• Genes and generalists: why we need professionals with added competencies.

• Breast cancer risks: some clinically useful approaches.

• Cystic fibrosis carrier screening. Are nurses ready to be on the front line?

• Influence of the apolipoprotein E epsilon4 allele on human embryonic development.

• Inherited pancreatic cancer: surveillance and treatment strategies for affected families.

• Molecular diagnosis of early pancreatic ductal adenocarcinoma in high-risk patients.

• Update of familial pancreatic cancer in Germany.

• Legal and policy issues in genetics and insurance.

• Screening for tetrahydrobiopterin deficiency among hyperphenylalaninemia patients in Southern China.

• [Genetic population screening--an ethical dilemma]

• [More specific analyses in neonatal screening using DNA techniques]

• Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients: interaction with HLA-DRB1*1501 and disease modulation.

• The FAS-670 polymorphism influences susceptibility to multiple sclerosis.

• Screening ABCG1, the human homologue of the Drosophila white gene, for polymorphisms and association with bipolar affective disorder.

• Stability of self-reported family history of prostate cancer among African American men.

• Current status of genetic testing for colorectal cancer susceptibility.

• [Prevention of cancer--what do we do in Denmark and what can we achieve?]

• MOMs (multiples of the median) and DADs (discriminant aneuploidy detection): improved specificity and cost-effectiveness of biochemical

• Gene therapy in the developing world.

• Preimplantation diagnosis for early-onset Alzheimer disease caused by V717L mutation.

• The role of the nurse in cancer genetics.

• Is the CACNA1A gene involved in familial migraine with aura?

• Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family.

• Gynecologic oncologists making strides in women's cancer care.

• Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson's disease.

• Genetic detection of liver micrometastases that are undetectable histologically.

• Gene patents and the standard of care.

• Genetics 101: detecting mutations in human genes.

• Sacred secrets--the privacy of medical records.

• The limits of state laws to protect genetic information.

• Genetic exceptionalism vs. paradigm shift: lessons from HIV.

• The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of

• Sample size and power determination for clustered repeated measurements.

• Effects of genetic consultation on perception of a family risk of breast/ovarian cancer and determinants of inaccurate perception after

• Mutation detection 2001: Novel technologies, developments and applications for analysis of the human genome. Proceedings of the 6th

• SNP genotyping with fluorescence polarization detection.

• Commercial molecular diagnostics in the U.S.: The Human Genome Project to the clinical laboratory.

• Analysis of SNPs and other genomic variations using gel-based chips.

• DHPLC screening of cystic fibrosis gene mutations.

• A surface invasive cleavage assay for highly parallel SNP analysis.

• Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: Identification of a novel deletion consistent with

• Evaluation and application of denaturing HPLC for mutation detection in Marfan syndrome: Identification of 20 novel mutations and two novel

• A BRCA1 mutation in Native North American families.

• ATM mutations are rare in familial chronic lymphocytic leukemia.

• Drosophila VAP-33A directs bouton formation at neuromuscular junctions in a dosage-dependent manner.

• The identification of novel wound-healing genes through differential display.

• Preserving privacy, preventing discrimination becomes the province of genetics experts.

1
UI - 10639883
AU - Reynolds PP; Benkendorf JL
TI - Genes and generalists: why we need professionals with added competencies.
SO - West J Med 1999 Nov-Dec;171(5-6):375-9
AD - Department of Medicine and History, Johns Hopkins University School of Medicine, Baltimore, MD, USA. preynold@welchlink.welch.jhu.edu

2
UI - 12116602
AU - Kelly PT
TI - Breast cancer risks: some clinically useful approaches.
SO - Curr Womens Health Rep 2002 Apr;2(2):128-33
AD - Cancer Risk Assessment, Saint Francis Memorial Hospital, 824 Cragmont Avenue, Berkeley, CA 94708, USA. ptkelly@ptkelly.com
Information about breast cancer risk is often confusing and may even be misleading when presented as a comparison of one risk versus another. Frequently used comparison formats include relative risks, odds ratios, and proportional risk reductions. This paper discusses five areas of breast cancer risk--average risk, prognosis following a breast cancer diagnosis, risk associated with use of hormone replacement therapy at menopause, use of tamoxifen as prevention, and risks associated with BRCA mutations--to show the clarity and clinical usefulness that are obtained when risks are presented not as comparisons, but in absolute terms with a time frame.

3
UI - 11975127
AU - Tinkle MB
TI - Cystic fibrosis carrier screening. Are nurses ready to be on the front line?
SO - AWHONN Lifelines 2002 Apr-May;6(2):134-9
AD - National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, USA.

4
UI - 12009520
AU - Zetterberg H; Palmer M; Ricksten A; Poirier J; Palmqvist L; Rymo L;
TI - Zafiropoulos A; Arvanitis DA; Spandidos DA; Blennow K Influence of the apolipoprotein E epsilon4 allele on human embryonic development.
SO - Neurosci Lett 2002 May 24;324(3):189-92
AD - Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Goteborg University, 41345 Gothenburg, Sweden. henrik.zetterberg@clinchem.gu.se
Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE epsilon2, epsilon3 and epsilon4) and has important functions in nerve development and repair. Inheritance of the 4 allele is a major risk factor for the development of Alzheimer's disease. To investigate the role of APOE polymorphisms in embryonic development, we analyzed the APOE genotypes of 81 spontaneously aborted embryos and 110 adult controls using a solid-phase minisequencing technique. The epsilon4 allele was significantly less frequent in the spontaneous abortion group than in the control group (P=0.009), while the frequency of epsilon3 was significantly increased (P=0.005), suggesting that epsilon4 may have protective effects during embryogenesis. These protective effects might counterbalance the deleterious age-related effects of the epsilon4 allele in natural selection.

