26 results on '"Haddow, James E."'
Search Results
2. Where have all the trisomies gone?
- Author
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Palomaki GE, Lambert-Messerlian GM, and Haddow JE
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- Amniocentesis, DNA blood, Decision Making, Female, Humans, Karyotyping, Maternal Serum Screening Tests, Pregnancy, Sensitivity and Specificity, Sex Chromosome Aberrations, Ultrasonography, Prenatal, Chromosome Aberrations, Chromosome Disorders diagnosis, Prenatal Diagnosis, Trisomy
- Abstract
Providing reliable prenatal screening performance estimates is critical for patient counseling and policy-making. Women who choose prenatal screening for aneuploidy are likely to be concerned not only with the common aneuploidies but with all causes of intellectual disability and serious birth defects. Sequential prenatal screening (combined serum and ultrasound testing) for aneuploidy detection commonly is offered as a primary screening test. Among women identified as screen positive, cell-free (cf)DNA has been added recently as a secondary, noninvasive screening option, before the consideration of invasive diagnostic testing (eg, amniocentesis and karyotype). With the anticipation of lower costs in the future, cfDNA might be an alternative to sequential screening in the general population. Sequential and cfDNA tests are both noninvasive, and both identify common aneuploidies. Screening via cfDNA detects more common chromosome abnormalities (eg, trisomy 21, sex trisomies). Sequential screening can identify other aneuploidies (eg, triploidy), as well as chromosome abnormalities associated with fetal structural abnormalities. When the advantages and disadvantages of routine sequential screening with routine cfDNA screening are compared, one important measure is the proportion and severity of chromosome abnormalities identified. When reporting these detection rates, authors need to carefully consider the impact of multiple well-described biases. For women to make informed choices in situations of this type, determining reliable comparative performance estimates is crucial., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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3. Confusion between analytic validity and clinical validity.
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Palomaki GE and Haddow JE
- Subjects
- DNA Copy Number Variations, Humans, Reproducibility of Results, Genetic Testing, Prenatal Diagnosis
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- 2016
- Full Text
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4. Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update.
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Veenstra DL, Piper M, Haddow JE, Pauker SG, Klein R, Richards CS, Tunis SR, Djulbegovic B, Marrone M, Lin JS, Berg AO, and Calonge N
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- Genetic Testing, Humans, Peer Review, Quality Assurance, Health Care, Evidence-Based Medicine, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing
- Abstract
To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development.
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- 2013
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5. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study.
- Author
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Palomaki GE, Deciu C, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Grody WW, Nelson SF, and Canick JA
- Subjects
- Adult, Case-Control Studies, Female, Humans, Middle Aged, Pregnancy, Prenatal Diagnosis, Reproducibility of Results, Sensitivity and Specificity, United States, Young Adult, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 18, DNA blood, Down Syndrome diagnosis, Sequence Analysis, DNA, Trisomy diagnosis
- Abstract
Purpose: To determine whether maternal plasma cell-free DNA sequencing can effectively identify trisomy 18 and 13., Methods: Sixty-two pregnancies with trisomy 18 and 12 with trisomy 13 were selected from a cohort of 4,664 pregnancies along with matched euploid controls (including 212 additional Down syndrome and matched controls already reported), and their samples tested using a laboratory-developed, next-generation sequencing test. Interpretation of the results for chromosome 18 and 13 included adjustment for CG content bias., Results: Among the 99.1% of samples interpreted (1,971/1,988), observed trisomy 18 and 13 detection rates were 100% (59/59) and 91.7% (11/12) at false-positive rates of 0.28% and 0.97%, respectively. Among the 17 samples without an interpretation, three were trisomy 18. If z-score cutoffs for trisomy 18 and 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies. An independent academic laboratory confirmed performance in a subset., Conclusion: Among high-risk pregnancies, sequencing circulating cell-free DNA detects nearly all cases of Down syndrome, trisomy 18, and trisomy 13, at a low false-positive rate. This can potentially reduce invasive diagnostic procedures and related fetal losses by 95%. Evidence supports clinical testing for these aneuploidies.
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- 2012
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6. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study.
