Category Archives: Guest Blogger

The GC Crucible: the pressures on modern genetic counselors open the doors to opportunity

A Guest Post By Brianne Kirkpatrick

In a chemistry lab, a ceramic crucible held over an open flame melds disparate materials into a single, new, cohesive thing. Indestructible, it stands up to the heat and pressure. When used in metaphor, it’s a severe test or tribulation that leads to transformation. What comes out of a metaphorical crucible is the true character brought about by the need to adapt and change in a new environment.


If there is one thing I can get behind, it’s a belief that our job as genetic counselors is getting

harder. We work in a cauldron of new pressures and new challenges, ones that are causing us to adapt and discover what is at the core of our profession and what make us strong and unique, as individuals and as a cohesive group. We’re in a crucible right now, and that Bunsen burner is cranked up high.


Our clinical challenge is that the more we learn about genetics, the more complexity we discover (see item two in Laura Hercher’s top ten stories list for 2015 ). More information makes our job harder, even as it provides new hope for our patients. Similarly, the challenges of discovery and complexity that complicate our lives also provide new opportunities for genetic counselors.


How do we capitalize on those opportunities? Here are three suggestions:


  1. Rally around the development of the Genetic Counseling Assistant vocation. The NSGC funded a grant to study this, and there have been discussions about this at recent meetings and on various listservs. GCAs job are available, and individuals are employed as GCAs around the country already, in laboratory and clinical settings. Like a para-legal to a lawyer, GCAs master administrative tasks and carry the burden of extra work that often sidelines the genetic counselor or reduces his or her efficiency – phone calls, paper work, records requests, insurance pre-certifications, initial intakes, and the like. The only way we are going to keep up with the demand for GC services is to increase efficiency for ourselves and free up genetic counselors from work that impedes their ability to serve all who need and are seeking their services.


  1. Evolve or die. We as a profession must figure out how the future of genomics will include us. To do this we must immerse ourselves in current issues – in the clinic, in the research world, in the spheres of business and government – and then speak up when the genetic counselor voice must be heard. Get involved in your state’s genetic counselors’ group (consider founding one if it doesn’t exist). Volunteer in groups and for projects of the National Society of Genetic Counselors. Develop a professional social media presence. I chose to involve myself in the NSGC Public Policy Committee, believing strongly that taking a stand on issues of policy that affect us as genetic counselors allows us to determine our profession’s destiny, not others. Every committee and special interest group and task force of the NSGC contributes important work to the genetic counseling profession, but none of that work happens unless individuals decide to take that step and get involved.


  1. Embrace the expansion of our professional opportunities, despite the shortage of genetic counselors to fill existing clinical and laboratory roles. GC’s are finding opportunities to do something new and different, which is fitting for a group who collectively are thinkers outside of boxes. For as long as the profession has existed, GCs have used creativity, ingenuity and chutzpah, trailblazing new roles out of necessity. In every city and in every specialty area, there was a “first” GC there. If you have been contemplating blazing your own trail, now might be a good time to test out the waters, to find your niche and try something you’ve been dreaming of.


There are role models for those looking for them, as GCs excel at identifying needs and making connections. We’re problem-solvers and sleuths, and we’re a resourceful bunch. From this, we have seen Bonnie Liebers develop Genetic Counseling Services, which creates specialized teams of genetic counselors for growing businesses who need them, utilizing a world-wide network of CGCs. A group of GCs recently published an article in the Journal of Genetic Counseling sharing their experiences working for startup companies. I recently launched my own solo venture, WatershedDNA, to provide consultations on ancestry and other home DNA tests, both privately and as a part of larger projects or for companies. The niche I found was filling a need for genetic genealogists, adult adoptees, the donor-conceived community and others, all of them looking for someone who understood the psycho-social dimensions and the science behind genetic testing for ancestry and ethnicity. A perfect role for a genetic counselor, and a match for my own natural interests and passion.


Currently, I work one-on-one with clients referred to me by the genetic genealogy community, mostly individuals who have already pursued a home DNA test or are considering it. Just as in a clinical setting, we begin with family history when available and identify a client’s goals and areas of concern. We review any results they already have and discuss additional testing options, and how they might affect them and family members, now and in the future. Working fee for service and owning my own business come with financial uncertainty and lots of unknowns, but it gives me other freedoms, including flexibility and the sense of adventure that comes with pursuing an entrepreneurial path (like my father and grandfather – genetics?). It isn’t easy; I’m a worrier by nature, and some days that Bunsen feels like it’s a-burnin’ hotter than usual. But like the genetic counseling profession as a whole, I’ve found myself in the midst of a crucible that isn’t trying to destroy me; it is providing me an opportunity. A chance to change and create, to extend the reach of genetic counselors. It will engender a future of great things, if I allow it.


