Expanded Carrier Screening Would Identify More Severe or Profound Conditions, but Expert Urges Caution in Proceeding

A retrospective modeling analysis of nearly 350,000 individuals found that expanded carrier screening for up to 94 severe or profound conditions could increase detection of carrier status for these conditions compared with current recommendations by professional groups (JAMA 2016;316:734–42). Led by researchers at Counsyl, a health technology company that offers DNA screening, the study aimed to assess expanded carrier screening among 15 self-reported racial or ethnic categories using either targeted genotyping or next-generation sequencing (NGS).

The researchers modeled the risk of recessive conditions identified through expanded carrier screening by determining the probability that a hypothetical fetus created through random pairing of individuals across and within categories would be homozygous or heterozygous for two mutations presumed to cause severe or profound disease. The calculated frequency of potentially affected fetuses ranged from 94.5 per 100,000 among Hispanic couples to 392.2 per 100,000 among couples of Ashkenazi Jewish descent. 

Participants’ physicians ordered their tests as part of regular prenatal care. Ordering physicians could select the testing platform used and customize the set of conditions screened for. Overall, samples from 308,668 individuals were tested via targeted genotyping, while 38,122 underwent NGS.

The researchers found that in all self-identified categories except African or African American and Southeast Asian, expanded carrier testing in comparison to current recommendations would be expected to detect at least twice as many hypothetical fetuses with severe or profound diseases.

In an accompanying editorial, Wayne Grody, MD, PhD, past president of the American College of Medical Genetics and Genomics and a professor of pathology and laboratory medicine, pediatrics, and human genetics at the UCLA School of Medicine, raised at least five major concerns about the study. Grody cited short-chain acyl-CoA dehydrogenase deficiency as one example of the disorders the researchers tested for that is “highly variable in severity, even between individuals with the same mutations,” making it hard to know whether expectant couples would be able to make “a truly informed decision about pregnancy termination” given such variable phenotypic expression.

Grody also pointed out that the study raises the specter of variants of uncertain significance, which would “create a difficult reporting challenge for the laboratory.”

Most Patients Taking Warfarin Do Not Maintain Stable INR Values

An analysis of 3,749 patients taking warfarin who were participating in a prospective atrial fibrillation study found that most do not maintain stable international normalized ratio (INR) values, either in the first 6 months of therapy or during the subsequent year (JAMA 2016;316:661–3).

The researchers defined stable INR values as ≥80% of values in the therapeutic range, designated as INR values between 2.0 and 3.0. Participants were enrolled in a registry, and of 10,132, a total of 6,383 either were not taking warfarin or did not meet the study requirements of having at least three INR measurements in the first 6 months of therapy and six or more in the subsequent year.

Just 26% of those who met study criteria had stable values in the first 6 months, and only one-third of these patients maintained stable values during the subsequent year. Similarly, most of those who had 100% stable values in the first 6 months also did not maintain stability during the ensuing year. In addition, about one-third of both groups had at least one far-out-of-range INR value in the following year.

The researchers concluded that “warfarin stability is difficult to predict and challenges the notion that patients who have done well taking warfarin should maintain taking warfarin.”

Diabetic Kidney Disease Prevalence Essentially Unchanged Over 2 Decades, Even as Characteristics of the Disease Have Evolved

An analysis of National Health and Nutrition Examination Surveys (NHANES) from 1988 through 2014 found that while the overall prevalence of diabetic kidney disease (DKD) did not change markedly, the prevalence of albuminuria declined even as the prevalence of reduced estimated glomerular filtration rate (eGFR) rose (JAMA 2016;316:602–10).

The investigators defined DKD as persistent albuminuria, persistent reduced eGFR, or both. They delineated albuminuria as urine albumin-to-creatinine ratio ≥30 mg/G. NHANES researchers measured serum creatinine via a kinetic rate Jaffe method, and they calibrated NHANES III and NHANES 1999-2000 values to account for laboratory drift in serum creatinine across NHANES cycles. They used the CKD-EPI eGFR equation, with reduced eGFR defined as <60 mL/min/1.73m2.

The prevalence of DKD declined slightly between NHANES 1988-1994 and NHANES 2009-2014, from 28.4% to 26.2%. Over the same time period, the prevalence of albuminuria declined from 20.8% to 15.9%, while the prevalence of reduced eGFR rose from 9.2% to 14.1%.

The authors speculated that the differences in the manifestations of DKD might be due to increased use of prescribed diabetes therapies, including glucose-lowering medications, renin-angiotensin-aldosterone system (RAAS) inhibitors, and statins. Clinical trials have found that lowering blood glucose levels has “consistently” reduced the development of albuminuria, while RAAS inhibitors and blood pressure control albuminuria through hemodynamic and other mechanisms, they wrote. Hemodynamic effects of RAAS inhibitors might also contribute to lower eGFR, as might an increasing duration of diabetes.

"What we found was a little surprising and a little complex," said lead author Ian de Boer, MD, MS, in a prepared statement.