- Author
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Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, van den Boom D, Bombard AT, Deciu C, Grody WW, Nelson SF, and Canick JA
- Subjects
- Adult, Case-Control Studies, Double-Blind Method, Down Syndrome blood, Down Syndrome genetics, False Positive Reactions, Female, Fetal Diseases blood, Fetal Diseases genetics, Humans, Karyotyping, Pregnancy, Reproducibility of Results, Sensitivity and Specificity, Down Syndrome diagnosis, Fetal Diseases diagnosis, Prenatal Diagnosis methods, Sequence Analysis, DNA methods
- Abstract
Purpose: Prenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problematic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement., Methods: A blinded, nested case-control study was designed within a cohort of 4664 pregnancies at high risk for Down syndrome. Fetal karyotyping was compared with an internally validated, laboratory-developed test based on next-generation sequencing in 212 Down syndrome and 1484 matched euploid pregnancies. None had been previously tested. Primary testing occurred at a CLIA-certified commercial laboratory, with cross validation by a CLIA-certified university laboratory., Results: Down syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471), and the testing failed in 13 pregnancies (0.8%); all were euploid. Before unblinding, the primary testing laboratory also reported multiple alternative interpretations. Adjusting chromosome 21 counts for guanine cytosine base content had the largest impact on improving performance., Conclusion: When applied to high-risk pregnancies, measuring maternal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Although implementation issues need to be addressed, the evidence supports introducing this testing on a clinical basis.
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- 2011
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7. Folic acid and neural tube defects.
- Author
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Haddow JE
- Subjects
- Female, Humans, Pregnancy, Dietary Supplements adverse effects, Folic Acid administration & dosage, Neural Tube Defects chemically induced, Neural Tube Defects prevention & control, Vitamin B Complex administration & dosage
- Published
- 2011
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8. Outcomes of interest in evidence-based evaluations of genetic tests.
- Author
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Botkin JR, Teutsch SM, Kaye CI, Hayes M, Haddow JE, Bradley LA, Szegda K, and Dotson WD
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- Genetic Predisposition to Disease, Genome-Wide Association Study methods, Genome-Wide Association Study standards, Humans, National Health Programs, Risk Assessment, Risk Factors, United States, Evidence-Based Medicine methods, Genetic Testing methods, Genetic Testing standards, Outcome Assessment, Health Care methods
- Abstract
Genetic tests are increasingly available for use in traditional clinical practice settings and through direct-to-consumer marketing. The need for evidence-based information and guidance on their appropriate use has never been more apparent. The independent Working Group of the Evaluation of Genomic Applications in Practice and Prevention Initiative commissions evidence-based reviews and develops recommendations to inform decision making surrounding the implementation of genetic tests and other applications of genomic technologies into clinical practice. A critical component of this analysis involves the identification and appropriate weighting of relevant health outcomes from genetic testing. Impacts of testing on morbidity and mortality are central considerations although research to document such outcomes can be challenging to conduct. In considering the broader impacts of genetic tests on the individual, familial and societal levels, psychosocial outcomes often take on increasing importance, and their systematic evaluation is a challenge for traditional methods of evidence-based review. Incorporating these types of outcomes in evidence-based processes is possible, however, and necessary to extract balanced and complete (or as complete as available data will allow) information on potential benefits and on potential harms. The framework used by the Evaluation of Genomic Applications in Practice and Prevention Working Group in considering, categorizing, and weighting health-related outcomes as applied to genomic technologies is presented here.
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- 2010
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9. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group.
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Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, Dotson WD, Douglas MP, and Berg AO
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- Centers for Disease Control and Prevention, U.S., Evaluation Studies as Topic, Genetic Techniques standards, Genetics, Medical trends, Humans, United States, Evidence-Based Medicine methods, Genetics, Medical methods, Genomics methods
- Abstract
The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative, established by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention, supports the development and implementation of a rigorous, evidence-based process for evaluating genetic tests and other genomic applications for clinical and public health practice in the United States. An independent, non-federal EGAPP Working Group (EWG), a multidisciplinary expert panel selects topics, oversees the systematic review of evidence, and makes recommendations based on that evidence. This article describes the EGAPP processes and details the specific methods and approaches used by the EWG.
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- 2009
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10. Sequential first- and second-trimester TSH, free thyroxine, and thyroid antibody measurements in women with known hypothyroidism: a FaSTER trial study.