Let’s be willing to face the uncertainty that the wild west of genetics brings, be daring, and embrace the shades of gray as we blaze new trails. None of us chose the profession of genetic counseling because we thought it would be easy.



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Guest Post: Sometimes It’s Okay To Fail

by Lisa Demers and Stephanie Snow

Stephanie Snow, MS, CGC has 11 years of prenatal genetic counseling experience. She worked as a clinical site coordinator and genetic counselor for the FASTER study and as a clinical research coordinator for the NEXT study. Lisa Demers, MS, LGC has 12 years of prenatal genetic counseling experience and currently works with Ariosa Diagnostics as a Medical Science Liaison.

The landscape of prenatal screening is changing. The use of non-invasive prenatal testing (NIPT) in clinical practice is already common and is being adopted quickly by generalist obstetricians and maternal fetal medicine specialists. While the cell-free DNA technology is innovative and the impact on patient care is significant, there is a rising chatter about NIPT failures – the 1-8% (depending on the company) of reports that return without a test result. This is a dual issue – there’s the underlying “annoyance” that NIPT occasionally fails to produce a result, and then there are publications suggesting an association between fetal aneuploidy and test failure. The latter is a conversation for another day.

Although these “no call” results frustrate patients and their doctors, the negativity surrounding these failures is surprising. The concept of a test failing is not new in medicine, and certainly not within prenatal medicine. Increasing rates of maternal obesity are just one reason for limited prenatal surveillance, with one study demonstrating that 41% or less of fetal survey ultrasounds on patients with a BMI of 30 or higher were able to be completed on the first try. When it comes to first trimester measurement of nuchal translucency (NT), the FASTER trial noted an overall 7.5% failure rate, either because of an inability to measure or due to inaccurate measurement. In a review of patients within one clinic, where nearly 50% of patients had a BMI over 25 and 25% had a BMI of 30 or more, 4% of patients had an NT failure on the first attempt and of those who opted for a second attempt, 18% failed. Overall in this population, 2.7% of patients did not achieve a NT measurement.

This is not to say that test failures are necessarily bad. When an NIPT test fails, it is often because quality metrics are in place to ensure proper test performance – just as there are standards for NT measurement which are established by the Fetal Medicine Foundation (FMF) and the Nuchal Translucency Quality Review (NTQR) program. An NT may “fail” because a patient presents for screening outside of the appropriate gestational age requirements or because of suboptimal fetal positioning. The nuchal translucency measurement is critical in obtaining aneuploidy risk assessment when combined with serum biochemistry, and even the slightest over or under estimation dramatically impacts clinical care. Such is the case with NIPT quality metrics. These metrics are in place to ensure appropriate risk assessment for the pregnancy, with the most important of these being fetal fraction. Fetal fraction is greatly affected by maternal weight, with obese women less likely having the required minimum concentration of fetal DNA in circulation. Here again, maternal obesity reduces our ability to accurately assess the well-being of a fetus.

In reality, any test failure rate can be a nuisance to a busy clinic. Having patients return for an additional visit is inconvenient to patient and provider alike. However, there are biological and technical reasons for at least some NIPT tests to fail. The thoughtful provider will consider the various metrics involved with the NIPT options and select one that balances high quality metrics (including fetal fraction) and low rate of technical failures.


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Guest Post: PPV Puffery? Sizing Up NIPT Statistics

by Katie Stoll and Heidi Lindh

Heidi and Katie are genetic counselors and both work with the newly established charitable nonprofit, the Genetic Support Foundation (twitter @GeneticSupport),

The importance of the Positive Predictive value (PPV) in interpreting Noninvasive Prenatal Testing (NIPT) results is increasingly on the minds of providers as evidenced by frequent discussions, presentations, and publications on the topic. But what if, in an effort to make their lab look like the best lab, the NIPT PPV was overstated in marketing materials or even on test reports? And what if providers and patients believed this information without question or further investigation?

Until 2014, four labs (Sequenom, Verinata Health/Illumina, Ariosa and Natera) were the only companies in the United States that offered NIPT. Over the past year, we have seen a burgeoning of new labs offering their own branded NIPT tests. In some cases, the 4 original companies act as “pass-through” labs in which the testing is branded and advertised through a secondary lab however the sample is ultimately sent to the primary lab for analysis and interpretation. In other cases, referral labs have brought NIPT testing in-house, developing their own algorithms and reporting, such as the case for the InformaSeqTM test offered by LabCorp and Integrated Genetics. In a recently published marketing document, Illumina lists 16 laboratory “partners” that all offer a version of the Illumina NIPT. The other primary NIPT labs are also distributing their tests through other labs as well; Quest Diagnostics and the Mayo Clinic have been secondary labs for the Sequenom NIPT (Quest also has their own brand, the “Q-Natal Advanced”and Natera’s NIPT is available through GenPath and ARUP).

