M J Mahoney

Yale-New Haven Hospital, New Haven, Connecticut, United States

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Publications (152)1693.13 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Detection of chromosomal structural abnormalities using conventional cytogenetic methods poses a challenge for prenatal genetic counseling due to unpredictable clinical outcomes and risk of recurrence. Of the 1,726 prenatal cases in a 3-year period, we performed oligonucleotide array comparative genomic hybridization (aCGH) analysis on 11 cases detected with various structural chromosomal abnormalities. In nine cases, genomic aberrations and gene contents involving a 3p distal deletion, a marker chromosome from chromosome 4, a derivative chromosome 5 from a 5p/7q translocation, a de novo distal 6q deletion, a recombinant chromosome 8 comprised of an 8p duplication and an 8q deletion, an extra derivative chromosome 9 from an 8p/9q translocation, mosaicism for chromosome 12q with added material of initially unknown origin, an unbalanced 13q/15q rearrangement, and a distal 18q duplication and deletion were delineated. An absence of pathogenic copy number changes was noted in one case with a de novo 11q/14q translocation and in another with a familial insertion of 21q into a 19q. Genomic characterization of the structural abnormalities aided in the prediction of clinical outcomes. These results demonstrated the value of aCGH analysis in prenatal cases with subtle or complex chromosomal rearrangements. Furthermore, a retrospective analysis of clinical indications of our prenatal cases showed that approximately 20% of them had abnormal ultrasound findings and should be considered as high risk pregnancies for a combined chromosome and aCGH analysis.
    American Journal of Medical Genetics Part A 07/2011; 155A(7):1605-15. DOI:10.1002/ajmg.a.34043 · 2.30 Impact Factor
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    ABSTRACT: Variable clinical presentations of patients with chromosomally detected deletions in the distal long arm (q) of chromosome 4 have been reported. The lack of molecular characterization of the deletion sizes and deleted genes hinders further genotype-phenotype correlation. Using a validated oligonucleotide array comparative genomic hybridization (oaCGH) analysis, we examined two patients with apparent chromosomal deletions in the distal 4q region. In the first, oaCGH identified a 2.441 megabase (Mb) duplication and a 12.651 Mb deletion at 4q34.1 in a pregnant female who transmitted this aberration to her son. This mother has only learning disabilities while her son had both renal and cardiac anomalies in the newborn period. Unrecognized paternal genetic factors may contribute to the variable expression. The second patient is a 17-year-old female with a history of Pierre Robin sequence, cardiac abnormalities and learning disabilities. She was diagnosed prenatally with a de novo 4q deletion, and oaCGH defined a 16.435 Mb deletion of 4q34.1-4q35.2. Phenotypic comparison and subtractive genomic mapping between these two cases suggested a 4 Mb region possibly harboring a candidate gene for Pierre Robin sequence. Our cases and review of reported cases with genomic findings indicated the presence of familial variants with variable expressivity as well as de novo or inherited pathogenic simple deletion, duplication and complex deletion and duplication in the distal 4q region.
    American Journal of Medical Genetics Part A 12/2009; 149A(12):2788-94. DOI:10.1002/ajmg.a.33088 · 2.30 Impact Factor
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    ABSTRACT: Pelizaeus-Merzbacher disease is a rare X-linked disorder caused by mutations of the proteolipid protein 1 gene that encodes a structural component of myelin. It is characterized by progressive psychomotor delay, nystagmus, spastic quadriplegia, and cerebellar ataxia. Variable clinical expression was seen in 5 members of a family bearing a novel missense mutation in proteolipid protein 1, c.619T>C. Symptomatic patients included a 6-year-old girl, her younger brother, and their maternal uncle, a 29-year-old college graduate initially diagnosed with cerebral palsy; their brain magnetic resonance imaging studies showed diffuse dysmyelination. The mother had a history of delayed walking, achieved independently by age 3; she and the maternal grandmother were asymptomatic on presentation. Review of clinical information and family history led to consideration of Pelizaeus-Merzbacher disease. Subsequent identification of the causal mutation enabled preimplantation genetic diagnosis and the birth of an unaffected child.