5
UI - 12120228
AU - Rulyak SJ; Brentnall TA
TI - Inherited pancreatic cancer: surveillance and treatment strategies for affected families.
SO - Pancreatology 2001;1(5):477-85
AD - Division of Gastroenterology, University of Washington, Seattle, Wash., USA.
BACKGROUND: Nearly 10% of pancreatic cancers are hereditary in origin, and in some individuals, the risk of pancreatic cancer approaches 50%. A number of defined syndromes can predispose families to pancreatic cancer, although many of the mechanisms that result in familial pancreatic cancers are unknown. This article reviews current knowledge regarding familial pancreatic cancers and highlights the rationale for screening and surveillance. Methods for screening and surveillance of these high-risk individuals are described that allow the detection of pancreatic dysplasia, the precursor to pancreatic cancer. We also describe a single-center experience with the management and surveillance of familial pancreatic cancer kindreds. METHODS: Thirty-five patients from 13 familial pancreatic cancer kindreds underwent screening and/or surveillance. Endoscopic ultrasound (EUS) is the initial test of choice. Endoscopic retrograde cholangiopancreatography (ERCP) is reserved for symptomatic individuals or to investigate abnormal findings on EUS. In the proper clinical setting, patients with abnormal findings on both EUS and ERCP are candidates for total pancreatectomy. RESULTS: Twelve of 35 patients were noted to have abnormal findings on EUS and ERCP. All of these individuals underwent pancreatectomy, 10 total and 2 partial. The patients who underwent partial pancreatectomy are currently awaiting resection of the pancreatic remnant. Histopathologic examination of all 12 specimens demonstrated pancreatic dysplasia (the precursor lesion to pancreatic cancer). These specimens had no evidence of pancreatic cancer; nor were any of the resected pancreata normal. Follow-up of the 35 high-risk patients at present varies from 1 to 48 months, and none of the patients under surveillance have developed pancreatic cancer. CONCLUSION: The screening and surveillance of high-risk members of familial pancreatic cancer kindreds using EUS and ERCP is an effective method for identifying individuals with pancreatic dysplasia prior to the onset of invasive pancreatic cancer. The surveillance needs to be performed by a team of specialists who have experience in dealing with pancreatic cancer and its precursors.

6
UI - 12120229
AU - Wong T; Howes N; Threadgold J; Smart HL; Lombard MG; Gilmore I; Sutton
TI - R; Greenhalf W; Ellis I; Neoptolemos JP Molecular diagnosis of early pancreatic ductal adenocarcinoma in high-risk patients.
SO - Pancreatology 2001;1(5):486-509
AD - Department of Surgery, University of Liverpool, UK.
The prevalence of pancreatic cancer in the general population is too low--even in high-prevalence areas such as Northern Europe and North America (8-12 per 10(5) population)--relative to the diagnostic accuracy of present detection methods to permit primary screening in the asymptomatic adult population. The recognition that the lifetime risk of developing pancreatic cancer for patients with hereditary pancreatitis (HP) is extremely high (20% by the age of 60 years and 40% by the age of 70 years) poses considerable challenges and opportunities for secondary screening in those patients without any clinical features of pancreatic cancer. Even for secondary screening, the detection of cancer at a biological stage that would be amenable to cure by surgery (total pancreatectomy) still requires diagnostic modalities with a very high sensitivity and specificity. Conventional radiological imaging methods such as endoluminal ultrasound and endoscopic retrograde pancreatography, which have proved to be valuable in the early detection of early neoplastic lesions in patients with familial pancreatic cancer, may well be applicable to patients with HP but only in those without gross morphological features of chronic pancreatitis (other than parenchymal atrophy). Unfortunately, most cases of HP also have associated gross features of chronic pancreatitis that are likely to seriously undermine the diagnostic value of these conventional imaging modalities. Pre-malignant molecular changes can be detected in the pancreatic juice of patients. Thus, the application of molecular screening in patients with HP is potentially the most powerful method of detection of early pancreatic cancer. Although mutant (mt) K-ras can be detected in the pancreatic juice of most patients with pancreatic cancer, it is also present in patients with non-inherited chronic pancreatitis who do not progress to pancreatic cancer (at least in the short to medium term), as well as increasingly in the older population without pancreatic disease. Nevertheless, the presence of mt-K-ras may identify a genuinely higher-risk group, enabling additional diagnostic imaging and molecular resources to be focussed on such a group. What is clear is that prospective multi-centre studies, such as that being pursued by the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC), are essential for the development of an effective secondary screening programme for these patients.