The growing number of laboratories that offer some version of NIPT presents a significant challenge for healthcare providers who are struggling to navigate the various testing options to determine what is in the best interest of their patients. The competitive commercial landscape and aggressive marketing of NIPT to both patients and providers can further confound clinical decision-making given the paucity of information available to providers that is not delivered with an angle aimed at selling the test.

NIPT Statistics in Marketing Materials

We have noted that multiple labs offering testing have promoted extraordinarily high positive predictive values (PPVs) in their marketing materials distributed over the past year and on their websites ^ and on laboratory test reports. These tables include information regarding PPV frequently reference data from the Illumina platform and VerifiTM methodology and a study by Futch et al. as the source.


Performance Data Presented in Marketing Brochures for NIPT
Condition PPV NPV Sensitivity Specificity
T21 0.994 0.999 >99.9% 99.8%
T18 0.910 0.999 97.4% 99.6%
T13 0.843 0.999 87.5% >99.9%

These figures (or slight variations thereof) have been observed in the marketing materials for multiple laboratories offering NIPT. These specific statistics were reproduced from an InformaSeq brochure and sample test reports available online


The PPVs reported in this table – being widely distributed on test reports and as educational information for providers – have NOT been demonstrated by the referenced study by Futch et al. or any published NIPT studies of which we are aware.

Of course, the PPV of a screening test depends on the prevalence of the condition in the population being screened. Using the sensitivity and specificity of testing accompanying these predictive value data in the same brochure, one could only derive PPV of >99% if the prevalence of Down syndrome in the screened population was 25% or 1 in 4 pregnancies, far higher than the a priori risk for the vast majority of women undergoing prenatal screening.

PPV = (sensitivity x prevalence) / ((sensitivity x prevalence) + (1 – specificity)(1 – prevalence))

.994 = (.999x.25)/((.999x.25) + (1-.998)(1-.25)

In contrast, if we utilize performance statistics provided by the laboratories, we calculate a PPV of 33% in a population with a prevalence of 1 in 1,000 (which is similar to the prevalence for women in their 20’s) and a PPV of 83% in a population with a prevalence of 1 in 100 (which is similar to the prevalence in women age 40).

The Futch Factor

The study by Futch and colleagues that is frequently cited in marketing materials for NIPT does not demonstrate the high PPVs that are referenced, although we suspect that these statistics were arrived at through a series of assumptions about the Futch data that we will attempt to outline.

This study reported that in a cohort of 5,974 pregnant women tested, there were 155 positive calls for T21, 66 positive calls for trisomy 18, and 19 positive calls for trisomy 13. In this published report, only a fraction of the positive NIPT results had confirmation of the fetal karyotype, 52/155 cases of Down syndrome (33.5%); 13/66 cases of trisomy 18 (19.7%); and 7/19 cases of trisomy 13 (53.8%). There was 1 case of Trisomy 21 that had a normal NIPT result (false negative result), however negative test results were not methodically followed-up, so the true false negative rate for the screened conditions is unknown.

In analyzing the data presented by Futch et al, for marketing materials to derive PPVs of >99% for Down syndrome, 91% for trisomy 18 and 84% for trisomy 13 would require that all of the positive calls WITHOUT follow-up by karyotype confirmation were true positives.


Outcomes data from Futch et al, 2013 and projected PPVs based on category inclusion or exclusion as true positive.
T21 T18 T13
NIPT Positive 155 66 19
Confirmed (karyotype or birth outcome) 52 13 7
Discordant (Unexplained NIPT results that do not match karyotype from a source or birth outcome) 1 6 3
No information (laboratory did not obtain any information on outcomes) 22 12 0
Pregnancy loss (miscarriage , demise or termination without karyotype) 7 5 2
Unconfirmed (no karyotype or birth outcome known but history of clinical findings suspicious of aneuploidy such as ultrasound findings or high-risk biochemical screening results ) 73 30 7
Total Positive NIPTs where follow-up karyotype not confirmed 102 47 9
High End PPV* 99.4 90.1 84.2
Low end PPV** 33.5 19.7 36.8

*High end PPV- It appears that marketing material PPVs are considering all categories, including confirmed, no information, pregnancy loss, and unconfirmed to be TRUE positives in determination of PPVs.