- Author
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McClain MR, Lambert-Messerlian G, Haddow JE, Palomaki GE, Canick JA, Cleary-Goldman J, Malone FD, Porter TF, Nyberg DA, Bernstein P, and D'Alton ME
- Subjects
- Adult, Autoantibodies blood, Female, Guidelines as Topic, Humans, Practice Guidelines as Topic, Pregnancy, Hypothyroidism blood, Pregnancy Complications blood, Pregnancy Trimester, First blood, Pregnancy Trimester, Second blood, Thyrotropin blood, Thyroxine blood
- Abstract
Objective: The purpose of this study was to examine how closely hypothyroidism management in the general pregnancy population satisfies recently issued guidelines and to determine whether improvements are indicated., Study Design: This was an observational study in which women at 5 recruitment centers in the first- and second-trimester evaluation of risk for aneuploidy trial allowed the use of sequentially obtained first- and second-trimester sera for additional research. Three hundred eighty-nine women had hypothyroidism by self-report. Thyroid-related measurements were performed on all samples between July 2004 and May 2005., Results: Forty-three percent of the thyroid-stimulating hormone (TSH) values are at or above recently recommended guidelines in the first trimester (2.5 mU/L), as opposed to 33% of the values in the second trimester (3.0 mU/L). Twenty percent of the TSH values are at or above a less restrictive 98th percentile of normal in the first trimester, as opposed to 23% of the values in the second trimester. Mean TSH levels are higher in women with antibodies. Free thyroxine values are unremarkable., Conclusion: Future strategies should focus on more effectively treating women with hypothyroidism who have persistently elevated TSH values.
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- 2008
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11. First- and second-trimester thyroid hormone reference data in pregnant women: a FaSTER (First- and Second-Trimester Evaluation of Risk for aneuploidy) Research Consortium study.
- Author
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Lambert-Messerlian G, McClain M, Haddow JE, Palomaki GE, Canick JA, Cleary-Goldman J, Malone FD, Porter TF, Nyberg DA, Bernstein P, and D'Alton ME
- Subjects
- Adult, Female, Gestational Age, Humans, Pregnancy, Pregnancy Trimester, First blood, Pregnancy Trimester, Second blood, Reference Values, Autoantibodies blood, Thyrotropin blood, Thyroxine blood
- Abstract
Objective: The purpose of this study was to calculate first and second trimester reference ranges and within-woman correlations for TSH, free T4, and thyroid antibodies., Study Design: TSH, free T4, and thyroid antibodies were measured in paired sera from 9562 women in the FaSTER trial of Down syndrome screening., Results: The median first trimester TSH (1.05 mIU/L) is lower than the second (1.23 mIU/L); and 98th centile is higher (4.15 vs 3.77 mIU/L). Within-woman paired TSH correlations are moderately strong (r(2) = 0.64). Among women with first trimester TSH values above the 98th centile, second trimester values are over the 95th centile in 68%. Median first trimester free T4 values (1.10 ng/dL) are higher than second (1.01 ng/dL). Paired free T4 measurements correlate weakly (r(2) = 0.23). Among women with first trimester free T4 values below the 2nd centile, second trimester values are below the 5th centile in 32%. Antibody measurements correlate strongly between trimesters (thyroperoxidase r(2) = 0.79, thyroglobulin r(2) = 0.83)., Conclusion: TSH and free T4 measurements require gestation-specific reference ranges.
- Published
- 2008
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12. Quality assessment of routine nuchal translucency measurements: a North American laboratory perspective.
- Author
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Palomaki GE, Neveux LM, Donnenfeld A, Lee JE, McDowell G, Canick JA, Summers A, Lambert-Messerlian G, Kellner LH, Zebelman A, and Haddow JE
- Subjects
- Humans, Linear Models, Down Syndrome diagnosis, Nuchal Translucency Measurement standards, Quality Assurance, Health Care methods
- Abstract
Purpose: To assess nuchal translucency measurements that were performed as part of routine prenatal screening for Down syndrome., Methods: Collect ultrasound measurements of nuchal translucency and crown rump length provided by individual sonographers over a 6-month period to six North American prenatal screening laboratories, along with the laboratory's nuchal translucency interpretation in multiples of the median. For sonographers with 50 or more observations, compute three nuchal translucency quality measures (medians, standard deviations, and slopes), based on epidemiological monitoring., Results: Altogether, 23,462 nuchal translucency measurements were submitted by 850 sonographers. Among the 140 sonographers (16%) who submitted more than 50 observations, 76 (54%) were found to have all three quality measures in the target range. These 140 sonographers collectively accounted for 14,210 nuchal translucency measurements (61%). The most common single measure to be out of range was nuchal translucency multiples of the median, found for 29 of the 140 sonographers (21%)., Conclusion: Laboratories should routinely monitor the quality of nuchal translucency measurements that are received for incorporation into Down syndrome screening risk calculations and interpretations. When possible, instituting sonographer-specific medians and providing individualized feedback about performance and numbers of women tested offer the potential to yield more consistent and improved performance.