7
UI - 12120230
AU - Bartsch DK; Sina-Frey M; Ziegler A; Hahn SA; Przypadlo E; Kress R;
TI - Gerdes B; Rieder H Update of familial pancreatic cancer in Germany.
SO - Pancreatology 2001;1(5):510-6
AD - Department of Surgery, Philipps University of Marburg, Baldingerstrasse, D-35033 Marburg, Germany. bartsch@mailer.uni-marburg.de
BACKGROUND/AIMS: The prevalence of familial pancreatic cancer (FPC) and the characteristics of FPC have not yet been well investigated in the German population. Therefore, a German case collection for FPC was METHODS: The prevalence of pancreatic cancer (PC) as well as other tumours and diseases was studied in families with at least 2 first-degree relatives with histologically confirmed PC, and in families of patients with PC and a first-degree relative with malignant melanoma. All participating family members were genetically counselled and evaluated by a standardised questionnaire. RESULTS: In an 18-month period, 73 independent kindreds with potential FPC contacted the national case collection. So far, 20 kindreds have fulfilled the criteria for FPC and have undergone complete workups. Most families revealed an autosomal dominant pattern of inheritance. Twelve families revealed an isolated accumulation of PC. Importantly, in 8 of 20 (35%) families, additional tumour types such as melanoma, breast and prostate cancer occurred. CONCLUSION: The observed phenotypic heterogeneity indicates an association with predisposing tumour suppressor genes p16 and BRCA2 in up to 30% of FPC families. Mutation analysis of these candidate genes might lead to the identification of the predisposing gene defect in a proportion of FPC families.

8
UI - 11865921
AU - McGleenan T
TI - Legal and policy issues in genetics and insurance.
SO - Community Genet 2000 Feb;3(2):45-9
AD - School of Law, Queen's University, Belfast, UK.
Genetic screening and testing techniques provide a powerful diagnostic tool for the acquisition of predictive information. The potential value of such diagnostic techniques cannot be overstated. However, commercial organisations such as insurance companies and employers are also highly interested in the acquisition and use of genetic information. Concerns about the potential abuse of genetic information have stimulated a counter-current of public pressure for restrictions on the use which can be made of genetic diagnostic information. In a number of countries this pressure has generated enough concern to stimulate legislatures to enact laws which curtail the use and acquisition of genetic information. This pattern has clearly emerged in the United States of America and there are indications that similar trends are developing in Europe. This paper examines the law and policy issues arising from the interface between genetics and insurance.

9
UI - 11940335
AU - Ye J; Liu X; Ma X; Zhang Y; Huang X; Chen R; Gu X
TI - Screening for tetrahydrobiopterin deficiency among hyperphenylalaninemia patients in Southern China.
SO - Chin Med J (Engl) 2002 Feb;115(2):217-21
AD - Department of Pediatric Endocrionolgy and Genetic Metabolism, Xin Hua Hospital, Shanghai Second Medical University and Shanghai Institute for Pediatric Research, Shanghai 200092, China. ssxyjc@online.sh.cn
OBJECTIVES: To assess the incidence of tetrahydrobiopterin (BH4) deficiency among patients with hyperphenylalaninemia (HPA) in southern Chinese and evaluate clinical outcome and gene mutations in tetrahydrobiopterin deficient patients. METHODS: Urinary neopterin (N) and biopterin (B) was analyzed in 87 patients with hyperphenylalaninemia by high-performance liquid chromatography. Further combined loading tests with phenylalanine (Phe) (100 mg/kg) and tetrahydrobiopterin (BH4) (7.5 mg/kg) were performed in suspected patients with abnormal urinary pterin profiles. Gene mutation analysis was performed for patients with BH4 deficiency and their parents. BH4 deficient patients were treated with BH4 and neurotransmitter precursors after diagnosis. Blood phenylalanine levels, clinical symptoms and mental development were followed up. RESULTS: Eleven patients were diagnosed as having BH4 deficiency caused by 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency. The incidence of tetrahydrobiopterin (BH4) deficiency among patients with hyperphenylalaninemia (HPA) in southern Chinese was 10%. Combined loading tests with phenylalanine and oral BH4 were done in 4 of 11 patients and their phenylalanine levels were decreased to normal 4 - 6h after BH4 administration. Four different mutations (P87S, N52S, D96N and G144R) in the PTPS gene were detected in 5 families. Five PTPS-deficient patients were treated with synthetic BH4, neurotransmitter precursors (L-dopa plus carbidopa, and 5-hydroxytryptophan). They had satisfactory physical and mental development after treatment. One patient with partial PTPS deficiency had normal growth and mental development without treatment. CONCLUSIONS: Our results emphasize that screening for BH4 deficiency should be carried out in all patients with hyperphenylalaninemia in order to minimize the misdiagnosis. Patients with BH4 deficiency should be treated early with BH4 and a combination of neurotransmitter precursors.

10
UI - 12043411
AU - Munthe C
TI - [Genetic population screening--an ethical dilemma]
SO - Lakartidningen 2002 Apr 25;99(17):1918-9
AD - Filosofiska institutionen, Goteborgs Universitet.

11
UI - 12043414
AU - Larsson A
TI - [More specific analyses in neonatal screening using DNA techniques]
SO - Lakartidningen 2002 Apr 25;99(17):1927-8
AD - Enheten for pediatrik, institutionen for klinisk vetenskap, Karolinska institutet, Barnens sjukhus, Huddinge Universitetssjukhus, Stockholm.