**Low end PPV- calculated considering all cases, which were not discordant to be false positive results. A minority of positive NIPT results were confirmed with birth outcome or fetal karyotype information.


Given that Futch et al. did not have confirmed fetal karyotype or birth outcome follow-up for the majority of positive calls, it seems at best unlikely, and at worst impossible, that all of these positive NIPT results were correctly called, rendering claims of such high PPVs in the marketing materials based on this assumption to be unfounded. On the other end of the spectrum, if the PPV was calculated to include the not-karyotyped/no-birth outcome information pregnancies as false positive, the assumed PPVs would be 33.5% for Down syndrome, 19.7% for trisomy 18 and 36.8% for trisomy 13. Since the study does not report follow-up karyotype for the majority of positive test results, the true PPV for these NIPTs test likely lies somewhere in-between the high end PPV and low end PPV, perhaps closer to the 40-45% (for T18 and T21) previously reported in another Illumina sponsored study.

While the PPV of NIPT for Down syndrome, trisomy 18 and trisomy 13 exceeds that of traditional biochemical screening, no studies have demonstrated test performance as high as those presented in many of the PPV/NPV tables that are being provided to healthcare providers in marketing materials and, in some cases, on test reports.

A Call For Truth In Advertising And In Test Reporting

Honest communication about test performance metrics must be available to providers so that they can provide accurate counseling to patients making critical decisions about their pregnancies. While most labs do state that NIPTs are screening tests and that confirmatory testing of positive results is recommended, it is not surprising that providers and patients are having difficulty appreciating the possibility of false positive results when the laboratories are incorrectly reporting positive predictive values that exceed 99%. The consequences of relying on lab-developed materials rather than a careful analysis of the available literature are significant. There are reports of patients terminating pregnancies based on NIPT results alone. It is not surprising that some women choose not to pursue diagnostic testing to confirm abnormal NIPT results given the very high stated predictive value.

It is imperative that we recognize not only the potential benefits of these new technologies but also their risks and limitations. Testing companies are primarily responsible to their shareholders and investors, so information provided by companies about their products is largely aimed at increasing test uptake. Professional societies need to call for independent data and federal funds need to be made available to support independent research related to NIPT. Policies and best practices cannot arise from the industry-influenced studies that are currently available. While some regulatory oversight of marketing materials will likely be necessary, we urge the laboratories to consider their marketing approach and how it is affecting patients and providers. If laboratories want to truly partner with patients and providers, they need to provide accurate and straight-forward information to limit provider liability and likewise, help patients avoid making life-changing decisions based on inaccurate and/or confusing information related to test performance. As a medical profession can we come together and make this change without regulatory oversight? Now that would be a medical breakthrough.

^ – Notably, Counsyl has also recently produced a table that provides more accurate estimates of their NIPT predictive values



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Guest Post: Starting a discussion on severity and the merits of carrier screening

By Gabriel Lazarin, MS, CGC

Gabriel is the Director of Genetic Counselors at Counsyl, a laboratory that offers expanded carrier screening.

Discussions about carrier screening inevitably center around disease severity. Is the disease severe enough that it is worth offering screening? Who defines severity and then who decides whether that category of disease severity merits population screening?

These questions are easily recognized, but subjectively answered. Both sides of a complicated equation must be balanced. Physicians and public health officials desire screening protocols that address pressing medical concerns knowing that any screening program comes with costs, financial and otherwise. Parents-to-be have an interest in knowing what daily challenges they may face. Unsurprisingly, these sometimes competing interests result in conflicting perspectives on disease severity.

The focus on severity has increased as carrier screening panels have expanded the list of potential diseases for which a person may be screened. Despite the lack of consensus on definition of the word, severity is nonetheless cited in literature and referenced in conversations about carrier screening. In the ACMG’s statement on expanded carrier screening, the first criterion for consideration is, “Disorders should be of a nature that most at-risk patients and their partners identified in the screening program would consider having prenatal diagnosis…” Setting aside for the moment the stipulation that prenatal diagnosis should be considered (I, and many prenatal GCs, have many times encountered the patient that changes decisions once a hypothetical scenario becomes real), a paraphrase is that a disease should be severe enough so as to be “worth” screening.

The ACMG statement references severity again, saying, “The inclusion of disorders…associated with a mild phenotype should be optional…” A physician offering the test (and the laboratory supplying it) can reasonably question which specific disorders have a “mild” phenotype. Is hearing loss a mild phenotype, and who has the authority to make that decision? The recent joint statement on expanded carrier screening notably excludes commentary on severity, which further highlights the difficulties of its use in panel design. 