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- 2008
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13. A rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding.
- Author
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McClain MR, Palomaki GE, Piper M, and Haddow JE
- Subjects
- Cytochrome P-450 CYP2C9, Dose-Response Relationship, Drug, Genotype, Hemorrhage genetics, Humans, Risk Assessment, Sensitivity and Specificity, Vitamin K Epoxide Reductases, Warfarin administration & dosage, Alleles, Anticoagulants adverse effects, Aryl Hydrocarbon Hydroxylases genetics, Hemorrhage chemically induced, Mixed Function Oxygenases genetics, Warfarin adverse effects
- Abstract
Purpose: Summarize evidence regarding genetic testing in adults to inform warfarin dosing to reduce adverse drug events such as serious bleeding., Methods: Review published (and selected gray) literature using the Rapid-ACCE structure that addresses analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications., Results: Preliminary data suggest overall analytic sensitivity and specificity will be 98% or higher for CYP2C9 genotyping, but strength of evidence for analytic validity is low, especially for VKORC1 testing. Strength of evidence is high for the clinical validity of both genes in predicting stable warfarin dose, an intermediate outcome, but is low for the association between CYP2C9 testing and severe bleeding events (clinical sensitivity 46% (95% CI 32-60%); specificity 69% (95% CI 62-75%) and absent for bleeding events associated with VKORC1 testing. No data are available to document clinical utility of genotyping before warfarin dosing., Conclusions: The most important gaps identified are: which variants should be included in a testing panel, lack of data from external proficiency testing, lack of validated dosing algorithm incorporating genetic and nongenetic factors, evidence of clinical utility, reliable economic analyses, and methods to address several ethical, legal, and social implications issues.
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- 2008
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14. Estimating first-trimester combined screening performance for Down syndrome in dried blood spots versus fresh sera.
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Palomaki GE, Neveux LM, Knight GJ, Haddow JE, and Lee J
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- Adult, Cohort Studies, False Positive Reactions, Female, Humans, Mass Screening, Pregnancy, Serum, Chorionic Gonadotropin blood, Down Syndrome blood, Down Syndrome diagnosis, Pregnancy Trimester, First blood, Pregnancy-Associated Plasma Protein-A analysis
- Abstract
Purpose: The study purpose was to examine the consequences of using dried blood spots rather than fresh sera in first-trimester Down syndrome screening., Methods: We collected and compared human chorionic gonadotropin and pregnancy-associated plasma protein-A results from clients providing dried blood spots (Cohort 1) and from other clients providing fresh sera (Cohort 2). Inclusion and exclusion criteria aimed at ensuring the two cohorts were similar., Results: The average concentrations of human chorionic gonadotropin and pregnancy-associated plasma protein-A are significantly different for the two cohorts. When the results are converted to multiples of the median and weight-adjusted, the variances for human chorionic gonadotropin and pregnancy-associated plasma protein-A in Cohort 1 are greater by 25% and 14%, respectively. Modeling the impact of this increased variance shows that Down syndrome detection is expected to be lower in Cohort 1 (83% vs. 85% at a 5% false-positive rate) or the false-positive rate is expected to be higher (3.9% vs. 3.0% at an 80% detection rate)., Conclusions: This study of two closely matched cohorts provides indirect evidence that dried blood spots will result in slightly lower Down syndrome screening performance. Studies should be undertaken to confirm and further quantify differences in assigned risks by a direct comparison using matched serum and dried blood spots collected from the same women.
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- 2007
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15. Screen-positive rates and agreement among six family history screening protocols for breast/ovarian cancer in a population-based cohort of 21- to 55-year-old women.