12
UI - 12098513
AU - Kikuchi S; Fukazawa T; Niino M; Yabe I; Miyagishi R; Hamada T; Tashiro K
TI - Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients: interaction with HLA-DRB1*1501 and disease modulation.
SO - J Neuroimmunol 2002 Jul;128(1-2):77-81
AD - Department of Neurology, Hokkaido University Graduate School of Medicine, Kita-15 Nshi-7, Kita-ku, Sapporo 060-8638, Japan. skikuti@med.hokudai.ac.jp
We investigated PvuII and XbaI polymorphism in the estrogen receptor gene (ERG) and HLA-DRB1*1501 positivity in 116 conventional multiple sclerosis (MS) patients and 101 healthy controls in a Japanese population. Logistic analysis revealed independent associations of [P] allele in the profiles for PvuII (p=0.0005, adjusted odds ratio (aOR)=3.17) and DRB1*1501 (p=0.0089, aOR=2.61) with conventional MS. Synergistic elevated risk of MS due to interaction between the [P] allele and HLA-DRB1*1501 allele was found among female patients (odds ratio=16.0; 95% CI=3.99-63.8, p<0.0001). The [P] allele-positive patients with disease duration of more than 5 years had a significantly higher progression index (PI) of disability (p=0.0230) and a worse ranked MS severity score (p=0.0152) than their non-[P] counterparts.

13
UI - 12098516
AU - van Veen T; Kalkers NF; Crusius JB; van Winsen L; Barkhof F; Jongen PJ;
TI - Pena AS; Polman CH; Uitdehaag BM The FAS-670 polymorphism influences susceptibility to multiple sclerosis.
SO - J Neuroimmunol 2002 Jul;128(1-2):95-100
AD - Department of Neurology, VU Medical Centre, De Boelelaan 1117, 1007 MB, Amsterdam, The Netherlands
Several studies have reported a defective Fas function in patients with multiple sclerosis (MS). We were interested whether this could result from a genetically altered Fas regulation. We examined the FAS-670 polymorphism in 382 patients with MS and 206 controls, and found that the carriership of allele FAS-670*G was significantly less frequent in patients than in controls. We found no association between the carriership of FAS-670*G and clinical features. For a subgroup of patients, longitudinal MRI data were available. We observed similar brain and lesion volumes in carriers and noncarriers of FAS-670*G. These data suggest that FAS-670*G decreases the risk of developing MS, but does not affect the course of disease.

14
UI - 11673795
AU - Kirov G; Lowry CA; Stephens M; Oldfield S; O'Donovan MC; Lightman SL;
TI - Owen MJ Screening ABCG1, the human homologue of the Drosophila white gene, for polymorphisms and association with bipolar affective disorder.
SO - Mol Psychiatry 2001 Nov;6(6):671-7
AD - Neuropsychiatric Genetics Unit, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK. kirov@cardiff.ac.uk
ABCG1 encodes a transporter protein that may be involved in the cellular uptake of tryptophan. Tryptophan is the precursor for serotonin, which is implicated in the regulation of mood. The gene maps to chromosome 21q22.3, a region implicated in bipolar disorder I (BPI) in genetic linkage studies. ABCG1 is thus a suitable candidate gene for study in BP1. We screened all 15 exons and 700 bases of the 5' flanking region of ABCG1 for mutations, using Denaturing High Performance Liquid Chromatography (DHPLC). A total of 13 single nucleotide polymorphisms (SNPs) were identified. Ten of the SNPs were intronic, two lie within the 5' flanking region and one within the 3' UTR. We identified a GCC repeat within Exon 1 and two novel intronic VNTRs. Eight of the SNPs, the two VNTRs, the GCC repeat and two known microsatellite markers within the gene were tested for association with BP1 in a sample of 110 parent-offspring trios using the Extended Transmission Disequilibrium Test (ETDT). No alleles or haplotypes were significantly preferentially transmitted from parents to affected offspring. However, the trend for preferential transmission of markers in the 3'UTR is in the same direction as in a previous report for association with mood and panic disorders and therefore warrants attempts at replication. Marker-to-marker linkage disequilibrium (LD) showed that strong LD was present over relatively short distances of up to 20 kb and was present for SNPs as well as for polymorphic repeats. The polymorphisms identified in this study will be useful in examining the role of this gene in other neuropsychiatric disorders and behavioural traits.

15
UI - 12048968
AU - Weinrich SP; Faison-Smith L; Hudson-Priest J; Royal C; Powell I
TI - Stability of self-reported family history of prostate cancer among African American men.
SO - J Nurs Meas 2002 Spring-Summer;10(1):39-46
AD - School of Nursing, University of Louisville, Kentucky 40292, USA. sally.weinrich@louisville.edu
The genome-wide search for the prostate cancer gene holds the promise of the availability of prostate cancer susceptibility testing in the near future. When this occurs, self-reported history of prostate cancer will be critical in determining who is eligible for cancer susceptibility testing. Little attention has been given to the reliability of self-reported family history of prostate cancer, particularly in African American men. This correlational study measured the stability of self-reported family history of prostate cancer over a one-year time period (between 1997 and 1998) with 96 African American men from a southern state. The men were asked on two separate occasions, 1 year apart, "Have any of your men blood relatives ever had prostate cancer?" The question had a prior test-retest reliability of 0.85 over a 2-week period. Forty-eight percent of the men changed their answers on the second administration. Men most likely to change their answers were low-income men and men who did not participate in a free prostate cancer screening. This research highlights the need for public genetic education and the recognition by health professionals that self-reported family history of cancer is a variable that changes as families have increased awareness and communication concerning family history of cancer.