    Journal of child neurology 04/2009; 24(5):618-24. DOI:10.1177/0883073808327833 · 1.59 Impact Factor
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    Roger D Klein, Maurice J Mahoney
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    ABSTRACT: In the United States, a longstanding legal rule exists against patenting natural phenomena. The Supreme Court recently had an opportunity to help define the boundaries and clarify the implications of this "natural phenomenon doctrine" in Laboratory Corporation of America v. Metabolite Labs., dismissed as improvidently granted. This article argues that the natural phenomenon doctrine renders both the patent claim at issue in LabCorp, and the patents that directly or indirectly claim biological correlations between genotypes and medical phenotypes, invalid or unenforceable under U.S. patent law.
    The Journal of Law Medicine &amp Ethics 02/2008; 36(1):141-9, 4. DOI:10.1111/j.1748-720X.2008.00243.x · 0.94 Impact Factor
  • Joe Leigh Simpson, Maurice J. Mahoney
    Clinical Obstetrics: The Fetus & Mother, Third Edition, 01/2008: pages 293 - 317; , ISBN: 9780470753293
  • Roger D Klein, Maurice J Mahoney
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    ABSTRACT: The capacity to diagnose fetal disease or abnormality continues to grow, especially in the genetic definition of the fetus. With this growth have come claims of medical malpractice that have mostly centered on a failure of informed consent. Failure may occur by omission or failed communication of pertinent information to the parents or by alleged error in the interpretation of diagnostic information. The usual claim against a physician or other provider is not that of causing damage or disease in the fetus but of causing a loss of opportunity to prevent conception or live birth of an infant who has an abnormality. Successful suits for "wrongful birth," brought by parents of an abnormal child, are common in many United States jurisdictions, but suits for "wrongful life," brought on behalf of the child, have usually been denied.
    Clinics in Perinatology 07/2007; 34(2):287-97, vi. DOI:10.1016/j.clp.2007.03.006 · 2.13 Impact Factor
  • American Journal of Obstetrics and Gynecology 12/2005; 193(6). DOI:10.1016/j.ajog.2005.10.645 · 3.97 Impact Factor
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    ABSTRACT: The genetic sonogram is a composite algorithm combining multiple individual markers to increase Down syndrome risk prediction. Transformation of sonographic information into a standard mathematical format represented an early challenge that has now been surmounted. Using increasingly sophisticated mathematical techniques, individual patient risk can be estimated. High diagnostic accuracy comparable to standard mid-trimester serum algorithms has been reported. Most recently, a few studies have reported the ability to combine serum and biochemical markers to achieve diagnostic accuracy comparable to first-trimester screen. Even fewer studies have reported combinations of ultrasound and maternal urine markers. While it is clear that consistently high sensitivity and specificity for Down syndrome can be achieved, almost all the studies are based on high-risk groups. Studies in low-risk populations have suffered from lack of standardization. The relevance of genetic sonogram in a low-risk population thus remains to be proven. The most significant challenge, however, remains the development of uniform and reproducible sonographic and measurement standards. This is likely to be the most important factor in optimizing the accuracy of the mid-trimester genetic sonogram.
    Seminars in Perinatology 09/2005; 29(4):209-14. DOI:10.1053/j.semperi.2005.06.005 · 2.42 Impact Factor
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    ABSTRACT: To document our experience with fragile X carrier screening. In this study, 29,103 women with no known or suspected family history of fragile X syndrome were offered fragile X carrier screening during their prenatal genetic counseling visit. Screening acceptance was analyzed by referral indication, carrier frequencies documented, and prenatal outcome data presented. Overall, 7.9% accepted carrier screening. The premutation frequency was 1 in 382, and the intermediate allele frequency was 1 in 143. Fragile X screening is a desirable option for some women seeking prenatal genetic counseling and should be made available to this population.