- Author
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Palomaki GE, McClain MR, Steinort K, Sifri R, LoPresti L, and Haddow JE
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- Adult, Age of Onset, Breast Neoplasms epidemiology, Cohort Studies, Female, Genes, BRCA1, Genes, BRCA2, Germ-Line Mutation, Humans, Middle Aged, Ovarian Neoplasms epidemiology, Risk Factors, United States epidemiology, Breast Neoplasms genetics, Genetic Testing methods, Ovarian Neoplasms genetics, Pedigree, Population Surveillance
- Abstract
Purpose: Mutations in the BRCA1 and BRCA2 genes are responsible for approximately 2% of breast cancers by age 70 years. Professional and governmental groups recommend using family history protocols as an initial step in identifying women and families for mutation testing. We assess screen-positive rates and levels of agreement between these protocols., Methods: We applied six family history screening protocols to a population-based cohort of 321 women, age 21 to 55 years, who reported their personal and family history of breast and ovarian cancer., Results: The proportion of women and families identified as candidates for mutation testing ranged from 4.4% to 7.8%, depending on the protocol. The protocols had low or fair agreement (kappa <0.75 for 14 of 15 comparisons), but all identified six women (1.9%, 95% confidence interval 0.7%-4.0%) as screen positive. When the effect of missing ages of cancer onset was modeled, these rates increased (range 6.5%-11.5%), and nine women (2.8%) were screen positive by all protocols., Conclusion: Given limitations of family history as a screening test for hereditary cancer related to BRCA1/2 mutations, 1% to 2% of women in the general population should initially be identified for mutation testing. One way to achieve this would be to require that multiple screening protocols agree.
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- 2006
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16. Screening for thyroid disorders during pregnancy: results of a survey in Maine.
- Author
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Haddow JE, McClain MR, Palomaki GE, Kloza EM, and Williams J
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- Family Practice statistics & numerical data, Female, Health Care Surveys, Humans, Maine, Obstetrics statistics & numerical data, Pregnancy, Reference Values, Thyrotropin blood, Mass Screening statistics & numerical data, Practice Patterns, Physicians', Pregnancy Complications diagnosis, Prenatal Care statistics & numerical data, Thyroid Diseases diagnosis
- Abstract
Objective: Guidelines regarding prenatal screening for thyroid deficiency are conflicting, and current practice in primary care settings is unknown. Our survey sought to determine the: 1) extent of screening in Maine; 2) factors associated with screening; and 3) laboratory cut-off levels used., Study Design: In 2004 we surveyed 61 prenatal care practices, representing 246 practitioners and 85% of Maine deliveries., Results: Screening via thyroid-stimulating hormone (TSH) testing was routine in 48% of the practices. Obstetrician practices screened at a significantly higher rate than family practices (56% vs 8%; odds ratio [OR] 15.0, 95% CI 1.9-130.0). Nonsignificant higher rates were found for urban versus rural, and multipractitioner versus solo practices. The lower TSH cut-off levels ranged between 0.1 and 0.5 mU/L among practices; the upper cut-off levels ranged between 3.5 and 5.5 mU/L., Conclusion: Prenatal screening for thyroid deficiency varies among practices, reflecting conflicting guidelines. TSH cut-offs are also variable and might benefit from standardization.
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- 2006
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17. Circulating angiogenic proteins in trisomy 13.