16
UI - 11866134
AU - Solomon CH; Pho LN; Burt RW
TI - Current status of genetic testing for colorectal cancer susceptibility.
SO - Oncology (Huntingt) 2002 Feb;16(2):161-71; discussion 176, 179-80
AD - Division of Gastroenterology, Huntsman Cancer Institute at the University of Utah, Salt Lake City 84112, USA.
Over 130,000 new cases of colon cancer are diagnosed annually. Approximately 20% to 30% of these are attributable to familial risk, and 3% to 5% belong to a hereditary colorectal cancer predisposition syndrome. Recent discoveries of the genes responsiblefor the inherited colorectal cancer conditions have expanded the field of commercial genetic testing. Health-care providers who use genetic testing in clinical practice are aware of the benefits that genetic testing can confer on screening, prevention, and treatment options for patients with a personal and/or family history of colon cancer. When genetic test results are correctly interpreted, the information they provide can offer medical guidance for the entire family. The psychological impact, however, of presymptomatic testing can be multifaceted. There are unprecedented benefits but also complex issues surrounding genetic testing. For these reasons, the practice of offering genetic testing to individuals at high risk for colon cancer is heavily fortified with guidelines and recommendations. This review covers the current availability and limitations of genetic testing for inherited colorectal cancer syndromes and focuses on guidelines that address the psychological, ethical, and social concerns stemming from genetic testing.

17
UI - 12082813
AU - Storm HH; Olsen J
TI - [Prevention of cancer--what do we do in Denmark and what can we achieve?]
SO - Ugeskr Laeger 2002 May 27;164(22):2876-81
AD - Aarhus Universitet, Center for Epidemiologisk Grundforskning. hans@cancer.dk
We know from our cancer registers and from epidemiological research that we have a major potential for cancer prevention. If the risk factors had been commonly known in the population and the population had been willing to change their risk behaviours, about one third or perhaps half of all new cases could have been avoided today. Cancer epidemiology has pointed to factors of major importance for public health, such as use of tobacco, dietary factors (including alcohol), physical activity, obesity, environmental exposure in leisure time (sun), and in the workplace. All of these can be subject to primary prevention, i.e. behavior to minimise the individual's risk of contracting cancer. Studies on secondary prevention such as screening for cancer have attracted much attention, perhaps at the expense of secondary prevention related to tobacco, alcohol, and diet in the treatment, thereby avoiding side effects and improving the outcome of therapy. Cancer epidemiology has a long tradition in Denmark, whereas translation of the epidemiological findings into prevention is lagging behind. In future, a close collaboration is needed between health professionals, communication and marketing experts, as well as specialists in education and psychology. Only by joining forces with different disciplines will it be possible to target primary and secondary prevention to ease the burden of disease in the population. Evidently, implementation of preventive measures, will benefit from political will and support.

18
UI - 7537020
AU - Evans MI; Chik L; O'Brien JE; Chin B; Dvorin E; Ayoub M; Krivchenia EL;
TI - Ager JW; Johnson MP; Sokol RJ MOMs (multiples of the median) and DADs (discriminant aneuploidy detection): improved specificity and cost-effectiveness of biochemical screening for aneuploidy with DADs.
SO - Am J Obstet Gynecol 1995 Apr;172(4 Pt 1):1138-47; discussion 1147-9
AD - Department of Obstetrics and Gynecology, Hutzel Hospital/Wayne State University, Detroit, MI 48201, USA.
OBJECTIVE: Our purpose was to assess the efficacy of double- and triple-screening paradigms for Down syndrome and to develop a more logical, statistical approach to risk prediction that will decrease the cost of screening and allow the incorporation of new parameters appropriately weighted for their contribution. STUDY DESIGN: Data from 24,504 patients who had biochemical screening for Down syndrome by single (alpha-fetoprotein), double (alpha-fetoprotein, beta-human chorionic gonadotropin), or triple screening (alpha-fetoprotein, beta-human chorionic gonadotropin, unconjugated estriol) who had complete outcome information were analyzed by (1) existing gaussian-based methods, (2) the Glasgow ratio method, and (3) a new statistical approach (i.e., directly adjusted data sets for discriminant aneuploidy detection [DADs]) RESULTS: By use of individual risk-based thresholds for "at risk" status, both double and triple screening performed far better than single screening, but the percentages of patients at risk varied widely. When the percentages at risk were held constant, the sensitivity of double and triple screenings was similar, suggesting that there are no benefits of using estriol as a third marker. For 25,000 patients the use of only alpha-fetoprotein and beta-human chorionic gonadotropin would save about $500,000, with no decrease in sensitivity. With the DADs approach a statistically sound model giving more stable estimates was developed that permits each factor to be analyzed for its own explained proportion of variance and allows each parameter to have different weighting. For this data set the same sensitivity was seen with, conservatively, a 1% reduction in the percentage of patients at risk, which would reduce by 250 the number of amniocenteses, at a further savings of about $400,000. CONCLUSIONS: By use of existing methods, double screening is equally as effective as triple screening, so that the expense of estriol is unnecessary. The DADs approach, by allowing for variable weighting of parameters, lowers the at risk percentage and will permit a much more flexible approach as new parameters become available. Changing to DADs and eliminating estriol should achieve higher specificity for the same sensitivity and save, conservatively, about $900,000 in this series. Extrapolated nationally, if confirmed, the annual savings could approach $72,000,000.