In December, PLoS ONE published a study conducted by myself and others at Counsyl that is a first attempt at defining severity. ACMG provided the backbone of this approach: severity was one characteristic assessed when developing a universal newborn screening panel recommendation. Nearly 300 people participated in this significant endeavor, including at least 3 experts for every disease. While successful, replicating that process — laboratories have been updating their screening panels at least once a year — is prohibitively labor-intensive. We aimed for a process that was easily replicated and did not require convening experts of rare diseases.

Our results validate an algorithm that incorporates easily identifiable characteristics such as shortened lifespan or sensory impairment, and places that disease into one of four categories (also derived from ACMG): mild, moderate, severe, and profound. This avails the following advantages: more consistency among laboratories for selection and presentation of screening panels, and a common vocabulary among providers for describing diseases (like the singular language offered by a tumor staging system). Furthermore, the survey was completed in just under 6 minutes on average, making it much more practical for frequent use.

The study population included GCs and physicians, the majority working in reproductive settings. We intentionally did not attempt to identify experts on the diseases surveyed. Instead, commonly known diseases (e.g., cystic fibrosis) and lesser-known diseases (Bardet-Biedl syndrome) were concurrently assessed. All were evaluated in a consistent manner, indicating that familiarity does not affect severity categorization. In addition, the algorithm is completed by identification of disease characteristics not disease names. Even if an evaluator was not familiar with homocystinuria per se, she would certainly understand a list of its characteristics, such as intellectual disability and shortened life expectancy.

So, what’s next? A status check on current expanded screening offerings seems reasonable – Counsyl GCs applied the algorithm to 63 diseases that are common to three commonly-used commercial panels and determined that 25 have profound severity (e.g., Herlitz junctional epidermolysis bullosa, Tay-Sachs disease and metachromatic leukodystrophy) and 38 are severe (cystic fibrosis, ataxia telangiectasia, primary hyperoxaluria). All being in the two most impactful categories, many providers would likely agree on their inclusions.

However, another reasonable next step is to identify and reconcile differences that might be discovered by surveying the reproductive-age patient population. We, the medical community, also need to determine the desired aims of a screening program and apply those aims with consistency and objectivity. It could very well be that expectant parents and obstetricians agree with the ACMG’s statement that interest in prenatal diagnosis should be an influencing factor in a screening panel (what patients want has historically been an absent consideration in constructing guidelines).

But what about those who are not yet pregnant? Without the pressures of pregnancy, is it reasonable to allow the opportunity to consider a wider range of diseases? Obstetricians and GCs are more accepting of pre-pregnancy expanded screening. In pregnant women, decision-making can be influenced by interests in reducing stress and delaying information until after birth in order to reduce anxiety. A carrier screening protocol should serve the interests of pregnant and non-pregnant women, perhaps utilizing different severity thresholds for each scenario.

Through this study and blog post, I hope to open the conversation about what diseases should be screened, who should be screened for them and when that screening should happen. Without a standardized, objective vernacular, these discussions are colored by personal beliefs (which may not align with patient beliefs) and assumptive interpretations of important criteria. This is but a first step that needs to involve all stakeholders – providers, patients and professional societies. By first developing this standard language, we can begin this important discussion.


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Guest Post: NIPS: Microdeletions, Macro Questions

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetics.

At the recent National Society of Genetic Counselors Annual Education Conference in New Orleans, a presentation raised some important questions about noninvasive prenatal screening (NIPS). According to the speaker, a woman with a vanishing twin pregnancy underwent NIPS with an expanded microdeletion panel and the results showed findings “suggestive” of a chromosomal microdeletion syndrome.

The patient underwent amniocentesis with a SNP microarray and the results were normal. In a follow-up call with the NIPS lab, the genetic counselor learned that multiple copy number variants were observed (not originally reported) in the original sample. The lab suggested that these variants could be associated with a malignancy or fibroid tumor (and were of course unlikely to be associated with a microdeletion syndrome in the fetus).

As a result of this genetic counselor’s follow-up phone call and due diligence, the patient underwent an extensive work up for possible cancer, but no explanation was found. NIPS was repeated and this follow-up study was normal.

My first thought in hearing this case was – That poor woman! First a lost twin pregnancy, then concern for a severe condition in her baby, anxiety about the amnio, and worry that she may have Cancer. Although I am not a health economist, my second thought was – Holy Cow! How can our healthcare system afford all of the follow-up testing that may come downstream from these tests? NIPS is promoted as a test that will lessen the need for follow-up procedures such as amniocentesis, but will that remain true as the list of screened conditions increases?

In October 2013 Sequenom expanded their NIPS test to include screening for microdeletion syndromes and Natera followed suit in Spring 2014. Some new companies entering the NIPS market are also advertising screening for microdeletion syndromes.

