"Why did I choose genetics?": A survey of current and recent medical genetics and genomics residents provides insight into recruitment efforts.

There is a shortage of clinical geneticists, even with concerted recruitment efforts. Previously, no data had been collected about why young career geneticists chose this specialty. To investigate this question, we carried out a survey of current and recent medical genetics and genomics residents. The goal of this survey was to understand their reasons for pursuing medical genetics and genomics as a specialty. Results demonstrate that, for most, interest in genetics begins in medical school and was largely influenced by mentorship. This suggests that placing greater focus on introducing medical genetics as a clinical specialty and fostering robust mentorship of students in preclinical years may increase recruitment into medical genetics residencies.

The 2019 medical genetics workforce: A focus on laboratory geneticists.

PURPOSE: The aim of this report is to inform the genetics and genomics field about the results of a 2019 workforce survey of US laboratory geneticists. METHODS: The American Board of Medical Genetics and Genomics distributed an electronic survey to board-certified/eligible diplomates in 2019. Analysis of the responses was performed by the American College of Medical Genetics and Genomics. RESULTS: A total of 422 individuals identified as laboratory geneticists. The respondents represent the range of possible certifications. Nearly one-third were Clinical Cytogenetics and Genomics diplomates, another third were Molecular Genetics and Genomics diplomates, and the others were Clinical Biochemical Genetics diplomates or held a combination of certificates. The majority of laboratory geneticists are PhDs. The others were physicians or other degree combinations. Most laboratory geneticists work in academic medical centers or commercial laboratories. Most respondents identified as females and White. The median age was 53 years. A third of the respondents have been in the profession for 21+ years and plan to reduce hours or retire in the next 5 years. CONCLUSION: The genetics field needs to foster the next generation of laboratory geneticists to meet the increasing complexity and demand for genetic testing.

The relationship between performance on the medical genetics and genomics in-training and certifying examinations.

PURPOSE: The American Board of Medical Genetics and Genomics (ABMGG) certifying examinations (CEs) are designed to assess relevant basic knowledge, clinical knowledge, and diagnostic skills of board-eligible candidates in primary specialty areas. The ABMGG in-training examinations (ITEs) provide formative feedback regarding knowledge and learning over time and assess readiness to attempt board certification. This study addresses the validity of the ABMGG ITE by evaluating its relationship with performance on CE utilizing established psychometric approaches. METHODS: Statistical analysis included bivariate Pearson correlation coefficients and linear regression to evaluate the strength of associations between ITE scores and CE scores. Logistic regression was used to assess the association between ITE scores and the probability of passing each CE. RESULTS: Logistic regression results indicated that ITE scores accounted for 22% to 44% of the variability in CE outcomes. Across 3 certification cycles, for every 1-point increase in ITE scores, the odds ratio for earning a passing score increased by a factor of 1.12 to 1.20 for the general CE, 1.14 to 1.25 for the clinical CE, and 1.12 to 1.20 for the laboratory CEs. CONCLUSION: The findings show a positive correlation between performance on the ITE examination and performance on and passing the ABMGG CE.

The training of future clinical geneticists: Evaluation and reflection on the ACMG Foundation for Genetic and Genomic Medicine Summer Genetics Scholars Program.

PURPOSE: The purpose of the Summer Genetics Scholars Program of the ACMG Foundation for Genetic and Genomic Medicine is to expose medical students to medical genetics and genomics early during school with the aim of increasing the number of physicians pursuing a career in this field. This survey study evaluated the Summer Genetics Scholars Program on the achievement of its goals. METHODS: Former Summer Genetics Scholars who had completed medical school were sent a 13-question survey aimed at evaluating the program and obtaining feedback about their experiences. RESULTS: Of 125 former scholars, 55 completed the survey with 2 additional participants partially completing the survey. The vast majority of former participants report either being very satisfied or satisfied with their experience (96%). CONCLUSION: Whereas most participants found their experience to be beneficial, evaluation of the initial 6 years of the program did not show an increase in the number of students entering residencies in medical genetics and genomics. It likely is too early to assess the program's true influence on entry into the field because data were only available for the first 6 years of the Summer Genetics Scholars Program, and many residents typically choose to complete another primary specialty before medical genetics and genomics.