19
UI - 9536259
AU - Sikora K
TI - Gene therapy in the developing world.
SO - Gene Ther 1998 Jan;5(1):3-4

20
UI - 11866650
AU - Verlinsky Y; Rechitsky S; Verlinsky O; Masciangelo C; Lederer K; Kuliev
TI - A Preimplantation diagnosis for early-onset Alzheimer disease caused by V717L mutation.
SO - JAMA 2002 Feb 27;287(8):1018-21
AD - Reproductive Genetics Institute, Chicago, IL, USA. rgi@flash.net
CONTEXT: Indications for preimplantation genetic diagnosis (PGD) have recently been expanded to include disorders with genetic predisposition to allow only embryos free of predisposing genes to be preselected for transfer back to patients, with no potential for pregnancy termination. OBJECTIVE: To perform PGD for early-onset Alzheimer disease (AD), determined by nearly completely penetrant autosomal dominant mutation in the amyloid precursor protein (APP) gene. DESIGN: Analysis undertaken in 1999-2000 of DNA for the V717L mutation (valine to leucine substitution at codon 717) in the APP gene in the first and second polar bodies, obtained by sequential sampling of oocytes following in vitro fertilization, to preselect and transfer back to the patient only the embryos that resulted from mutation-free oocytes. SETTING: An in vitro fertilization center in Chicago, Ill. PATIENTS: A 30-year-old AD-asymptomatic woman with a V717L mutation that was identified by predictive testing of a family with a history of early-onset AD. MAIN OUTCOME MEASURES: Results of mutation analysis; pregnancy outcome. RESULTS: Four of 15 embryos tested for maternal mutation in 2 PGD cycles, originating from V717L mutation--free oocytes, were preselected for embryo transfer, yielding a clinical pregnancy and birth of a healthy child free of predisposing gene mutation according to chorionic villus sampling and testing of the neonate's blood. CONCLUSION: This is the first known PGD procedure for inherited early-onset AD resulting in a clinical pregnancy and birth of a child free of inherited predisposition to early-onset AD.

21
UI - 12040228
AU - Middelton L; Dimond E; Calzone K; Davis J; Jenkins J
TI - The role of the nurse in cancer genetics.
SO - Cancer Nurs 2002 Jun;25(3):196-206
AD - Urology Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md. 20892-1873, USA.
Knowledge gained from the Human Genome Project and related genetic research is already impacting clinical oncology nursing practice. Because cancer is now understood to be a genetic disease, changes in the traditional approaches to prevention, diagnosis, and therapeutic management of cancer are becoming increasingly genetically based. Therefore, to ensure competency in oncology nursing practice at all levels, nurses must incorporate an understanding of the underlying biology of carcinogenesis and the molecular rationale underlying strategies to prevent, diagnose, and treat cancer.

22
UI - 12111613
AU - Brugnoni R; Leone M; Rigamonti A; Moranduzzo E; Cornelio F; Mantegazza
TI - R; Bussone G Is the CACNA1A gene involved in familial migraine with aura?
SO - Neurol Sci 2002 Apr;23(1):1-5
AD - Department of Neuromuscular Diseases, C. Besta National Neurological Institute, Milan, Italy.
The discovery of mutations in the neural calcium channel (CACNA1A) gene in familial hemiplegic migraine (FHM), variant of migraine with aura, led to the suggestion that this gene might be involved in familial migraine with aura (FMA). We investigated whether the mutations in FHM are present in FMA patients, analyzing genomic DNA by PCR, single stranded conformation polymorphism, sequencing and restriction enzyme. No mutations were found. A known polymorphism (5682-14C>T) was found in exon 36. These findings suggest that the mutations found in FHM and the other known mutations of the CACNA1A gene are not the genetic basis of FMA. Genetic alterations in FMA patients may be localized on chromosome 19 but not in the CACNA1A exons we investigated.

23
UI - 12111614
AU - Cevoli S; Pierangeli G; Monari L; Valentino ML; Bernardoni P; Mochi M;
TI - Cortelli P; Montagna P Familial hemiplegic migraine: clinical features and probable linkage to chromosome 1 in an Italian family.
SO - Neurol Sci 2002 Apr;23(1):7-10
AD - Institute of Clinical Neurology, University of Bologna Medical School, Via Ugo Foscolo 7, I-40123 Bologna, Italy.
We describe an Italian family with familial hemiplegic migraine (FHM), subtle cerebellar signs and probable linkage to chromosome 1. FHM is genetically heterogeneous; in about 50% of families it is caused by mutations within the CACNA1A gene on chromosome 19. Linkage to 1q31 and 1g21-23 has also been established. Other families do not link either to chromosome 19 or 1. Chromosome 19-linked FHM may display nystagmus and cerebellar ataxia. Affected family members were neurologically examined; linkage analysis was performed with markers for chromosomes 19p13, 1q21-23, and 1q32. Five family members had hemiplegic migraine, and 3 displayed additional cerebellar signs (scanning speech and nystagmus). In 1 patient, episodes of hemiplegic migraine triggered by mild head trauma. Epilepsy and mental retardation were also found in 1 affected relative each. Lod scores for linkage to 19p13 were negative, while the maximum two-point lod score was 1.81 to 1q21-23. This family with FHM and associated subtle cerebellar signs, epilepsy and mental retardation showed probable linkage to 1q21-23.