    Genetics in Medicine 05/2005; 7(4):246-50. DOI:10.1097/01.GIM.0000159898.90221.D3 · 6.44 Impact Factor
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    ABSTRACT: We sought to evaluate the association between first trimester nuchal translucency measurement and the risk for major congenital heart defect in chromosomally normal fetuses. First trimester (10 weeks 4 days of gestation to 13 weeks 6 days of gestation) nuchal translucency was obtained in a large prospective multicenter National Institute of Child Health and Human Development study for Down syndrome prediction. The study, which was conducted between May 1998 and December 2000, was restricted to singleton pregnancies. Gestational age was determined by crown rump length measurements. Perinatal outcomes were determined and included the frequency of major congenital heart defect, which was defined as those cases that potentially could require surgery, intensive medical therapy, or prolonged follow-up time. Logistic regression analysis was used to determine whether nuchal translucency was a significant predictor of congenital heart defect. There were 8167 chromosomally normal pregnancies, of which 21 cases of major congenital heart defect were identified at follow-up examination (incidence, 2.6/1000 pregnancies). The risk of congenital heart defect rose with increasing nuchal translucency measurements. The mean nuchal translucency value for the normal and congenital heart defect groups were 1.5 mm and 1.9 mm, respectively (P = .05). With a nuchal translucency measurement of < 2.0 mm, the incidence of congenital heart defect was 13 of 6757 pregnancies (1.9 of every 1000 pregnancies). At 2.0 to 2.4 mm, the incidence was 5 of 1032 pregnancies (4.8 of every 1000 pregnancies). At 2.5 to 3.4 mm, the incidence was 2 of 335 pregnancies (6.0 of every 1000 pregnancies). At > or = 3.5 mm, the incidence was 1 of 43 pregnancies (23 of every 1000 pregnancies). Logistic regression analysis confirmed that nuchal translucency was associated significantly with congenital heart defect (odds ratio, 2.1; 95% CI, 1.4-3.1; P = .0004). Increased first trimester nuchal translucency measurement was associated with a higher risk of major congenital heart defect in chromosomally normal pregnancies. The practical implications of our findings are that patients with unexplained elevations of nuchal translucency may need referral for a fetal echocardiogram.
    American Journal of Obstetrics and Gynecology 05/2005; 192(5):1357-61. DOI:10.1016/j.ajog.2004.12.086 · 3.97 Impact Factor
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    ABSTRACT: To evaluate the potential relationship between placental disruption in weeks 13 and 14 and the subsequent development of gestational hypertension or preeclampsia. Using subjects recruited during a randomized trial funded by the National Institute of Child Health and Human Development, which compared early amniocentesis and late transabdominal chorionic villus sampling (CVS) in weeks 13 and 14, rates of gestational hypertension and preeclampsia were compared between cases with varying degrees of placental disruption. A total of 3,698 of 3,775 randomized subjects had cytogenetically normal pregnancies and were analyzed. A significantly higher rate of hypertension/preeclampsia was observed in the late CVS group (5.4%, n = 1,878) compared with the early amniocentesis cohort (3.5%, n = 1,820; P = .005). This difference persisted after controlling for maternal age, body mass index, parity, previous preterm delivery, smoking, and fetal gender. Early amniocentesis cases were further stratified on the basis of whether the placenta had been penetrated (n = 460) or not (n = 1,360). Risk of hypertensive complications was lowest if the placenta was not traversed (3.4%), greater with placental penetration (3.9%), and highest when the placenta was directly sampled during CVS (5.4%, P = .02). We hypothesize that focal disruption of the placenta at 13-14 weeks may increase the risk of hypertension/preeclampsia. These findings provide support for the theory that disturbances in early placentation lead subsequently to maternal hypertension.
    Obstetrics and Gynecology 04/2005; 105(3):587-92. DOI:10.1097/01.AOG.0000152343.08096.c3 · 4.37 Impact Factor
  • Ugeskrift for laeger 04/2005; 167(11):1293-6.
