid schema/schemaless database; the database engine enforces some constraints on each record (the presence of certain columns, the type of certain columns, uniqueness) while also allowing free-form data.

This behavior is implemented by storing annotations in a PostgreSQL JSON column — a column type in that accepts any JSON object, stores the object efficiently, and allows efficient queries to be executed on the object’s contents. Because it is just a PostgreSQL table, we can still define constraints and keys on all other columns as usual.

chromosome offset reference sequence allele sequence annotator annotations
5 3342342 G T VEP {“PhyloP”: 5.5, …}
13 32900276 G C ESP {“frequency”: 0.0117}

Annotators Running in Docker Containers

Because deploying and running bleeding-edge academic annotators can be challenging, each executes in its own Docker container. Docker is a library for managing Linux containers: isolated execution environments much like virtual machines but running in the host OS, sharing software packages when possible. Docker allows us great flexibility in configuring each annotator’s execution environment without sacrificing performance.

Big Picture

As the amount of DNA being sequenced increases, the bottleneck in many labs is becoming the interpretation of the sequences, especially the curation of never-before-seen alleles. The more we move in the direction of quantitative analysis, the easier the job of the curators becomes: we can precisely define protocols based on the scores that reliably determine if an arbitrary mutation is benign or deleterious, reducing the need for curators to analyze data and do research by hand.

Although “automatic” quantitative methods cannot replace human curators, the increasing power of these methods will help us keep pace and improve accuracy as the rate of sequencing at Counsyl increases.

lucaswoj
Lucas Wojciechowski was a software engineering intern at Counsyl and is currently a Computer Science student at Waterloo.

Team Counsyl at FabFest 2014

16 Sep

This past weekend, energized from our recent profile in Fast Company magazine, Team Counsyl flew to Chicago to partake in Bright Pink FabFest 2014. At the opening ceremony, CEO Lindsay Avner talked about the goal of reaching 52 million women between the ages of 18 and 45, so that they can each be proactive about their breast and ovarian health. Lindsay lost her grandmother and great-grandmother to breast cancer, and watched her mother survive breast and ovarian cancer. Her mother was present at FabFest to support the cause. At the end of a high-energy day of intense workouts, yoga classes, meditation, makeovers and hair braiding, over 800 women gathered to listen to BRCA positive women, like Brianna, who tweeted:

 

 

Team Counsyl was inspired by the positive energy of every woman who attended FabFest. We sent a big group of Counsyl ladies from across the country to participate in the event: Laura Martini, our Director of Product Design; Kathleen Berentsen, our Boston-based genetic counselor; Elizabeth Collins, our variant curation specialist and very own yoga teacher; Terri Meyer, our Regional Director of Sales; Shivani Nazareth, our Director of Women’s Health; Megan Lundin, our Strategic Accounts Executive; Michelle Ostrowski, one of our midwest-based Clinical Accounts Executives, and Emily Leung, our San Francisco-based team lead. We were thrilled to support the cause and truly believe in the Bright Pink mission of saving lives by giving people the tools to live proactively at a young age.

Screen Shot 2014-09-16 at 12.47.56 PMProcessed with VSCOcam with m3 presetTerri Michelle

The New Counsyl

8 May

Starting last summer, we surveyed thousands of people who took our Family Prep Screen, and spent hundreds of hours speaking with physicians and patients in order to understand how Counsyl fits into their lives. We talked with an incredibly diverse set of people, including an opera singer, a military wife, a physician in Long Island, and a man in Costa Rica who’d flown to the U.S. to get Counsyl.

What did we hear? It has become clear that Counsyl is doing something special; when we spoke to our patients, what stood out was a sense of relief after learning their results. In fact, many of them said “it’s good to know,” when describing the value of Counsyl, which is why we have now made this phrase the tagline of our company.

We’ve quietly been testing a new “Get Counsyl” approach over the past few months, and are thrilled to report that it has already introduced over a hundred new doctors to Counsyl. Our vision is to give millions of men and women access to vital information about their bodies so they can confidently make choices about their lives. Today’s launch is the first step in making this vision a reality.

As a part of this launch, you’ll see:

  • Results available online to any patient who requests them from our support team
  • New educational videos featuring our very own Kaylene Ready, MS, CGC
  • Counsyl Complete, a service that allows providers and patients to communicate about results in real-time
  • On-call counseling with a medical professional for immediate consultations on positive results
  • Get Counsyl, a way for people to request a prescription through their doctor
  • A price estimator that provides people with transparency around the cost of screening
  • An improved Family Prep Screen which can pick up 50% more carriers using new sequencing technology
  • Our Inherited Cancer Screen, starting with cancer susceptibility genes BRCA1 and BRCA2

We’re energized about our new offerings. But more importantly, we’re excited at what these new services can do for patients.  The chance to help patients make clinical choices is an incredible responsibility, and one that we take very seriously. And as they made these choices, some patients have been gracious enough to share their stories with us. Jodi K. learned that she inherited a BRCA1 mutation from her father. Jodi consulted several medical specialists and decided to pursue a preventative mastectomy. Similarly, Holly T., a hairstylist in California recently learned of her BRCA positive status and is weighing her options. Holly said “I want to be here for my kids, and I want to do everything I can to stay healthy.”