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Bdolah Y, Palomaki GE, Yaron Y, Bdolah-Abram T, Goldman M, Levine RJ, Sachs BP, Haddow JE, and Karumanchi SA
- Subjects
- Case-Control Studies, Chromosomes, Human, Pair 18, Down Syndrome, Enzyme-Linked Immunosorbent Assay, Female, Humans, Placenta Growth Factor, Pregnancy Proteins blood, Pregnancy Trimester, First, Pregnancy Trimester, Second, Single-Blind Method, Vascular Endothelial Growth Factor Receptor-1 blood, Angiogenic Proteins blood, Chromosomes, Human, Pair 13, Pregnancy blood, Trisomy
- Abstract
Objective: Women who are carrying a trisomy 13 fetus are more prone to develop preeclampsia. Excess circulating soluble fms-like tyrosine kinase-1 has been implicated recently in the pathogenesis of preeclampsia. Since the fms-like tyrosine kinase-1/soluble fms-like tyrosine kinase-1 gene is located on chromosome 13q12, we hypothesized that the extra copy of this gene in trisomy 13 may lead to excess circulating soluble fms-like tyrosine kinase-1, reduced free placental growth factor level, and increased soluble fms-like tyrosine kinase-1/placental growth factor ratio. This may then contribute to the increased risk of preeclampsia that has been observed in these patients. Our objective was to characterize the maternal circulating angiogenic proteins in trisomy 13 pregnancies., Study Design: Maternal serum samples of trisomy 13, 18, 21 and normal karyotype pregnancies were obtained from first and second trimester screening programs. We chose 17 cases of trisomy 13 that were matched for maternal age, freezer storage time, and parity with 85 normal karyotype control samples. Additionally, 20 cases of trisomy 18 and 17 cases of trisomy 21 were included. Cases and control samples were assayed for levels of soluble fms-like tyrosine kinase-1 and placental growth factor by enzyme-linked immunosorbent assay in a blinded fashion. Because of the skewed distributions of soluble fms-like tyrosine kinase-1 and placental growth factor, nonparametric analytic techniques were used, and the results are reported as median and ranges., Results: In early pregnancy trisomy 13 cases and control samples, the median circulating soluble fms-like tyrosine kinase-1/placental growth factor ratios were 17.0 (range, 1.2-61.3) and 6.7 (range, 0.8-62.9), respectively (P = .003). The median soluble fms-like tyrosine kinase-1/placental growth factor ratios in trisomy 18 and 21 were 4.8 (range, 0.9-53.9) and 5.1 (range, 1.0-18.1), which were not significantly different than the control samples. Furthermore, the differences between trisomy 13 and control samples were more pronounced in the second trimester specimens than in the specimens from the first trimester., Conclusion: These data suggest that alterations in circulating angiogenic factors may be involved intimately in the pathogenesis of preeclampsia in trisomy 13. A larger clinical study that measures these factors longitudinally and correlates them with pregnancy outcomes is needed to further establish the link between trisomy 13, altered angiogenic factors, and preeclampsia.
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- 2006
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18. Adjusting the estimated proportion of breast cancer cases associated with BRCA1 and BRCA2 mutations: public health implications.
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McClain MR, Palomaki GE, Nathanson KL, and Haddow JE
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- Adult, Aged, Breast Neoplasms genetics, Female, Genetic Predisposition to Disease genetics, Genetic Testing, Humans, Middle Aged, Penetrance, Prevalence, Risk Factors, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms epidemiology, Genetic Predisposition to Disease epidemiology, Mutation, Neoplasm Proteins genetics
- Abstract
Purpose: Mutations in BRCA1 or BRCA2 genes increase breast cancer risk. Assuring reliability of information about these mutations is increasingly important to the health care community; mutation testing is becoming more widespread. We describe a methodology for assessing such information., Methods: Our approach integrates four interdependent epidemiologic parameters: (1) the probability of developing breast cancer, (2) the proportion of breast cancer cases with a BRCA1 or BRCA2 mutation, (3) the proportion of women that carries a mutation, and (4) the proportion of women with a mutation that develops cancer. We assess the plausibility of estimates of these parameters from published reports and commonly accessed information sources., Results: Assuming a fixed probability of developing breast cancer, the following estimates for the other three epidemiologic parameters are derived for women by age 70: 1% to 2% of all breast cancer cases are associated with a BRCA1 or BRCA2 mutation; 1 in 300 to 1 in 465 women carry a mutation; and 35 to 65% of mutation carriers develop breast cancer. Within these ranges, however, only selected combinations are plausible. The proportion of mutation-related breast cancer is lower than listed in some common information sources (1 to 2% vs 6%). Also, penetrance is somewhat lower and the carrier rate somewhat higher., Conclusions: The four epidemiologic parameters can be integrated to test their plausibility. BRCA1 and BRCA2 mutations are associated with only one-third as many breast cancer cases in the general population as reported by commonly accessed information sources.
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- 2005
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19. An evaluation of BRCA1 and BRCA2 founder mutations penetrance estimates for breast cancer among Ashkenazi Jewish women.