  • American Journal of Obstetrics and Gynecology 12/2004; 191(6). DOI:10.1016/j.ajog.2004.09.088 · 3.97 Impact Factor
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    ABSTRACT: To evaluate the performance and use of second-trimester multiple-marker maternal serum screening for trisomy 21 by women who had previously undergone first-trimester combined screening (nuchal translucency, pregnancy-associated plasma protein A, and free beta-hCG), with disclosure of risk estimates. In a multicenter, first-trimester screening study sponsored by the National Institute of Child Health and Human Development, multiple-marker maternal serum screening with alpha-fetoprotein, unconjugated estriol, and total hCG was performed in 4,145 (7 with trisomy 21) of 7,392 (9 with trisomy 21) women who were first-trimester screen-negative and 180 (7 with trisomy 21) of 813 (52 with trisomy 21) who were first-trimester screen-positive. Second-trimester risks were calculated using multiples of the median and a standardized risk algorithm with a cutoff risk of 1:270. Among the first-trimester screen-negative cohort, 6 of 7 (86%) trisomy 21 cases were detected by second-trimester multiple-marker maternal serum screening with a false-positive rate of 8.9%. Among the first-trimester screen-positive cohort, all 7 trisomy 21 cases were also detected in the second trimester, albeit with a 38.7% false-positive rate. Our data demonstrate that a sequential screening program that provides patients with first-trimester results and offers the option for early invasive testing or additional serum screening in the second trimester can detect 98% of trisomy 21-affected pregnancies. However, such an approach will result in 17% of patients being considered at risk and, hence, potentially having an invasive test. II-2
    Obstetrics and Gynecology 11/2004; 104(4):661-6. DOI:10.1097/01.AOG.0000139832.79658.b9 · 4.37 Impact Factor
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    ABSTRACT: The purpose of this study was to determine the association between first-trimester trisomy 21 screening markers (free human chorionic gonadotropin-beta [hCG], pregnancy-associated plasma protein A [PAPP-A], and nuchal translucency) and adverse pregnancy outcome. This was a cohort study of 8012 patients enrolled in a National Institute of Child Health and Human Development-sponsored study of first-trimester trisomy 21 and 18 screening. Trisomy 21 and 18 risk results and individual marker levels in unaffected pregnancies and pregnancies with adverse outcomes were evaluated. PAPP-A <1st percentile (OR 5.4, 95% CI 2.8-10.3) and PAPP-A <5th percentile (OR 2.7, 95% CI 1.9-3.9) and free beta-hCG <1st percentile (OR 2.7, 95% CI 1.3-5.9) were associated with increased risk of intrauterine growth restriction (IUGR) with positive predictive values of 24.1%, 14.1%, and 14.3%, respectively. PAPP-A <5th percentile (OR 2.3 95% CI 1.1-4.7) and nuchal translucency >99th percentile (OR 3.5, 95% CI 1.1-11.3) were associated with increased risk of preterm delivery before 34 weeks. Increased risk at screening for trisomy 21 and 18 identified 16 of the 29 other chromosomal abnormalities (55%). Low free beta-hCG, low PAPP-A, and increased nuchal translucency were all associated with an increased rate of fetal abnormality. Extreme values of first-trimester free beta-hCG, PAPP-A, and nuchal translucency are all associated with adverse outcomes. The especially high predictive value for IUGR of PAPP-A levels below the 1st percentile suggests that patients within this group may benefit from increased surveillance for this condition.