We are going to keep pushing the envelope and continue to innovate here at Counsyl, because real people like Jodi, Holly, and the countless others who shared their personal stories with us, depend on it. As Brittany M. from Maine told us, “It was just really good to finally have the information that we wanted.”

-Ramji, Rishi and Eric

 

Encouraging Screening Before Pregnancy: My JScreen Story

12 Dec

JScreen’s creation involved multiple people in different circumstances, times, and places all experiencing some event or spark of intuition and creativity that grew into the will to do “something” to prevent Jewish genetic diseases.  “Something” grew into JScreen. For me, inspiration first struck when I was giving a talk to a group of other faculty members at Emory University in Atlanta about Jewish genetic screening in 2007.  The idea that we should use a combination of online education and saliva screening to make it easier for people to be screened struck me so suddenly, that I stopped my talk and just stood still for what was probably seconds, but felt like minutes. 

I had been wrestling with the dilemma of how best to encourage screening for years.  Trained as a genetic counselor, I had witnessed couple after couple bringing their infants into our clinic, only to be told that their child was suffering from a devastating condition.  The parents inevitably cried out “but no one in our family has this!”  They were right, of course, but that didn’t help their baby.  These types of diseases often come out of nowhere.  Sadly, many of these parents hadn’t been offered screening by their physicians, or if they had, the issue wasn’t raised until the pregnancy was well underway. As it stands today, genetic carrier screening is typically offered, if at all, when a couple is already pregnant.  This timing is understandable, because they may not show up in a clinic before conceiving.  Pregnancy, though, is not the optimal time for screening to be offered.

Professional groups, such as the American College of Obstetrics & Gynecology[1] and the American College of Medical Genetics[2], support the belief that preconception screening should be encouraged.  Studies bear out the reasons why.  Sparbel et al. published an article in 2009[3] eloquently describing the difficulties that prenatal screening raises for women who can’t help but view their options through the “prism” of their pregnancies.  Prior to conception, a couple who discovers that their children are at risk for a genetic disease can carefully review their reproductive options, which can range from using an egg or a sperm donor to adoption to preparing for the possibility of having an affected child by marshalling resources for early treatment.  Outside of the pressures of pregnancy, couples can take their time to learn about the condition, talk with parents of children who are affected, and make the best decisions for themselves.  Many of the ethical concerns surrounding carrier screening evaporate outside of the context of pregnancy.

To be clear, I do not mean to imply that prenatal screening is not helpful.  Many couples find the information they learn from prenatal diagnosis to be invaluable for providing peace of mind, deciding whether to continue a pregnancy, or planning for the birth of an affected child.  For example, a couple who learns that their child will have a condition might decide to move closer to relatives who can help with the care of a child with special health care needs.  Prenatal diagnosis is an important tool.   If the goal, though, is to prevent disease, many options are simply not available by the time prenatal screening is being considered.

Also, while newborn screening programs exist to identify children with some genetic conditions, only a few conditions are included, leaving parents in the dark about their child’s need for early intervention.  While newborn screening is designed to find babies before they become sick and begin treatment early, affected babies are still sometimes identified too late. Knowing that a baby is at risk or is affected early can be lifesaving in these situations.

As a Southerner, perhaps I feel the painful preconception/prenatal screening dilemma more acutely than do some of my colleagues.  Interest in prenatal testing is considerably lower where I practice in Georgia due to the politically conservative or religious values that are prevalent.  I feel a grave sense of urgency to figure out a way for screening to become common place BEFORE pregnancy.  I know that if we don’t find a way to make this a reality, screening won’t be an option for many of the people I work with, and they and their children will continue to suffer from preventable conditions.

So, why doesn’t preconception screening readily occur?  One reason is that ordering the testing is logistically difficult in many cases.  One of my past roles at Emory was to work with the Newborn Screening (NBS) Program, as their genetic counselor.  As such, I received calls from parents and other relatives of babies diagnosed through NBS wanting to arrange for carrier screening.  They had seen firsthand the impact of a condition on their family, and wanted to learn if their children would be at risk.    Few of these people who contacted me lived anywhere near a genetic counselor.  In one case, the uncle of a child diagnosed through NBS wanted screening, but he lived in rural Colorado.  I spent upwards of 5 hours on the phone with his physician’s office helping them identify the best place to send a sample, determine how much it would cost, and explain the results when they were finally available. In another case, a woman whose daughter was found to be a carrier of cystic fibrosis through NBS didn’t have a physician who could order the screen at all.  As a result, she was never able to have screening.  I couldn’t help but believe that it just shouldn’t be this hard!  For these reasons, when the idea for JScreen struck me, I couldn’t help but answer the call.