The addition of microdeletions is a brilliant business strategy for expanding the testing market to include all pregnant women. Even though microdeletions are rare, their incidence—unlike that of Down syndrome –is not linked to maternal age. Women who are currently not offered NIPS because they are not included in the high-risk categories proposed by the American College of Obstetricians and Gynecologists (ACOG) guidelines could now be given a reason to undergo NIPS—even though the predictive ability of the NIPS for rare conditions is less than impressive.

Women who elect the test because of an interest in Down syndrome or because they are eager to learn fetal gender may unknowingly be screened for rare microdeletion syndromes which they know little to nothing about. To add to the complexity, a maternal microdeletion condition may be an incidental finding. In a poster presented at the NSGC meeting this year, Sequenom presented a series of 22q11 deletions detected with their MaterniT21 PLUS test. Included in this report were two mothers who were themselves incidentally diagnosed with 22q11 deletion syndrome. Based on the consent form on the Sequenom website it seems unlikely that these women had any idea such a result may occur.

Where is the evidence to support this expanded screening?

These tests are being performed despite there being no published clinical validation studies. There have been some case reports and proof of concept studies; however given that this testing has been commercially available for over a year now, there is shockingly little published about cell free DNA screening for microdeletions. An abstract from a poster presentation at the ACOG annual meeting in April 2014 evaluated 6 samples (or is it 7? – it is not clear from the abstract) from pregnancies known to be affected with microdeletions and 8 simulated samples. They conclude, “This is the most comprehensive, accurate validation of noninvasive microdeletion detection hitherto… This approach will enable accurate, noninvasive, prenatal population screening for these severe disorders.”

Proof of concept is one thing; proof of clinical validity is another. If we value evidence-based medicine, a sample of six (or seven) affected pregnancies is a long way from being a basis for population screening. Whether population-wide screening for extremely rare disorders is worth paying for is, of course, a question in itself.

But in the unregulated environment of laboratory-developed tests, we adopt first and report out results later. Accompanying this process is a lack of transparency – labs performing NIPS with microdeletions have not made performance statistics publicly available and thus patients and providers have no way of determining the accuracy of microdeletion NIPS. In a webinar hosted by Sequenom , the presenters were asked about the positive predictive value (PPV) of Sequenom’s screen for microdeletions. One speaker replied, “We have calculated them. However, what we would like is essentially to wait a little bit to give you more clinically relevant results. Because so much depends on the fetal fraction of the sample and so on and so forth, so we feel that the more appropriate number to release is after we have done 50,000 samples, how many have we found, how many have we reported back, how many were confirmed, how many were in line with the clinical picture.”

Shouldn’t the accuracy of the test be publicly known before it is run clinically on 50,000 women?

Labs have given us only a glimpse of their performance statistics. I was previously provided information from Natera regarding estimated PPVs for the microdeletions on their panel, but I cannot locate this information anywhere in the public forum. The table I was provided stated a 1/19 PPV (5.3%) for 22q11 with a Fetal Fraction >6% and dropping much lower (to 1/45) with decreased fetal fraction (interesting thread here of multiple women with a 1/19 chance of 22q11 on their NIPS result).

In a letter to the editor, former CMO of Sequenom Allan Bombard and colleagues reported that they had evaluated 264 samples from pregnancies with known microdeletion and microduplications or “enriched genomic mixtures” and report a 100% sensitivity and 99.3% specificity. Applying these statistics to 22q11.2 deletion syndrome (the most common microdeletion syndrome on the panel with an incidence of 1 in 4,000) indicates a PPV of about 0.036 or 3.6% . The overall PPV would be expected to be lower given the very low incidence of the other microdeletions on the panel. At the NSGC meeting this year, Sequenom presented some preliminary data from a series of 120,726 samples screened from October 2013 – July 2014 with test performance that exceeds those estimates. Although they did not have complete follow-up data for positive and negative results, a press release from the company following the NSGC meeting reports “high positive predictive values (estimated combined PPV ranged from 62% to 94%)”.

The limited information available suggests PPVs for microdeletion syndromes fall within a broad range of <3% – >90%. Published peer-reviewed studies are needed to help clarify the PPV associated with this testing so that healthcare providers and patients can make informed decisions about utilizing and interpreting this testing.