The 2019 US medical genetics workforce: a focus on clinical genetics.

PURPOSE: This study characterizes the US clinical genetics workforce to inform workforce planning and public policy development. METHODS: A 32-question survey was electronically distributed to American Board of Medical Genetics and Genomics board-certified/eligible diplomates in 2019. We conducted a descriptive analysis of responses from practicing clinical geneticists. RESULTS: Of the 491 clinical geneticists responding to the survey, a majority were female (59%) and White (79%), worked in academic medical centers (73%), and many engaged in telemedicine (33%). Clinical geneticists reported an average of 13 new and 10 follow-up patient visits per week. The average work week was 50 hours and the majority (58%) worked over half-time in clinical duties. Providers indicated that 39% of new emergency patients wait 3 days or more, and 39% of nonemergency patients wait over 3 months to be seen. Respondents were geographically concentrated in metropolitan areas and many reported unfilled clinical geneticist job vacancies at their institution of more than 3 years. CONCLUSION: With the rapid expansion of genomic medicine in the past decade, there is still a gap between genetics services needed and workforce capacity. A concerted effort is required to increase the number of clinical geneticists and enhance interdisciplinary teamwork to meet increasing patient needs.

A comparison of first trimester blood pressures obtained at the time of first trimester pre-eclampsia screening and those obtained during prenatal care visits.

OBJECTIVE: To determine if enrollment blood pressures in a study on first trimester preeclampsia prediction significantly differed from those obtained during routine prenatal care visits in the first trimester. STUDY DESIGN: Women carrying a singleton gestation were prospectively enrolled in a first trimester study on preeclampsia prediction, and had systolic and diastolic blood pressure (SBP, DBP) measured at the time of enrollment. Blood pressure was also measured with the same technique by clinic nurses during the routine prenatal visits throughout the first trimester of pregnancy (9-14 weeks). The enrollment-BP (E-BP) and average first trimester-BP (aFT-BP) were compared using a paired samples t-test or Wilcoxon test, as appropriate. Smokers and patients on antihypertensive medications were excluded from the analysis. test. RESULTS: 644 women had prenatal care in the primary study center and met study criteria. The mean gestational age at study enrollment was 12.5 weeks. No significant difference was found between E-SBP and aFT-SBP (p = 0.10). Enrollment DBP and mean arterial pressure (MAP) were significantly lower than the aFT- DBP and -MAP (median DPB 67 vs 70 mm Hg and median MAP 83.7 vs 85 mmHg, respectively, p < 0.001). However, the difference was not clinically relevant (3 mmHg for DBP, and 1.3 mmHg for MAP). CONCLUSIONS: Blood pressures obtained in a setting of preeclampsia screening are not higher than those obtained during regular prenatal care in the first trimester. This suggests that the setting in which pre-eclampsia screening is performed is unlikely to be a confounder for blood pressure measurements and the risk assessment.

Medical genetics and genomics training in obstetrics and gynecology residencies: are we ready for the future?

OBJECTIVE: The primary objective of this study is to evaluate the availability and duration of formal medical genetics and genomics (MGG) education during obstetrics and gynecology (OB/GYN) residency training in the United States compared to other noncore OB/GYN rotations. METHODS: We performed a review of rotation schedules published in all American Council for Graduate Medical Education (ACGME)-accredited OB/GYN residency programs' websites during the month of December 2016. Information regarding availability and duration of MGG rotation and other noncore OB/GYN rotations (ultrasound, breast health, and family planning) were collected. RESULTS: Among 256 ACGME-accredited OB/GYN residency programs, rotation schedule was available for 238 (93%). Only 34 programs (14.3%) had some form of MGG rotations. In the GLM, when compared to other noncore OB/GYN rotations, the mean duration of MGG rotation was significantly less than ultrasound (0.07 versus 0.57 months, p < .05) and family planning (0.07 versus 0.42 months, p < .05). The number of residents was the only variable significantly correlated with the availability of an MGG rotation (OR 1.07, 95%CI 1.02-1.13). CONCLUSIONS: Despite the growing importance of MGG in day-to-day OB/GYN practice, only a limited number of ACGME-accredited OB/GYN residency programs offer an MGG rotation. When compared to other noncore OB/GYN rotations, such as, ultrasound and family planning, any MGG rotation was significantly shorter. With clear evidence that MGG will continue to radically change practice of OB/GYN in the future, it is imperative that steps need to be taken to address this deficiency in training.

Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed/refractory acute myeloid leukemia.

Depletion of glutamine (Gln) has emerged as a potential therapeutic approach in the treatment of acute myeloid leukemia (AML), as neoplastic cells require Gln for synthesis of cellular components essential for survival. Asparaginases deplete Gln, and asparaginase derived from Erwinia chrysanthemi (Erwinaze) appears to have the greatest glutaminase activity of the available asparaginases. In this Phase I study, we sought to determine the dose of Erwinaze that safely and effectively depletes plasma Gln levels to ≤ 120 µmol/L in patients with relapsed or refractory (R/R) AML. Five patients were enrolled before the study was halted due to issues with Erwinaze manufacturing supply. All patients received Erwinaze at a dose of 25,000 IU/m2 intravenously three times weekly for 2 weeks. Median trough plasma Gln level at 48 h after initial Erwinaze administration was 27.6 µmol/L, and 80% (lower limit of 1-sided 95% CI 34%) of patients achieved at least one undetectable plasma Gln value (< 12.5 µmol/L), with the fold reduction (FR) in Gln level at 3 days, relative to baseline, being 0.16 (p < 0.001 for rejecting FR = 1). No dose-limiting toxicities were identified. Two patients responded, one achieved partial remission and one achieved hematologic improvement after six doses of Erwinaze monotherapy. These data suggest asparaginase-induced Gln depletion may have an important role in the management of patients with AML, and support more pharmacologic and clinical studies on the mechanistically designed asparaginase combinations in AML.

Maternal blood pressures during pregnancy and the risk of delivering a small-for-gestational-age neonate.

OBJECTIVE: To determine the relationship between maternal blood pressures throughout pregnancy and the risk of delivering a small-for-gestational-age (SGA) neonate. METHODS: Women were prospectively enrolled at 9-14 weeks and had serial blood pressure measurements throughout pregnancy. SGA prevalence was compared to maternal blood pressure at enrollment, average blood pressure during each trimester, and blood pressure trends throughout gestation. Blood pressure was categorized as normotension, prehypertension, or hypertension using Joint National Committee on Hypertension-7 (JNC-7) definitions. Information on preeclampsia prevalence was also obtained due to its frequent concurrence with SGA. RESULTS: A total of 758 women had 8438 blood pressure measurements taken (average 11.1, range 3-14) and 65 (8.6%) delivered an SGA neonate. Forty-two of 514 (8.2%) normotensive women at enrollment and 23/244 (9.4%) women with enrollment prehypertension or hypertension delivered an SGA neonate. Women with persistent hypertensive range blood pressures had an SGA rate 2-3 times higher than other women (p = 0.272) as well as a significantly higher preeclampsia rate (p < 0.001). Women with elevated enrollment blood pressures did not have an increased SGA rate if their blood pressures improved throughout pregnancy. Logistic regression identified enrollment uterine artery Doppler, pregnancy-associated plasma protein-A levels, and ethnicity as primary contributors to SGA. CONCLUSION: Blood pressure improvement throughout pregnancy decreases the preeclampsia rate without increasing SGA frequency. Theoretical risks of fetal growth delay should not prevent investigations into improved maternal blood pressure control, possibly at thresholds lower than commonly used in obstetric practice, beginning in the first trimester of pregnancy.

Second-trimester prediction of delivery of a small-for-gestational-age neonate: integrating sequential Doppler information, fetal biometry, and maternal characteristics.