JScreen is a public health initiative whose goal is to overcome many of the barriers to preconception screening by taking advantage of the fact that we can now test saliva.   By combining online education with access to certified genetic counselors, our program aims to make screening easily accessible, affordable, and on a very pragmatic level useful in a way that prenatal screening just can’t be.

JScreen opened its virtual doors in September of this year.  It would be simplistic to believe that this program is the singular answer to preventing Jewish genetic diseases; people smarter than I have wrestled with this problem for decades.  The barriers to screening are complex, and will continue to be so.   I do believe, though, that JScreen is a step in the right direction; we are a piece of the puzzle that can ultimately lead to widespread preconception screening.  It’s an audacious goal.  For now, though, I can’t help but smile when a JScreen test is requested by someone who has checked the box “non-pregnant.”  I can’t help but pray for many, many more.

T_Page_2012_crop

 Tricia Page is the Senior Director for the JScreen program at Emory University in Atlanta, GA.  After receiving her B.S.  in Genetics from the University of Georgia, she received her Master’s degree in Genetic Counseling from the University  of Texas Health Science Center at Houston in 1996 and h er certification from the American Board of Medical Genetics  in 1999. At Emory, Tricia worked as the Director of Genetic Counseling Services, Program Manager for Newborn  Screening, and the Assistant Director of the Genomics and Public Health Program prior to taking her current roles.  In  her current position, Tricia focuses on delivery of genetic services from both a clinical and public health perspective.  She is interested in non-traditional service delivery models, especially those capitalizing on advances in genetic testing and health education.  Tricia is a fourth generation Georgian who enjoys spending time with her family, gardening, and training for triathlons.

1. Genetics ACo: ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.Obstetrics and Gynecology 2009, 114(4):950-953.

2. Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ: Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med 2001, 3(2):149-154.

3. Sparbel KJH, Williams JK: Pregnancy as Foreground in Cystic Fibrosis Carrier Testing Decisions in Primary Care. GENETIC TESTING AND MOLECULAR BIOMARKERS 2009, 13(1):133-142.

One Step Closer to Genetic Literacy

11 Nov

At Counsyl, we are starting a free series of educational webinars to promote genetic literacy. Clinical genetics is evolving quickly, and genetic counselors are a limited resource. Physicians and nurses often tell us that it’s hard to keep up. Even as a genetic counselor, I find it challenging to stay current with all of the new clinical applications of genetics, like non-invasive prenatal screening, whole exome sequencing, inherited cancer panels, and personalized genomics. There is plenty of data showing that physicians and nurses are not very comfortable with genetics. Depending on the specialty, some may have only had one course of genetics in school.  At a time when genetics is becoming an integral part of all facets of medicine, this is surely a problem.

Our goal is simple: engage medical professionals through simple and practical tools for education. We’re all about making things accessible at Counsyl. So, mark your calendars and spread the word. Our first webinar is scheduled for January 23, 2014 and the speakers include Caroline Lieber, Dr. John Marshall, and Dr. Bryce Mendelsohn.  The topic is “Understanding Expanded Carrier Screening & Its Benefits to Your Patients.” You can sign up at www.counsyl.com/webinar. Future topics will expand beyond Counsyl to include a broad range of “hot topics.”

For a glimpse of what to expect from our first webinar, check out the bios of our awesome speakers:

Dr. John Marshall

Dr. John Marshall

 

Dr. Marshall has served as Clinical Professor of Obstetrics and Gynecology at UCLA, Chairman of Obstetrics and  Gynecology at Harbor/UCLA Medical Center,  and Clinical Professor of Biomedical Sciences and Medical Education at Mercer University School of Medicine Savannah Campus.  He authored over 100 scientific publications and currently works for Counsyl.

Caroline Lieber

Caroline Lieber

 

Caroline Lieber is the former Director of the Joan Marks Graduate Program in Human Genetics at Sarah Lawrence College. She is actively involved in professional education and recently traveled to Guatemala to assess the provision of genetic counseling services abroad. Caroline is a genetic counseling consultant for Counsyl.

 

Dr. Bryce Mendelsohn

Dr. Bryce Mendelsohn

          

Bryce Mendelsohn received his MD/PhD in Molecular Genetics and Genomics from Washington University in St. Louis. Since that time, he completed a clinical residency in Pediatrics. He studies metabolic disorders and has tremendous interest in the pediatric application of genome-era technologies.

 

For suggestions on future webinars or a chance to speak on a hot topic, submit ideas to Kenny Wong, Director of Genetic Services at Counsyl, by filling out this form: http://csyl.us/qzfPO

A Fun Friday Post

25 Oct

We were so amused by this rap video on the discovery of DNA, we just had to share. Enjoy!

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