MDs get a “shared language” for discussions on carrier screening

18 Mar

When an oncologist assigns Stage One status to a tumor he’s letting his patient know they’re catching the problem early. It’s the kind of shorthand that’s missing in most clinical conversations about expanded carrier screening. Basically, there’s been no easy way for a doctor to indicate how serious a particular genetic disease is. Gabriel Lazarin, who works closely with physicians in his job as Director of Genetic Counselors on Counsyl’s clinical sales team, decided to see if he could change that.

Gabriel Lazarin at Counsyl headquarters.

Gabriel Lazarin at Counsyl headquarters.

“I wanted to give physicians and patients a shared language,” says Lazarin, who joined Counsyl five years ago as its first genetic counselor. “A way to talk about the impact of a disease in a way that’s more objective than saying “it’s not that bad,” or “it is bad.” Two years ago he helped organize a study to establish a scale for rating genetic diseases and in December the Severity Index was published in Plos One Journal.

The result is that a physician can now easily guide patients interested in carrier screening to a customized outcome. There are patients who find it alarming that they’re carriers for early hearing loss, for instance, while others don’t really mind. Patients can choose to be tested for every disease on the panel, including GJB2-related hearing loss, rated 2, or moderate. Or maybe they only want to be evaluated for conditions that have been rated 4, or profound, such as Canavan disease and Smith-Lemli-Opitz Syndrome. The beauty of the Severity Index is that it’s up to patients to decide on their level of tolerance. Says Lazarin, “I hope this starts us down a path of making it easier for physicians to discuss screening with their patients.”

Internship with a genetic counselor sparks a career

Lazarin has always loved science and as an undergrad at Stanford was naturally drawn to genetics. News about the genome was exploding in the early 2000s and when an advisor noticed his interest he suggested Lazarin consider genetic counseling. Intrigued, he shadowed a genetic counselor and discovered he loved it. He spent a couple of years after graduation working in the Stanford admissions office but couldn’t shake the connection he’d felt so he applied to the masters program at the University of Texas Health Science Center at Houston.

IMG_2205Lazarin arrived at Counsyl after a stint working in a high-risk pregnancy clinic in Phoenix doing prenatal genetic counseling. His chance to be a Counsyl client came a couple of years ago when he and his wife, a family physician who lives with him in New York City, decided to have a baby. “I knew to not expect anything bad but I also know from clinical experience that the unexpected happens,” he says. So it was a relief, he says, to find their children weren’t at significant risk. In December, he and his wife welcomed a healthy baby girl.

Lazarin, who recently explained his study approach in a guest post on the DNA Exchange, says he’d love to do more research. “I think we’re helping advance the field of genetic counseling by taking something complicated and turning it into something predictable,” he says. “I’m happy to be working with an organization that’s so willing to share information that benefits everyone.”


Statement issued by medical experts recognizes growing popularity of expanded carrier screening

4 Mar

Explaining the value of expanded carrier screening just got a whole lot easier. Five professional organizations, including ACOG, ACMG, SMFM, NSGC, and the Perinatal Quality Foundation, recently issued a joint statement in the March issue of Journal of Obstetrics & Gynecology (1) that helps clarify for physicians how to use expanded carrier screening and, even more important, who can benefit from it. By doing so the group clears up misconceptions that have prevented many men and women from getting screened. It also validates Counsyl’s commitment to reaching a broader population and offering genetic counseling support.

This is the first instance in which a coalition of medical organizations has issued a statement on expanded carrier screening, and it was time. Thanks in part to the drive by Counsyl, among others, to make screening more affordable, expanded carrier screening has become a much more common practice. “One impetus for doing this was the recognition that many practitioners were already offering it and it was time to provide some guidance,” says Dr. Jim Goldberg, Counsyl’s Chief Medical Officer and a reproductive genetics expert who was one of the authors of the Joint Statement prior to joining Counsyl.

Misconceptions about who’s eligible for ECS hurts families

Another even more important reason for issuing the statement on carrier screening is that outdated thinking means many growing families are missing out on its benefits. Carrier screening, the group says, is no longer just for people with a family history of a disease or a parblog image journalticular ethnic background. “Ethnic-based panels miss couples at risk for an offspring with a significant disorder,” says Dr. Goldberg. In acknowledging the importance of making carrier screening a routine part of preparing for a baby, the joint statement “basically supports everything we’ve been saying about the utility of screening more people for more diseases,” says Shivani Nazareth, Counsyl’s Director of Women’s Health.

There’s still no consensus on the severity of diseases a screening should include but that may be next. Says Nazareth, “I think this is an acknowledgment that we’re moving in the direction of having a standard of panel of diseases that we screen for prior to pregnancy, no matter what your background or ethnicity.”

Highlights of the joint statement:

Carrier screening is useful and gives patients critical information and options. “Carrier identification allows for preconception planning as well as the option of prenatal diagnosis for the couple at risk. Early identification of affected pregnancies allows condition-specific counseling and care.”

