Impact of gene patents and licensing practices on access to genetic testing for long QT syndrome

Genetics in Medicine

Volumn 12, Issue 4 SUPPL., 2010, Pages

  Angrist, Misha ^a   Chandrasekharan, Subhashini ^a   Heaney, Christopher ^a   Cook Deegan, Robert ^a  

^a DUKE UNIVERSITY   (United States)

Author keywords

Arrhythmia; Genetic testing; Intellectual property; Long QT syndrome; Patents; University of Utah

Indexed keywords

BETA ADRENERGIC RECEPTOR BLOCKING AGENT; DNA;

COMMERCIAL PHENOMENA; CONSUMER; DEFIBRILLATOR; GENE MUTATION; GENETIC ANALYSIS; GENETIC SUSCEPTIBILITY; GOLD STANDARD; HEALTH CARE ACCESS; HEALTH CARE PERSONNEL; HEART ARRHYTHMIA; HUMAN; INTERPERSONAL COMMUNICATION; LABORATORY; LICENSING; LONG QT SYNDROME; MARKETING; OUTCOME ASSESSMENT; PROFESSIONAL PRACTICE; PUBLICATION; QUALITY CONTROL; RESEARCH; REVIEW; SCIENCE; UNITED STATES;

EID: 77951456770     PISSN: 10983600     EISSN: None     Source Type: Journal    
DOI: 10.1097/GIM.0b013e3181d68293     Document Type: Review

References (136)

1. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008;51: 2291-2300.
2. Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med 2008; 358:169-176.
3. Goldenberg I, Moss AJ, Peterson DR, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 2008;117:2184-2191.
4. Berul CI. Congenital long-QT syndromes: who's at risk for sudden cardiac death? Circulation 2008;117:2178-2180.
5. Tester DJ, Ackerman MJ. Sudden infant death syndrome: how significant are the cardiac channelopathies? Cardiovasc Res 2005;67:388-396.
6. Ackerman MJ. Cardiac channelopathies: it's in the genes. Nat Med 2004; 10:463-464.
7. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 2000; 101:616-623.
8. Choi GR, Porter CB, Ackerman MJ. Sudden cardiac death and channelopa-thies: a review of implantable defibrillator therapy. Pediatr Clin North Am 2004;51:1289-1303.
9. Passman R, Kadish A. Sudden death prevention with implantable devices. Circulation 2007;116:561-571.
10. Zareba W, Moss AJ, Daubert JP, Hall WJ, Robinson JL, Andrews M. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol 2003;14:337-341.
11. Wang LX. Role of left cardiac sympathetic denervation in the management of congenital long QT syndrome. J Postgrad Med 2003;49:179-181.
12. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803.
13. Wang Q, Shen J, Li Z, et al. Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. Hum Mol Genet 1995;4:1603-1607.
14. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-811.
15. Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996;12:17-23.
16. Marban E. Cardiac channelopathies. Nature 2002;415:213-218.
17. Lehnart SE, Ackerman MJ, Benson DW Jr, et al. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation 2007;116:2325-2345.
18. Ueda K, Valdivia C, Medeiros-Domingo A, et al. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci USA 2008;105:9355-9360.
19. Genaissance Pharmaceuticals. EX-99.1 of 8-K, May 11, 2004. Available at: http://www.sec.gov/Archives/edgar/data/1110009/000110465904013687/ a04-5741-1ex99d1.htm. Accessed September 26, 2008.
20. Statement of Marc Grodman at stifling or stimulating\the role of gene patents in research and genetic testing. House Judiciary Subcommittee on Courts, the Internet, and Intellectual Property. Washington, DC; 2007. Available at: http://judiciary.house.gov/hearings/pdf/Grodman071030.pdf. Accessed March 2, 2010
21. Stifling or stimulating: the role of gene patents in research and genetic testing. Subcommittee on Courts, the Internet, and Intellectual Property of the Committee on the Judiciary. One Hundred Tenth Congress; First Session. Washington, DC; October 30, 2007.
22. Written statement of Wendy Chung at stifling or stimulating\the role of gene patents in research and genetic testing. House Judiciary Subcommittee on Courts, the Internet, and Intellectual Property. Washington, DC; 2007. Available at: http://judiciary.house.gov/hearings/pdf/Grodman071030.pdf. Accessed March 2, 2010.
23. Fromkin AJ. Letter to the Honorable Howard L. Berman from Clinical Data CEO Andrew J Fromkin. In: Howard LB, The house judiciary subcommittee on courts, the internet and intellectual property. Washington, DC; April 1, 2008.
24. Ebersole T, Guthrie M, Goldstein JA. Patent pools as a solution to the licensing problems of diagnostic genetics. IP Technol Law J 2005;17: 6-13.
25. Ebersole TJ, Guthrie MC, Goldstein JA. Patent pools and standard setting in diagnostic genetics. Nat Biotechnol 2005;23:937-938.
26. Goldstein J, Golod E. Human gene patents. Acad Med 2002;77(12 Part 2):1315-1328.
27. Moss AJ, Schwartz PJ. 25th anniversary of the International Long-QT Syndrome Registry: an ongoing quest to uncover the secrets of long-QT syndrome. Circulation 2005;111:1199-1201.
28. John Welsh Cardiovascular Diagnostic Laboratory. Panels offered by disease 2009 http://www.bcm.edu/pediatrics/index.cfm? Realm=99992426&This- Template=Genetic-Testing. Accessed November 19 2008.
29. Boettiger S, Bennett AB. Bayh-Dole: if we knew then what we know now. Nat Biotechnol 2006;24:320-323.
30. Thursby JG, Thursby MC. Intellectual property. University licensing and the Bayh-Dole Act. Science 2003;301:1052.
31. Genaissance Pharmaceuticals to merge with Clinical Data. Pharmacog-enomics 2005;6:459.