24
UI - 12078562
AU - Cockey CD
TI - Gynecologic oncologists making strides in women's cancer care.
SO - AWHONN Lifelines 2002 Jun-Jul;6(3):203-4

25
UI - 12084438
AU - Lin JJ; Yueh KC; Chang DC; Lin SZ
TI - Association between genetic polymorphism of angiotensin-converting enzyme gene and Parkinson's disease.
SO - J Neurol Sci 2002 Jul 15;199(1-2):25-9
AD - Department of Neurology, Chushang Show-Chwan Hospital, No. 75 Section 2, Chi-Shang Road, Chushang Jenn, Nantou 557, Taiwan. jjlinn@tcts.seed.net.tw
This study was designed to investigate the hypothesis that deletion/insertion (D/I) polymorphism of the angiotensin-converting enzyme (ACE) gene may contribute to increased risk of Parkinson's disease (PD). A case-control study was carried out to examine the association between the ACE genotype and the allele frequency in 127 sporadic PD patients compared with 198 healthy controls. The frequency of the homozygote DD genotype of the ACE gene was significantly increased in patients with PD than in the controls (chi(2)=6.09, p=0.048), despite that there was no significant difference in D/I allele frequency (chi(2)=2.25, p=0.133). Moreover, PD patients carrying the homozygote DD genotype were 1.13 times more frequent than subjects without the DD genotype (chi(2)=5.67, 95% CI=1.01-1.25, p=0.017). A stepwise logistic regression analysis of the presence of the DD genotype and data on risk factors for PD confirmed that the homozygote DD genotype was a modest independent risk factor for PD (OR=1.32, 95% CI=1.12-2.16). In addition, there was a trend of increasing number of DD genotype in older PD patients and the modest risk factor of DD genotype in PD was due to the significant difference of the DD homozygosity in old patients with onset age at or after 60 years. In conclusion, results of our study support the hypothesis that the ACE gene may indicate genetic susceptibility to PD, particularly in older individuals.

26
UI - 12127817
AU - Ikawa K; Terashima Y; Sasaki K; Tashiro S
TI - Genetic detection of liver micrometastases that are undetectable histologically.
SO - J Surg Res 2002 Jul;106(1):124-30
AD - Department of Digestive Surgery, The University of Tokushima School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
BACKGROUND: Predicting liver metastasis from colon cancer is essential for improving its prognosis. We studied to what extent genetic detection of cancer cells in the resected liver tissue can predict the incidence of macroscopic liver metastasis with a similar mouse model to clinical colorectal cancer that causes a several decade percentage of metachronous hepatic metastases after resection of the primary lesions. MATERIALS AND METHODS: A LS174T human colorectal cancer cell suspension was injected into the spleens of nude mice. One to 10 days after splenic injection, 3 x 3 mm of liver tissue was removed, and a splenectomy was performed. Liver tissue was used for genetic detection and histological examination. Five weeks after splenic injection, the number of macroscopic metastases on the surface of the liver was counted. RESULTS: Eight of the 45 cases were positive for tumor cells in liver tissue genetically, while only 1 was positive for tumor cells histologically. Macroscopic liver metastases were seen 5 weeks after splenic injection in 11 of 37 (29.7%) cases negative for tumor cells genetically and in 8 of 8 (100%) cases positive for tumor cells genetically. Five or more metastases were seen in 3 of 37 (8.1%) cases negative for tumor cells genetically and in 7 of 8 (87.5%) cases positive for tumor cells genetically. CONCLUSIONS: The cases which were positive for tumor cells in liver tissue genetically at the time of splenectomy had more significantly macroscopic liver metastases some weeks later than the cases negative for tumor cells. This study suggests that if micrometastasis was detected genetically, the development of metachronous macroscopic liver metastasis could be predicted.

27
UI - 12186172
AU - Gold R; Caulfield TA; Ray PN
TI - Gene patents and the standard of care.
SO - CMAJ 2002 Aug 6;167(3):256-7
AD - Faculty of Law, McGill University, Montreal, Que.

28
UI - 12186176
AU - Sinclair A
TI - Genetics 101: detecting mutations in human genes.
SO - CMAJ 2002 Aug 6;167(3):275-9
AD - alisonsinclair@shaw.ca

29
UI - 11484697
AU - Welch CA
TI - Sacred secrets--the privacy of medical records.
SO - N Engl J Med 2001 Aug 2;345(5):371-2

30
UI - 11484711
AU - Annas GJ
TI - The limits of state laws to protect genetic information.
SO - N Engl J Med 2001 Aug 2;345(5):385-8
AD - Health Law Department, Boston University School of Public Health, USA.

31
UI - 11508189
AU - Ross LF
TI - Genetic exceptionalism vs. paradigm shift: lessons from HIV.
SO - J Law Med Ethics 2001 Summer;29(2):141-8
AD - Department of Pediatrics, College at the University of Chicago, USA.

32
UI - 11510469
AU - Fonesca R; Oken MM; Greipp PR; Eastern Cooperative Oncology Group
TI - Myeloma Group The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of undetermined significance.
SO - Blood 2001 Aug 15;98(4):1271-2

33
UI - 12111912
AU - Liu A; Shih WJ; Gehan E
TI - Sample size and power determination for clustered repeated measurements.
SO - Stat Med 2002 Jun 30;21(12):1787-801
AD - Biostatistics Unit, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA. liual@gunet.gerogetown.edu
It is common in epidemiological and clinical studies that each subject has repeated measurements on a single common variable, while the subjects are also 'clustered'. To compute sample size or power of a test, we have to consider two types of correlation: correlation among repeated measurements within the same subject, and correlation among subjects in the same cluster. We develop, based on generalized estimating equations, procedures for computing sample size and power with clustered repeated measurements. Explicit formulae are derived for comparing two means, two slopes and two proportions, under several simple correlation structures. Copyright 2002 John Wiley & Sons, Ltd. abstract