Carrier screening is an important part of preconception and prenatal care. While the statement does not replace individual society medical guidelines, it offers direction to doctors who wish to offer carrier screening to patients. In other words, it validates that this practice is here to stay.“Carrier screening for inherited genetic conditions is an important component of preconception and prenatal care.” They go on to state“Whether the practitioner follows current professional society recommendations or uses expanded carrier screening, the goal of preconception and prenatal carrier screening is to provide couples with information to optimize pregnancy outcomes based on their personal values and preferences.”

Carrier screening should not be limited by ethnicity. The authors acknowledge that relying on ethnicity and/or ancestry to determine what diseases to screen for has limitations, especially in our “increasingly multiethnic society.” The authors indicate that carrier screening should offer the same set of diseases to all patients, regardless of race or ethnicity.
“All individuals, regardless of race or ethnicity, are offered screening for the same set of conditions” due to “inaccurate knowledge of ancestry in our increasingly multiethnic society” and “recognition that genetic conditions do not occur solely in specific ethnic groups.”

Candidates for carrier screening include: a) women of reproductive age before conception; b) egg and sperm donors; and c) pregnant couples. Preconception screening can be offered sequentially or in tandem (both partners at the same time) but for pregnant couples it makes more sense to screen mom and dad at the same time.

Genetic counseling for at-risk couples is an important part of the expanded carrier screening process. The authors agree that it is not practical or necessary for doctors to explain each condition to patients before testing. But while pre-test genetic counseling for each disease is not required, at-risk couples need genetic counseling to understand what it means to be a carrier.“Health care providers who use expanded carrier screening should have a plan to provide accurate information to patients identified as carriers of a condition.” This is further evidence that Counsyl, which offers post-test genetic counseling with every screen, is doing it right.

1. Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the american college of medical genetics and genomics, american college of obstetricians and gynecologists, national society of genetic counselors, perinatal quality foundation, and society for maternal-fetal medicine. Obstet Gynecol. 2015 Mar;125(3):653-62

Leading expert in reproductive genetics joins Counsyl as CMO

18 Feb

JIMBefore Dr. James Goldberg joined Counsyl as its Chief Medical Officer he was a client. In the nine years he worked as a partner at San Francisco Perinatal Associates, he talked to hundreds of patients about the value of expanded carrier screening. In the course of assuring them that the Family Prep Screen is affordable and reliable, he became intrigued by the organization behind it. It didn’t hurt that three of the genetic counselors he’d worked with ended up joining the Counsyl team and could vouch for it.

By the time Counsyl reached out to him he was already receptive. The query came at a time when Dr. Goldberg was also considering making a major career change. “I sat back recently and realized I’d have the biggest impact on genetic medicine if I could come at it from the industry side,” he says. “Then I just had to decide where best to do that. Since I’ve known Counsyl for a long time and know they do good work the decision was actually pretty easy.”

In his new job as CMO, Dr. Goldberg will focus on increasing awareness of expanded screening within the medical community and finding effective ways to implement new screening tests. He already sees an uptick in acceptance based on the increasing information available. It’s now much easier for doctors to provide educational support. When couples were tested for only two or three disorders a typical counseling session included detailed discussions on each one. Now, with a test that screens for more than 100 diseases, there’s been a shift to talking about the diseases only if a risk has been identified. If a couple is not found to be at increased risk, counseling remains optional.

Dr. Goldberg first became excited about the potential of reproductive medicine as a graduate student at the University of Minnesota Medical School when the field was just taking off. Prenatal screening was brand new and typically recommended for couples with known family histories or specific ethnic backgrounds. But Dr. Goldberg, who eventually earned a masters in genetics and after medical school, residency, and a fellowship went on to practice reproductive genetics, recognized its potential almost immediately. “I committed to this field of study because it had the most direct and quickest applications that could be brought into clinical care,” he says. New discoveries could be rapidly applied to patient care.

When it came time to do his residency in Obstetrics and Gynecology he chose the University of California, San Francisco – and balmy weather. The Bay Area suited him. “I had no idea life could be so good,” says Dr. Goldberg, who has lived here ever since. His 30-year-long career includes serving as the director of the Reproductive Genetics Unit at UCSF and subsequently as co-director of the Prenatal Diagnosis Center at California Pacific Medical Center. At San Francisco Perinatal Associates he was director of the Prenatal Diagnosis Center. A well-respected researcher, Dr. Goldberg has worked closely with ACOG, among other notable organizations, and co-authored its recent release on expanded carrier screening. He will continue to organize and oversee clinical studies within Counsyl. “I’ve experienced the full length of the clinical spectrum in reproductive genetics,” he says.

Dr. Goldberg lives with his wife, Vicki, in Tiburon and “dimly” remembers undergoing screening when she was pregnant with his oldest daughter who is now a 27-year-old lawyer in Boston. “I think it was for Tay-Sachs,” he says. He has moved into Counsyl’s East Wing, in the cubicle next to the white board that says “Welcome Jim” (for now, anyway), and is looking forward to meeting everyone. “I’m hoping people will reach out to me with any concerns or questions,” he says. “I want to be a resource for any clinical issues that may come up.”

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.

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



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