OBJECTIVE: The aim of this study was to investigate the predictive accuracy of second-trimester ultrasound parameters, maternal characteristics, and sequential Doppler changes between first and second trimesters for the prediction of small-for-gestational-age (SGA) infants (birth weight < 10th percentile). METHODS: We conducted a prospective study of singleton pregnancies enrolled in the first trimester with subsequent second-trimester follow-up. Maternal characteristics, uterine artery (UtA) pulsatility index (PI), fetal biometry, and umbilical artery (UA)-PI were ascertained. UtA and UA-PI change from first to second trimester was calculated (ΔUtA-PI and ΔUA-PI). These parameters were tested for their ability to predict delivery of an SGA infant. RESULTS: Among 1982 women, 172 delivered an SGA neonate. African-American ethnicity, nulliparity, tobacco use, and low abdominal circumference (AC) z-score were independent predictors of SGA. No difference was found in the magnitude of ΔUtA-PI and ΔUA-PI between SGA and no-SGA. Receiver-operating characteristics curve analysis yielded an area under the curve of 0.700 for AC z-score. The combination of low AC and bilateral notching had high specificity (99%) but low sensitivity (7%) for SGA prediction. CONCLUSIONS: A small second-trimester fetal AC is a specific marker for SGA when found with bilateral UtA notching. Only a small proportion is predicted by the factors studied, suggesting a small contributory role or later evolution of SGA.

Prediction of preeclampsia utilizing the first trimester screening examination.

OBJECTIVE: To derive a prediction rule for preeclampsia and early onset preeclampsia requiring delivery <34 weeks using first trimester maternal, ultrasound, and serum markers. STUDY DESIGN: Prospective cohort study of women enrolled at first trimester screening. Maternal history, demographics, anthropometry, ultrasound parameters, and serum analytes were compared between women with preeclampsia and normal outcome. The prediction rule was derived by Lasso logistic regression analysis. RESULTS: In 2441 women, 108 (4.4%) women developed preeclampsia, and 18 (0.7%) early preeclampsia. Nulliparity, prior hypertension, diabetes, prior preeclampsia, mean arterial pressure, and the log pregnancy-associate pregnancy protein-A multiples of the median were primary risk factors. Prediction rules for preeclampsia/early preeclampsia had an area under the curve of 0.82/0.83 respectively. Preeclampsia was predicted with 49% sensitivity and early preeclampsia with 55% sensitivity for a 10% false positive rate. CONCLUSION: First trimester prediction rules using parameters currently available at first trimester screening identify a significant proportion of women with subsequent preeclampsia.

Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program.

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine.

First-trimester prediction of small-for-gestational age neonates incorporating fetal Doppler parameters and maternal characteristics.

OBJECTIVE: First-trimester screening for subsequent delivery of a small-for-gestational-age (SGA) infant typically focuses on maternal risk factors and uterine artery (UtA) Doppler. Our aim is to test if incorporation of fetal umbilical artery (UA) and ductus venosus (DV) Doppler improves SGA prediction. STUDY DESIGN: Prospective screening study of singletons at 11-14 weeks. Maternal characteristics, serum concentrations of pregnancy-associated plasma protein-A (PAPP-A) and free ß-human chorionic gonadotropin are ascertained and UtA Doppler, UA, and DV Doppler studies are performed. These parameters are tested for their ability to predict subsequent delivery of a SGA infant. RESULTS: Among 2267 enrolled women, 191 (8.4%) deliver an SGA infant. At univariate analysis women with SGA neonates are younger, more frequently African-American (AA), nulliparous, more likely to smoke, have lower PAPP-A and free ß-human chorionic gonadotropin levels. They have a higher incidence of UtA Doppler bilateral notching, higher mean UtA Doppler-pulsatility index z-scores (P < .001) and UA pulsatility index z-scores (P = .03), but no significant difference in DV-pulsatility index z-scores or in the incidence of abnormal qualitative UA and DV patterns. Multivariate logistic regression analysis identifies nulliparity and AA ethnicity (P < .001), PAPP-A multiple of the median and bilateral notching (P < .05) as determinants of SGA infant. Predictive sensitivity was low; receiver operating characteristic curve analysis yields areas under the curve of 0.592 (95% confidence interval, 0.548-0.635) for the combination of UtA Doppler and UA pulsatility index z-scores. CONCLUSION: Delivery of a SGA infant is most frequent in nulliparous women of AA ethnicity. Despite the statistical association with UtA Doppler first-trimester SGA prediction is poor and not improved by the incorporation of fetal Doppler.