32. DNA Sciences. S-1, January 5, 2001; Available at: http://www.sec.gov/ Archives/edgar/data/1130013/000091205701000445/a2033717zs-1.htm. Accessed September 22, 2008.
33. Clinical Data. 10-K, 2006. Available at: http://www.sec.gov/Archives/ edgar/data/716646/000095013506004150/b61410cie10vk.htm. Accessed November 21, 2009.
34. Genaissance Pharmaceuticals. 10-K, March 30, 2004. Available at: http://www.sec.gov/Archives/edgar/data/1110009/000104746904010049/a2131537z10-k. htm. Accessed September 23, 2008.
35. Genaissance Pharmaceuticals. Genaissance Pharmaceuticals launches its proprietary FAMILION™ test for genetic mutations associated with sudden cardiac death, 2004. Available at: http://www.medscape.com/pages/editorial/ pressreleases/pr-crm-genaissance2. Accessed September 17, 2008.
36. Napolitano C, Bloise R, Priori SG. Long QT syndrome and short QT syndrome: how to make correct diagnosis and what about eligibility for sports activity. J Cardiovasc Med (Hagerstown) 2006;7:250-256.
37. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to geno-typing in clinical practice. JAMA 2005;294:2975-2980.
38. Ackerman MJ. Genetic testing for risk stratification in hypertrophic cardiomyopathy and long QT syndrome: fact or fiction? Curr Opin Cardiol 2005;20:175-181.
39. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999;99:529-533.
40. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866-1874.
41. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation 2007;115:2613-2620.
42. Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation 2006;114:2096-2103.
43. Ackerman MJ. Genotype-phenotype relationships in congenital long QT syndrome. J Electrocardiol 2005;38(4 suppl):64-68.
44. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89-95.
45. Wilde AA, Jongbloed RJ, Doevendans PA, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999;33:327-332.
46. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol 2007;49:1092-1098.
47. Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007;115:2481-2489.
48. Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004;292:1341-1344.
49. Ching CK, Tan EC. Congenital long QT syndromes: clinical features, molecular genetics and genetic testing. Expert Rev Mol Diagn 2006;6:365-374.
50. Oliva A, Bjerregaard P, Hong K, et al. Clinical heterogeneity in sodium channelopathies. What is the meaning of carrying a genetic mutation? Cardiology 2008;110:116-122.
51. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e385-e484.
52. Sudden Arrhythmia Death Syndromes Foundation. Genetic testing 2009 http://www.sads.org/index.php/Table/Genetic-Testing/. Accessed September 15 2008.
53. Sudden Arrhythmia Death Syndromes Foundation. Annual report 2005 http://www.sads.org/images/stories/pdf/newsletter/2005/SADS-Sm-05-Annual-Report. pdf. Accessed November 21 2009.
54. Hlatky MA, Mark DB. The high cost of implantable defibrillators. Eur Heart J 2007;28:388-391.
55. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999;97:175-187.
56. Larsen LA, Andersen PS, Kanters J, et al. Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome. Clin Chem 2001;47:1390-1395.
57. Neyroud N, Richard P, Vignier N, et al. Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome. Circ Res 1999;84:290-297.
58. Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT. Genomic structure of three long QT syndrome genes: KVLQT1, HERG, andKCNE1. Genomics 1998;51:86-97.
59. Syrris P, Murray A, Carter ND, McKenna WM, Jeffery S. Mutation detection in long QT syndrome: a comprehensive set of primers and PCR conditions. J Med Genet 2001;38:705-710.
60. Tsui LC, Durie P. Genotype and phenotype in cystic fibrosis. Hosp Pract (Minneap) 1997;32:115-129.
61. Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Reed CR, Ackerman MJ. Clinical phenotype and the yield of the Familion(TM) genetic test for congenital Long QT syndrome. Abstract presented at Heart Rhythm Society Meeting. Denver, CO, May 9-12, 2007.
62. Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Reed CR, Ackerman MJ. The effect of mutation class on QTc in unrelated patients referred for the Familion(TM) genetic test for Long QT syndrome. Abstract presented at Heart Rhythm Society Meeting. Denver, CO, May 9-12, 2007.
63. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol 2006;47:764-768.
64. Centers for Medicare and Medicaid Services. Overview Clinical Laboratory Improvement Amendments (CLIA). Available at: http://www.cms.hhs.gov/clia/. Accessed November 11, 2008.