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McClain MR, Nathanson KL, Palomaki GE, and Haddow JE
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- Adult, Aged, Breast Neoplasms genetics, Cross-Sectional Studies, Female, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Genetic Testing, Humans, Jews, Middle Aged, Public Health, BRCA1 Protein genetics, BRCA2 Protein genetics, Breast Neoplasms epidemiology, Founder Effect, Mutation genetics, Neoplasm Proteins genetics, Penetrance
- Abstract
Purpose: Three founder mutations in BRCA1 or BRCA2 genes increase breast cancer risk among Ashkenazi Jewish women. Reported estimates of the magnitude of this risk vary widely. We describe an integrated approach for assessing the plausibility of these estimates., Methods: Our approach integrates four epidemiologic parameters: (1) the proportion of all breast cancer cases with a founder mutation, (2) the proportion of women that carry one of these mutations, (3) the proportion of women with a mutation that develops cancer, and (4) the number of women who will develop cancer, regardless of mutation status. We then assess the published estimates of the proportion of Ashkenazi Jewish women with a mutation that develops cancer in the context of the other three parameters., Results: Penetrance for the founder mutations by ages 40, 50, and 70 are approximately 7%, 20%, and 40%, respectively. In two of the four published studies that evaluated at least two of the four parameters, penetrance estimates were internally consistent with the other three parameters and were also consistent with our consensus estimate. The third study had incomplete data. In the fourth study, the penetrance estimate was not internally consistent with the other three parameters, nor was it consistent with the consensus estimate., Conclusions: The four epidemiologic parameters are interdependent and can be used to test the plausibility of any one parameter. Based on the range of breast cancer penetrance estimates for BRCA1 and BRCA2 founder mutations derived by our approach, recently reported penetrance estimates appear to be overestimated.
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- 2005
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20. Clinical sensitivity of prenatal screening for cystic fibrosis via CFTR carrier testing in a United States panethnic population.
- Author
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Palomaki GE, FitzSimmons SC, and Haddow JE
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- Black or African American genetics, Asian genetics, Cystic Fibrosis epidemiology, Cystic Fibrosis ethnology, Ethnicity, Female, Gene Frequency, Genetic Carrier Screening, Genetics, Population, Hispanic or Latino genetics, Humans, Jews genetics, Pregnancy, Sensitivity and Specificity, United States, White People genetics, Cystic Fibrosis diagnosis, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Genetic Testing, Prenatal Diagnosis
- Abstract
Purpose: To estimate CFTR mutation frequencies, clinical sensitivities (proportions of carrier couples or affected fetuses detected), and birth prevalence estimates for broad racial/ethnic groups and for a panethnic U.S. population., Methods: Published sources of information were identified, corrected when appropriate, and summarized. Combining racial/ethnic-specific mutation frequencies and birth prevalence estimates allowed the computation of panethnic estimates., Results: Two of the 25 recommended mutations do not meet the 0.1% threshold in a panethnic population set by the American College of Medical Genetics. The clinical sensitivities are estimated to be 71.9%, 51.7%, 41.6%, 88.6%, and 23.4% for non-Hispanic Caucasians, Hispanic Caucasian, African American, Ashkenazi Jewish Caucasian, and Asian American couples, respectively. Birth prevalence estimates are 1:2,500, 1:13,500, 1:15,100, 1:2,270, and 1:35,100, whereas the number of couples needed to screen to detect an affected fetus are about 3,200, 26,120; 36,040; 2,600, and 129,600, respectively, for the same racial/ethnic groups., Conclusions: Overall, the panethnic estimates for CFTR mutation frequencies are similar to those for non-Hispanic Caucasians. However, large differences in both clinical sensitivity and birth prevalence exist between the broad racial/ethnic groups examined. Whether and how the differences in the numbers of couples needed to screen to detect an affected fetus are to be included in prenatal screening for cystic fibrosis needs to be more explicitly addressed.
- Published
- 2004
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21. Is first trimester measurement of sex hormone binding globulin a possible screening test for gestational diabetes mellitus.
- Author
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McClain MR, Palomaki GE, and Haddow JE
- Subjects
- Biomarkers analysis, Case-Control Studies, Female, Humans, Predictive Value of Tests, Pregnancy, Pregnancy Trimester, First, Prenatal Care, Reference Values, Risk Assessment, Sensitivity and Specificity, Diabetes, Gestational diagnosis, Pregnancy Outcome, Sex Hormone-Binding Globulin analysis
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- 2004
- Full Text
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22. Estimated analytic validity of HFE C282Y mutation testing in population screening: the potential value of confirmatory testing.