34
UI - 12160914
AU - Huiart L; Eisinger F; Stoppa-Lyonnet D; Lasset C; Nogues C; Vennin P;
TI - Sobol H; Julian-Reynier C Effects of genetic consultation on perception of a family risk of breast/ovarian cancer and determinants of inaccurate perception after the consultation.
SO - J Clin Epidemiol 2002 Jul;55(7):665-75
AD - Epidemiology and Social Sciences Unit (INSERM U379), Institut Paoli-Calmettes, 232 Bd Ste Marguerite, 13273 Marseille cedex 09, France.
The aim of this study was to assess the effects of cancer genetic consultations on women's perception of their family risk of breast/ovarian cancer, and to determine which factors were associated with an inaccurate perception after the consultation. A multicenter prospective survey was carried out on women (n = 397) attending cancer genetic clinics in France for the first time, in which the perceived family risk was measured both before and after the consultation, using self-administered questionnaires. The effects of the consultation on risk perception were significant among low (P <.001) and moderate risk women (P <.05). However, after the consultation, 76.3% of the "low"-risk women did not perceive their family as "low"-risk families, and 21.9% of the moderate-risk women were still definitely sure there was a genetic risk running in their family. The consultation did not affect the family risk perception of the high risk women (n = 171): the risk was thought to be very high both before (87.7%) and after (89.5%) the consultation (NS); however 10.5% of this group still perceived their family as being unlikely to be at risk after the consultation. In the low- and moderate-risk groups after multivariate adjustment, the inaccurate perceptions varied, depending on the clinics and on the psychosocial context of the consultation: they increased when the consultee was personally affected by cancer, and decreased when the consultee had a health occupation. Cancer genetic consultations had only marginal effects on the perception of family risk on the whole, although they were significant in the case of low- and moderate-risk women. The question arises as to whether a more comprehensive approach should be implemented and how to go about providing efficient cancer risk information in the context of health care systems.

35
UI - 11933185
AU - Anonymous
TI - Mutation detection 2001: Novel technologies, developments and applications for analysis of the human genome. Proceedings of the 6th International Symposium on Mutations in the Human Genome. Bled, Slovenia, 2001.
SO - Hum Mutat 2002 Apr;19(4):313-463

36
UI - 11933186
AU - Kwok PY
TI - SNP genotyping with fluorescence polarization detection.
SO - Hum Mutat 2002 Apr;19(4):315-23
AD - Division of Dermatology and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA. kwok@genetics.wustl.edu
When a fluorescent molecule is excited by plane polarized light, the fluorescence emitted is also polarized. The degree of fluorescence polarization (FP) detected, under constant temperature and solvent viscosity, is proportional to the molecular weight of the dye molecule. By monitoring the FP of a fluorescent dye, one can detect significant changes in the molecular weight of the molecule without separation or purification. Because the size of the probe is altered in the course of a number of single nucleotide polymorphism (SNP) genotyping reactions, FP is therefore an excellent detection mechanism for these assays. Indeed, FP detection can be used in SNP genotyping with the primer extension TaqMan((R)) and Invader((R)) assays. Use of FP detection makes it possible to reduce the cost of TaqMan((R)) and Invader((R)) probes by abrogating the need for a fluorescence quencher. Moreover, inexpensive, unpurified, and unlabeled probes are used in the primer extension reaction with FP detection. As an end-point detection mechanism, FP detection is suitable for high-throughput SNP genotyping. Copyright 2002 Wiley-Liss, Inc.

37
UI - 11933187
AU - Amos J; Patnaik M
TI - Commercial molecular diagnostics in the U.S.: The Human Genome Project to the clinical laboratory.
SO - Hum Mutat 2002 Apr;19(4):324-33
AD - Specialty Laboratories, Santa Monica, California, USA. jamos@specialtylabs.com
Molecular diagnosis is the detection of pathogenic mutations in DNA and RNA samples to aid in detection, diagnosis, subclassification, prognosis, and monitoring response to therapy. Principles underlying nucleic-based diagnosis originate from localization, identification, and characterization of genes responsible for human disease. Clinical molecular genetics is now part of the mainstream of medical care in the United States. All commercial clinical reference laboratories now have a molecular genetic diagnostic unit, many of which are in contractual agreement with third party payers to provide services. Gene discovery provides valuable insight into the mechanisms of disease processes and gene-based markers will enable clinicians to study disease predisposition, as well as improved methods for diagnoses, prognosis, and monitoring of therapy. The broad range of mutation spectrum and type performed in the clinical laboratory requires the use of multiple technologies rather than a single typing platform. Platform choice depends on such diverse factors as local expertise, test volume, economies of scale, R&D budget, and royalties. Test validation is a major hurdle and positive control samples are often not readily available. Oversight and the regulatory environment for clinical molecular genetics laboratories in the United States are evolving rapidly. Several government agencies and private organizations are currently involved in revision of specific laboratory standards, including the Secretary's Advisory Committee on Genetic Testing (SACGT), Food and Drug Administration (FDA), Center for Disease Control (CDC), College of American Pathologists (CAP), American College of Medical Genetics (ACMG), and the individual states. Copyright 2002 Wiley-Liss, Inc.

38
UI - 11933189
AU - Kolchinsky A; Mirzabekov A
TI - Analysis of SNPs and other genomic variations using gel-based chips.
SO - Hum Mutat 2002 Apr;19(4):343-60
AD - Health Front Line Ltd., Champaign, Illinois, USA.
Application of microarrays for the analysis of point mutations and SNPs in genomic DNAs is currently under intensive development. Various technologies are being investigated, employing enzymatic, chemical, and physical tools [for

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