    American Journal of Obstetrics and Gynecology 11/2004; 191(4):1452-8. DOI:10.1016/j.ajog.2004.05.068 · 3.97 Impact Factor
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    ABSTRACT: To estimate the likelihood of clinical early and late pregnancy loss as a function of first-trimester maternal serum analytes and fetal nuchal translucency measurements. Study subjects were recruited for a National Institute of Child Health and Human Development-sponsored multicenter cohort study initially designed to study the detection of Down syndrome during the first trimester of pregnancy. The cohort consisted of women who had a live fetus between 10 and 14 weeks of gestation and had no significant vaginal bleeding. Women with prior fetal trisomy (T21/18) and those with structural or chromosomal abnormalities in the index pregnancy were excluded. First-trimester screening consisted of pregnancy-associated plasma protein A (PAPP-A), free beta-hCG, and nuchal translucency. Pregnancy loss rates in women with various levels of PAPP-A, free beta-hCG, or nuchal translucency (less than 1st, less than 5th, more than 95th, and more than 99th percentile) were compared with losses in women with normal values (5th to 95th percentile). The mean gestational age at screening of 7,932 women meeting study criteria was 12.1 weeks. Loss rates were only 0.36% at less than 20 weeks after normal free beta-hCG, PAPP-A, and nuchal translucency. Conversely, low levels of PAPP-A and free beta-hCG as well as increased nuchal translucency were individually associated with increased early loss. These associations persisted after controlling for maternal age and race using logistic regression analysis. Normal values of PAPP-A, free beta-hCG, and nuchal translucency are associated with a very low risk of pregnancy loss at less than 20 weeks.
    Obstetrics and Gynecology 08/2004; 104(1):30-6. DOI:10.1097/01.AOG.0000129969.78308.4f · 4.37 Impact Factor
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    ABSTRACT: To assess, in a randomized trial, the safety and accuracy of amniocentesis and transabdominal chorionic villus sampling (CVS) performed at 11-14 weeks of gestation, given that this time frame is increasingly relevant to early trisomy screening. We compared amniocentesis with CVS from 77 to 104 days of gestation in a randomized trial in a predominantly advanced maternal age population. Before randomization, the feasibility of both procedures was confirmed by ultrasonography, and experienced operators performed sampling under ultrasound guidance; conventional cytogenetic analysis was employed. The primary outcome measure was a composite of fetal loss plus preterm delivery before 28 weeks of gestation in cytogenetically normal pregnancies. We randomized 3,775 women into 2 groups (1,914 to CVS; 1,861 to amniocentesis), which were comparable at baseline. More than 99.6% had the assigned procedure, and 99.9% were followed through delivery. In contrast to previous thinking, in the cytogenetically normal cohort (n = 3,698), no difference in primary study outcome was observed: 2.1% (95% confidence interval 1.5, 2.8) for CVS and 2.3% (95% confidence interval, 1.7, 3.1) for amniocentesis. However, spontaneous losses before 20 weeks and procedure-related, indicated terminations combined were increased in the amniocentesis group (P =.07, relative risk 1.74). We found a 4-fold increase in the rate of talipes equinovarus after amniocentesis (P =.02) overall and in week 13 (P =.03, relative risk = 4.65), but data were insufficient to determine this risk in week 14. Amniocentesis at 13 weeks carries a significantly increased risk of talipes equinovarus compared with CVS and also suggests an increase in early, unintended pregnancy loss. I
    Obstetrics and Gynecology 07/2004; 103(6):1164-73. DOI:10.1097/01.AOG.0000128049.73556.fb · 4.37 Impact Factor
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    ABSTRACT: Screening for aneuploid pregnancies is routinely performed after 15 weeks of gestation and has a sensitivity of approximately 65 percent, with a false positive rate of 5 percent. First-trimester markers of aneuploidy have been developed, but their use in combination has not been adequately evaluated in clinical practice. We conducted a multicenter study of screening for trisomies 21 and 18 among patients with pregnancies between 74 and 97 days of gestation, based on maternal age, maternal levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A, and ultrasonographic measurement of fetal nuchal translucency. A screening result was considered to be positive for trisomy 21 if the calculated risk was at least 1 in 270 pregnancies and positive for trisomy 18 if the risk was at least 1 in 150. Screening was completed in 8514 patients with singleton pregnancies. This approach to screening identified 85.2 percent of the 61 cases of Down's syndrome (95 percent confidence interval, 73.8 to 93.0), with a false positive rate of 9.4 percent (95 percent confidence interval, 8.8 to 10.1). At a false positive rate of 5 percent, the detection rate was 78.7 percent (95 percent confidence interval, 66.3 to 88.1). Screening identified 90.9 percent of the 11 cases of trisomy 18 (95 percent confidence interval, 58.7 to 99.8), with a 2 percent false positive rate. Among women 35 years of age or older, screening identified 89.8 percent of fetuses with trisomy 21, with a false positive rate of 15.2 percent, and 100 percent of fetuses with trisomy 18. First-trimester screening for trisomies 21 and 18 on the basis of maternal age, maternal levels of free beta human chorionic gonadotropin and pregnancy-associated plasma protein A, and measurement of fetal nuchal translucency has good sensitivity at an acceptable false positive rate.