- Author
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Palomaki GE, Haddow JE, Bradley LA, Richards CS, Stenzel TT, and Grody WW
- Subjects
- Hemochromatosis Protein, Humans, Sensitivity and Specificity, Genetic Testing, Hemochromatosis genetics, Histocompatibility Antigens Class I genetics, Membrane Proteins genetics, Mutation genetics
- Abstract
Purpose: The purpose of this study was to estimate analytic sensitivity and specificity of HFE testing for C282Y homozygosity in the hypothetical setting of population screening for hemochromatosis., Methods: We analyzed published results of the Molecular Genetics Survey performed by the American College of Medical Genetics/College of American Pathologists between 1998 and 2002, taking into account its educational nature., Results: Analytic sensitivity for C282Y homozygosity is 98.4% (95% CI 95.9%-99.5%). The analytic specificity is 99.8% (99.4%-99.9%). At a frequency of 40 per 10,000 for the homozygous genotype, the analytic positive predictive value is 66%., Conclusion: HFE testing for C282Y homozygosity is highly reliable. Homozygosity is uncommon in population screening, however, and confirmatory testing should be considered.
- Published
- 2003
- Full Text
- View/download PDF
23. Analytic validity of cystic fibrosis testing: a preliminary estimate.
- Author
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Palomaki GE, Bradley LA, Richards CS, and Haddow JE
- Subjects
- Alleles, Cystic Fibrosis genetics, DNA Mutational Analysis, Data Collection, Female, Humans, Mass Screening, Sensitivity and Specificity, Cystic Fibrosis diagnosis, Genetic Testing methods
- Abstract
Purpose: Derive estimates of analytic sensitivity and specificity of DNA testing for cystic fibrosis in the United States., Methods: Analyze published results of the American College of Medical Genetics (ACMG)/College of American Pathologists (CAP) Molecular Genetics Survey between 1996 and 2001, taking into account difficult, simulated clinical samples included for educational purposes., Results: Analytic sensitivity is 97.9% [95% confidence interval (CI) 96.8-98.7%], and analytic specificity is 99.4% (95% CI 98.7-99.9%) after removing challenges involving delI507 and performing other adjustments. Analytic sensitivity is consistent over the 6 years. Specificity was lower in 1997., Conclusion: These preliminary estimates indicate that analytic validity of cystic fibrosis testing is very good and can likely be improved. To date, fewer than half of the mutations in the panel recommended for preconceptional or prenatal screening have been challenged. The present study highlights the value of performing confirmatory testing when a mutation is identified to reduce false-positive results.
- Published
- 2003
- Full Text
- View/download PDF
24. Thyroid-stimulating-hormone concentrations and risk of hypothyroidism.
- Author
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Haddow JE, Palomaki GE, and Williams J
- Subjects
- Case-Control Studies, Child, Female, Humans, Hypothyroidism drug therapy, Pregnancy, Thyrotropin therapeutic use, Hypothyroidism blood, Prenatal Exposure Delayed Effects, Thyrotropin blood
- Published
- 2002
- Full Text
- View/download PDF
25. Apolipoprotiens and prediction of fatal myocardial infarction.
- Author
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Wald NJ, Law M, Haddow JE, and Craig WY
- Subjects
- False Positive Reactions, Humans, Myocardial Infarction mortality, Apolipoprotein A-I blood, Apolipoproteins B blood, Myocardial Infarction blood
- Published
- 2002
- Full Text
- View/download PDF
26. Updated assessment of cystic fibrosis mutation frequencies in non-Hispanic Caucasians.
- Author
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Palomaki GE, Haddow JE, Bradley LA, and FitzSimmons SC
- Subjects
- Cystic Fibrosis diagnosis, Genetic Testing, Humans, North America, Prenatal Diagnosis, Risk Assessment, Cystic Fibrosis genetics, Gene Frequency, Mutation, White People genetics
- Abstract
Purpose: To update estimates of individual and cumulative cystic fibrosis (CF) mutation frequencies in non-Hispanic Caucasians for the prenatal screening panel recommended by American College of Medical Genetics and to determine the impact on screening performance., Methods: Two data sources were used. In the first (CF Genetic Analysis Consortium), our re-analysis was restricted to North American studies. In the second (CF Foundation National Patient Registry), we performed a new analysis restricted to individuals tested at eight Therapeutic Development Network sites., Results: The updated average cumulative proportion of mutations identified is 88.34% (higher than previously reported), indicating that 78% of high-risk couples (and affected fetuses) can potentially be identified., Conclusion: Prenatal CF screening in U.S. non-Hispanic Caucasians is more effective than previously thought.
- Published
- 2002
- Full Text
- View/download PDF
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