First-trimester risk factors for preeclampsia development in women initiating aspirin by 16 weeks of gestation.

OBJECTIVE: The residual risk of preeclampsia in high-risk women on aspirin prophylaxis exceeds that of low-risk populations, and this study aimed to identify first-trimester maternal characteristics associated with aspirin prophylaxis failure. METHODS: This is a nested cohort study of prospectively enrolled women with verified initiation of risk-indicated aspirin prophylaxis by 16 weeks of gestation. First-trimester maternal history, demographics, anthropometry, ultrasound parameters, and serum analytes were compared between women who developed preeclampsia and those who did not. Blood pressure measurements were classified as prehypertension or hypertension according to the Joint National Committee on Hypertension guidelines. Chi square, nonparametric, and logistic regression analyses were used to determine the contributors to preeclampsia development. RESULTS: Six hundred fourteen women prospectively enrolled at 9-14 weeks of gestation initiated aspirin by 16 weeks of gestation. The 59 (9.6%) women who developed preeclampsia were more likely to have chronic hypertension, diabetes, and obesity and had higher first-trimester blood pressure and lower serum pregnancy-associated plasma protein-A concentrations (all P<.05). Having first-trimester Joint National Committee on Hypertension prehypertension or hypertension was associated with a 2.18-fold increased risk of developing preeclampsia, whereas normotension was associated with a reduction of risk of 56%. CONCLUSION: Women who develop preeclampsia while taking aspirin prophylaxis are more likely to have elevated first-trimester blood pressures. Conversely, first-trimester normotension is associated with a reduced risk of preeclampsia.

First trimester maternal characteristics, Doppler parameters and serum analytes after preeclampsia.

OBJECTIVE: To evaluate the impact of prior preeclampsia on first trimester assessment in subsequent pregnancy. METHODS: A total of 1283 parous patients were prospectively enrolled at 9-14 weeks of gestation. Maternal biophysical characteristics, ultrasound parameters and placental analytes were compared between women with and without prior preeclampsia. RESULTS: There is no association between prior preeclampsia and the first trimester ultrasound parameters or placental analytes studied. The effects of prior preeclampsia in subsequent pregnancy are exaggerated by increasing parity and are predominantly blood pressure-related, independent of other cardiovascular risk factors. CONCLUSION: There is a potential role for lifestyle modification and stricter pregnancy blood pressure control in patients with prior preeclampsia.

Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening.

Tay-Sachs disease (TSD) is the prototype for ethnic-based carrier screening, with a carrier rate of ∼1/27 in Ashkenazi Jews and French Canadians. HexA enzyme analysis is the current gold standard for TSD carrier screening (detection rate ∼98%), but has technical limitations. We compared DNA analysis by next-generation DNA sequencing (NGS) plus an assay for the 7.6 kb deletion to enzyme analysis for TSD carrier screening using 74 samples collected from participants at a TSD family conference. Fifty-one of 74 participants had positive enzyme results (46 carriers, five late-onset Tay-Sachs [LOTS]), 16 had negative, and seven had inconclusive results. NGS + 7.6 kb del screening of HEXA found a pathogenic mutation, pseudoallele, or variant of unknown significance (VUS) in 100% of the enzyme-positive or obligate carrier/enzyme-inconclusive samples. NGS detected the B1 allele in two enzyme-negative obligate carriers. Our data indicate that NGS can be used as a TSD clinical carrier screening tool. We demonstrate that NGS can be superior in detecting TSD carriers compared to traditional enzyme and genotyping methodologies, which are limited by false-positive and false-negative results and ethnically focused, limited mutation panels, respectively, but is not ready for sole use due to lack of information regarding some VUS.