    New England Journal of Medicine 11/2003; 349(15):1405-13. DOI:10.1056/NEJMoa025273 · 54.42 Impact Factor
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    ABSTRACT: Experience gathered over the last decade from high-risk centers provide strong evidence that mid-trimester sonographic markers are sensitive for Down syndrome prediction. More recent data indicate that combining mid trimester sonography with traditional serum markers significantly improves diagnostic accuracy over either group of markers by themselves.
    Seminars in Perinatology 05/2003; 27(2):145-51. DOI:10.1053/sper.2003.50013 · 2.42 Impact Factor
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    ABSTRACT: The purpose of this study was to determine the Down syndrome sensitivity of early genetic sonography (14-<16 weeks of gestation) and to compare its diagnostic accuracy with that later in the mid trimester (16-24 weeks of gestation). Nuchal thickness, humerus and femur lengths, hyperechoic bowel, hypoplastic fifth digit (clinodactyly), and any gross anatomic defects were measured or ascertained in singleton pregnancies that were undergoing genetic amniocentesis. Multiple stepwise logistic regression analysis was used to determine the significant sonographic markers for Down syndrome detection in each group. Multivariate gaussian algorithms that included maternal age were used to estimate patient-specific Down syndrome risk. Sensitivity and false- positive rates, receiver-operating characteristic curves, and area under the curves were calculated and compared for both groups. There were 1,727 pregnancies with 22 Down syndrome fetuses (1.27%) in the early group versus 3,914 pregnancies with 86 Down syndrome fetuses (2.2%) in the later group. The mean +/- SD ages were 15.5 +/- 0.4 weeks versus 17.6 +/- 1.4 weeks, respectively. Early genetic sonography (14-<16 weeks) had a 100% detection rate, with a 21.2% false-positive rate. The early versus later genetic sonography had an 81.8% versus 61.6% detection rate, respectively, at a fixed 4.8% false-positive rate. Early sonography had significantly higher diagnostic accuracy (area under the curve, 0.962 vs 0.871, respectively; P =.005). In fetuses at 14 to 15 weeks, the genetic sonography was also highly accurate, with 100% detection with a 21.9% false-positive rate. Early genetic sonography is highly sensitive and statistically superior to later ultrasonography for Down syndrome detection. Early midtrimester sonography achieved a diagnostic accuracy similar to that currently reported for first-trimester nuchal translucency.
    American Journal of Obstetrics and Gynecology 11/2002; 187(5):1235-8. DOI:10.1067/mob.2002.126975 · 3.97 Impact Factor

Publication Stats

4k Citations
1,693.13 Total Impact Points


  • 1971–2011
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2008
    • University of Maryland, Baltimore
      • Department of Medicine
      Baltimore, Maryland, United States
  • 1973–2005
    • Yale University
      • • Department of Genetics
      • • Department of Pediatrics
      New Haven, Connecticut, United States
  • 2004
    • Drexel University
      Filadelfia, Pennsylvania, United States
  • 2003
    • University of Cincinnati
      • Department of Obstetrics and Gynecology
      Cincinnati, OH, United States
  • 1992
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1988–1992
    • University of New Haven
      New Haven, Connecticut, United States
    • Danbury Hospital
      Danbury, Connecticut, United States
  • 1990
    • Bridgeport Hospital
      Bridgeport, Connecticut, United States
  • 1985
    • Mount Sinai Medical Center
      New York, New York, United States