65. PGxHealth. Patients, 2009. Available at: http://www.pgxhealth.com/ familion/patients/. Accessed November 21, 2009.
66. PGxHealth. Patients: frequently asked questions, 2009. Available at: http://www.pgxhealth.com/familion/patients/faq.cfm. Accessed November 21, 2009.
67. Clinical Data. EX-99.1 of 8-K, July 9, 2008. Available at: http://www.sec. gov/Archives/edgar/data/716646/000095013508004859/ b71062cdexv99w1. htm. Accessed September 17, 2008.
68. Clinical Data. 10-K, June 16, 2008. Available at: http://www.sec.gov/ Archives/edgar/data/716646/000095013508004390/b70423cde10vk.htm. Accessed September 17, 2008.
69. Saenen JB, Vrints CJ. Molecular aspects of the congenital and acquired long QT Syndrome: clinical implications. J Mol Cell Cardiol 2008;44:633-646.
70. Schwartz PJ. The congenital long QT syndromes from genotype to phenotype: clinical implications. J Intern Med 2006;259:39-47.
71. Wang DW, Yazawa K, George AL Jr, Bennett PB. Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome. Proc Natl Acad Sci USA 1996;93:13200-13205.
72. Williams-Jones B. History of a gene patent: tracing the development and application of commercial BRCA testing. Health Law J 2002;10:123-146.
73. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 2002;20:1480-1490.
74. Clinical Data Launches Genetic Test for Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)\company to release its genetic databases for inherited cardiac conditions. Business Wire. November 10, 2008. Available at: http://investor.clda.com/releasedetail.cfm?ReleaseID=346585. Accessed January 27, 2010.
75. Ackerman MJ, Splawski I, Makielski JC, et al. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 2004;1: 600-607.
76. Judson RS, Salisbury BA, Reed CR, Ackerman MJ. Pharmacogenetic issues in thorough QT trials. Mol Diagn Ther 2006;10:153-162.
77. Tester DJ, Cronk LB, Carr JL, et al. Allelic dropout in long QT syndrome genetic testing: a possible mechanism underlying false-negative results. Heart Rhythm 2006;3:815-821.
78. Salisbury BA, Carr JL, Harris-Kerr C, Ackerman MJ. Abstract 2215: clinical genetic testing for congenital Long QT syndrome: spectrum of mutations discovered in the first two years. Abstract presented at American Heart Association Meeting. November 2006.
79. Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Reed CR, Ackerman MJ. Should a minimum corrected QT interval (QTc) be a prerequisite for Long QT syndrome genetic testing? Abstract presented at American Heart Association Meeting. November 6, 2007.
80. Ackerman MJ, Tester DJ, Valdivia C, Salisbury BA, Wilde AAM, Makielski JC. Is A572-SCN5A a LQT3/sudden death susceptibility mutation or background genetic noise? Abstract presented at Heart Rhythm Society Meeting. San Francisco, CA, May 14-17, 2008.
81. Johnson JN, Haglund CM, Tester DJ, et al. Prevalence of early onset atrial fibrillation in congenital Long QT syndrome. Abstract presented at Heart Rhythm Society Meeting. Denver, CO, May 9-12, 2007.
82. Kapa S, Tester DJ, Salisbury BA, Wilde AA, Ackerman MJ. Distinguishing Long QT Syndrome-causing mutations from "background" genetic noise. Abstract presented at Heart Rhythm Society Meeting. San Francisco, CA, May 16, 2008.
83. Kapa S, Tester DJ, Salisbury BA, Wilde AA, Ackerman MJ. Amino acid physicochemical differences may serve as an adjunct to frequency analysis to determine mutation pathogenicity in Long QT syndrome. Abstract presented at Heart Rhythm Society Meeting. San Francisco, CA, May 15, 2008.
84. Salisbury B, Judson RS, Pungliya M, et al. The single nucleotide polymorphism D85N-KCNE1 is associated with both congenital and drug-induced Long QT. Abstract presented at Heart Rhythm Society Meeting. Boston, MA, May 17-20, 2006.
85. Salisbury BA, Pungliya M, Harris-Kerr C, et al. Distinguishing causative and non-causative mutations in Long QT syndrome. Abstract presented at Heart Rhythm Society Meeting. Boston, MA, May 17, 2006.
86. Tester DJ, Will ML, Salisbury BA, et al. Allelic drop-out in long QT syndrome genetic testing: a possible mechanism underlying false negative results. Abstract presented at Heart Rhythm Society Meeting. New Orleans, LA, May 4-7, 2005.