About a year and a half ago I published a piece on the DNA Exchange that discussed the importance of PPV in interpreting NIPS results. This was written for an audience of genetic counselors, but the posting is being increasingly used as a venue for patients to share their stories and seek information about their test results. Many patients report considerable anxiety – “the waiting is killing us…we have been devastated for the better part of 3 weeks now” – and some express regret for undergoing this testing at all, “I too wish I would of just done the typical old fashion test so nothing was in the back of my mind and hours of my life would be given back…” Recently, a woman remarked that she did not consent to additional testing for microdeletions and indicates her frustration with not being able to find information about the PPV for this test, “Not only are they essentially experimenting on us…they are not transparent about the potential problems with validity or low PPV.”

As genetic counselors, we are implicated in these companies’ approach. We should be demanding better evidence before leading our patients towards testing that could create this kind of distress. We need to be asking good questions, and we should demand good answers. If we cannot figure out how reliable a screening test is from a thorough review of the literature, I think we really need to ask ourselves if we should be offering it in a clinical setting.


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Guest Post: Going Public

By Sean Hazell

Sean is VP Brand at Idea Couture, a global innovation consultancy, where he leads teams through the design of new products, services, and programs for Fortune 500 brands. Prior to joining Idea Couture Sean held strategy and communications planning roles at some of North America’s top advertising agencies.

A view from the sidelines

Full disclosure: my wife, Allison Hazell, is a contributor and one of the co-creators of the DNA Exchange.

Prior to the days of the DNA Exchange I would comment to Allie how fascinating I found it that GCs were involved in such innovative health services, and yet the field as a whole felt a bit traditional. Today, however, the community appears more open-minded than ever. From my view, it’s been amazing to observe how much has changed over these past 6 years.

Today, genetic testing is more culturally relevant than I can remember. The levels of testing-related coverage across major media is evidence of the growing public interest; to say nothing of the mentions the DNA Exchange has received. The world of genetics is growing at an almost unfathomable pace, and as we know, with that speed comes complexity and risk of misunderstanding.

Advertisement supporting the Globe & Mail's recent "DNA Dilemma" series.

Advertisement supporting the Globe & Mail’s recent “DNA Dilemma” series.

As the spouse of a GC I can’t tell you how many times I’ve participated in the dreaded “what do you do?” conversation. Recently, the number of blank stares returned is dwindling. This isn’t to say everyone is fully versed in the role of GCs. Rather, its still surprising how unfamiliar most are with the field. But the levels of public awareness around testing are clearly rising. Of late, “what do you do?” is likely to lead to a dozen follow-up questions for Allie – representing a very wide range of understanding on the subject (if we don’t take it upon ourselves to beeline for the veggies and dip).

Which brings me back to the opportunity I see from the sidelines. For all of genetics recent popularity, public understanding is still very low. This gap between interest and understanding will likely only continue to widen, at the rate at which new findings are being reported. Today the GC field has the opportunity – and you might even argue the responsibility – to help to interpret the latest ongoings in genetics for the general public. It’s an opportunity for GCs to repurpose your one-to-one counseling skillset to help to inform public discourse and grow mainstream literacy.

The GC community could become Gen Pop’s go-to source for unbiased interpretation on news and notes of human genetics. With a mandate to narrow the gap between professional and public understanding, the field could not only tackle its own awareness issues, but perform a social service that’s increasingly essential.

If you’re nodding along, the likely next question is… how? There’s never a quick solution to increasing public recognition, but here are a few starter suggestions to spur thinking:

  1. Identify the existing cultural conversations where a GC’s perspective can add value. It’s a lot easier to earn attention through existing conversations rather than finding followers for entirely new ones.
  2. Connect with people and parties who are driving related dialogue. Find ways to collaborate with peripheral parties, even if your perspective differs. Responding through an official statement is far less compelling than having a constructive conversation.
  3. Develop awareness initiatives that help to demonstrate what you do, versus those that simply state what you do. Good comedians don’t tell you they are funny. Find creative ways to show the general public how valuable your role is today.

I realize the notion of inserting GCs into the public arena is not a new idea (most recently, see #3 in Bob’s future post). But the timing feels right to make a push. Whereas many GC awareness initiatives I’ve followed have focused on physicians, the bigger opportunity could lie in aiming straight for the mainstream. An age of health information overload is emerging. As direct-to-consumer services increase awareness, there’s a corresponding need for a direct-to-consumer approach to increasing genetic understanding. And from where I’m standing, there seems no group better suited to guide that conversation.

Thanks for having me. I’d love to hear your thoughts, responses, or related experiences.

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Guest Post: The Most Powerful Breakthrough in Genetic Science is…Hope

By Jim Small


Jim Small is an entrepreneur, speaker, author and successful real estate investor. A sudden family tragedy led him to discover his life’s purpose and career passion. Jim uses his real estate passion to help others create abundance and fulfill his life’s purpose of helping one million children reach their full potential. Jim is currently expanding his global reach on this mission by partnering with other world class speakers, motivators and industry game changers. Jim continues to speak around the world to groups about his personal journey and how others may find their purpose, passion and prosperity, through his Triumphant Legacy™ program (

Our family story and experiences with genetic counselors revolves around our oldest daughter, Sophia. Sophia was born totally typical with high APGAR scores and developed quite normally for her first year life. Then, somewhere between 15 to 18 months old, my wife and I noticed that she was regressing in her engagement with others – in her language and in her social skills — and she continued to deteriorate from there. We took Sophia to therapists and doctors, and the only thing that they could say was that she might potentially have the behaviorally diagnosed disorder of autism. So, for a couple of years, my wife and I tried to help Sophia with therapies, diet and alternative medical treatments, presuming that she had autism… and she really wasn’t getting any better.

A friend advised us to get a full-team assessment at a hospital in California. We took Sophia there for a work up which included neurologists, cardiologists, gastroenterologists, infectious disease doctors, immunologists – the full gamut. These specialists evaluated Sophia and then met as a team. One of the outcomes was to do some additional genetic screening for Sophia. She had already been tested for Fragile X, Rett Syndrome, Angelman and some other things that had all come up negative in the past, so my wife and I reluctantly agreed to do some more blood draws for additional genetic tests. When the results came back, we were asked to return to the hospital to discuss the findings with a neurologist and a genetic counselor. Before the meeting, Audra was told over the phone that Sophia had tested positive for Rett Syndrome and we were then sent the test results.

Not really knowing what Rett was, we waited to meet with the neurologist and the genetic counselor to learn about it. Our appointment was horrible. The doctor was clearly very experienced in neurology and she briefly explained a little bit about the genetic mechanism that causes Rett Syndrome – a mutation of the MECP2 gene on the X chromosome. Then the genetic counselor started to guide the conversation as she handed us a book on Rett syndrome. They both proceeded to tell us all the things that Sophia would NOT be able to do, how horrible her prognosis was, how difficult her life would be and how sorry they were that no treatments were known or forthcoming to help with the situation.

Needless to say, my wife and I left there feeling quite shocked, devastated and powerless. Basically, we went home and waited for our daughter to deteriorate as they said she would, doing nothing to improve her health for the next six months.

Then, as we were trying to treat her seizures (one symptom of Rett syndrome), we ended up seeing a neurologist at a hospital in Massachusetts, who suggested that we meet with a geneticist and a genetic counselor affiliated with that hospital and a very prominent medical school. Naturally, my wife and I were reluctant to do so after our experience at the hospital in California, but we really respected this neurologist, as he was extremely insightful, up on the research and very progressive. So we agreed to see this new geneticist in Boston. In meeting with him, we were given hope for the first time – he explained that there had been a reversal of Rett Syndrome symptoms in mice and that he was of the belief that in the coming years, we would be able to find a mechanism to help girls like Sophia reverse Rett syndrome completely. Moreover, he had been working with girls with Rett syndrome for many years, and told us that girls who presented like Sophia actually have a much better prognosis than what was described to us bythe genetic counselor at the California hospital.

Then his genetic counselor colleague came in to join the conversation. She explained once again the cause of Rett syndrome, and then began to elaborate on how they were looking into trials for particular drugs and treatments that may reduce the severity. Both the doctor and the genetic counselor stressed the many girls they had seen, like our daughter, who ended up having all kinds of abilities that weren’t in the text books and weren’t part of the old school prognosis (which they believed was outdated) and suggested that the future for our daughter was actually quite positive. Although my wife and I respect the first doctor’s and genetic counselor’s prognosis as historically accurate, we were struck with the 180 degree difference between that negative and de-motivating scenario and the hopeful perspective of the second geneticist.

Working with the team in Massachusetts, wife and I have felt very empowered and optimistic about our daughter’s future. Although the research available to both groups of genetic counselors was the same, the presentation of the facts, the future, and the prognosis were dramatically different. We hope that all families experiencing an issue that requires the help of a genetic counselor will have an experience as favorable as our second encounter, where we got hope along with the facts and an understanding of the reality. I think that optimism can make genetic counselors more effective, more empowering and more giving.

With medicine, nobody knows the future. Although experience and literature allows us to be familiar with the past, no one ever knows what scientific and medical breakthroughs will happen over the course of a human lifetime. So, as genetic counselors provide information, help and resources to families, I think it’s critical that they remain optimistic about the potential changes we are going to see in the future and how those will, almost inevitably, make the prognosis for today’s patients affected by genetic disease much, much better.Sophia_and_Daddy

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