87. Will ML, Tester DJ, Salisbury BA, et al. Repeat long QT syndrome genetic testing of phenotype positive cases: prevalence and etiology of detection misses. Abstract presented at Heart Rhythm Society Meeting. New Orleans, LA, May 4-7, 2005.
88. Judson RS, Salisbury BA, Pungliya M, et al. A common single nucleotide polymorphism associated with congenital long QT syndrome. Abstract presented at the American Society of Human Genetics Meeting. Salt Lake, UT, October 28, 2005.
89. Pungliya M, Salisbury BA, Judson RS, Tester DJ, Will ML, Ackerman MJ. A comparison of mutation patterns in suspected cases of congenital long QT syndrome and controls. Abstract presented at the American Society of Human Genetics Meeting. Salt Lake, UT, October 28, 2005.
90. Ramsden SC, Deans Z, Robinson DO, et al. Monitoring standards for molecular genetic testing in the United Kingdom, the Netherlands, and Ireland. Genet Test 2006;10:147-156.
91. Hertzberg M, Neville S, McDonald D. External quality assurance of molecular analysis of haemochromatosis gene mutations. J Clin Pathol 2006;59:744-747.
92. Keating MT, Curran ME, Wang Q; University of Utah Research Foundation, assignee. Long QT syndrome genes. US patent 5,599,673. 4 February, 1997.
93. Keating MT, Sanguinetti MC, Splawski I; University of Utah Research Foundation, assignee. Mutations in the KCNE1 gene encoding human MINK which cause arrhythmia susceptibility thereby establishing KCNE1 as an LQT gene. US patent 6,432,644 B1. August 13, 2002.
94. Keating MT, Splawski I; University of Utah Research Foundation, assignee. Mutations in and genomic structure of HERG\a Long QT syndrome gene. US patent 6,207,383 B1. March 27, 2001.
95. Company news\DNA sciences declares bankruptcy, sells assets to Genaissance. Biotechnol Law Rep 2003;22:307.
96. Genaissance Pharmaceuticals. Event Transcript: GNSC\Q4 2003 Genaissance Pharmaceuticals, Inc. Earnings Conference Call: CCBN Street Events; 2004.
97. Clinical Data. 10-K, June 29, 2006. Available at: http://www.sec.gov/ Archives/edgar/data/716646/000095013506004150/b61410cie10vk.htm. Accessed September 23, 2008.
98. Butkus B. BU Genetics Center stops using Athena Dx tests after firm tightens IP restrictions. Biotech Transfer Week. August 20, 2008.
99. Bio-Reference Laboratories, Inc. announces agreement to acquire gene-based testing laboratory, third quarter results and reaffirms guidance for year; company signals major initiative into gene-based testing by acquiring GeneDx. Business Wire, August 29, 2006. Available at: http://phx. corporate-ir.net/phoenix.zhtml?c=84759&p=irol-newsArticle-Print&ID= 900168&highlight=. Accessed January 27, 2010.
100. Verbeure B, van Zimmeren E, Matthijs G, Van Overwalle G. Patent pools and diagnostic testing. Trends Biotechnol 2006;24:115-120.
101. Wang Q, Li Z, Shen J, Keating MT. Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics 1996;34:9-16.
102. Genaissance Pharmaceuticals. 10-Q, August 9 2005. Available at: http://www.sec.gov/Archives/edgar/data/1110009/000110465905037531/ a05-13057-110q.htm. Accessed September 24, 2008.
103. Genaissance Pharmaceuticals. 10-K, March 15, 2005. http://www.sec.gov/ Archives/edgar/data/1110009/000104746905006537/a2152822z10-k.htm. Accessed September 24, 2008.
104. Clinical Data. Clinical Data announces second quarter fiscal 2009 financial results, 2008. Available at: http://www.clda.com/uploads/CLDA-Q2- 09%2011-3-08FINAL.pdf. Accessed November 4, 2008.
105. Clinical Data. Clinical Data announces license agreement with Victorian Clin Genet Services Ltd., 2007. Available at: http://www.clda.com/uploads/ LQTaustralia-draft%20press%20release10107FINAL.pdf. Accessed October 6, 2008.
106. Hypertrophic Cardiomyopathy Association. Who can conduct genetic testing in HCM? 2008. Available at: http://www.4hcm.org/WCMS/index. php?id=81,0,0,1,0,0. Accessed October 7, 2008.
107. Correlagen Diagnostics Inc. Laboratory receives accreditation from College of American Pathologists, 2007. Available at: http://www.correlagen. com/about/downloads/Correlagen-CAP-NewsRelease-030507.pdf Accessed November 19, 2008.
108. Tester DJ, Ackerman MJ. Genetic testing for cardiac channelopathies: ten questions regarding clinical considerations for heart rhythm allied professionals. Heart Rhythm 2005;2:675-677.
109. Phillips KA, Ackerman MJ, Sakowski J, Berul CI. Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases. Heart Rhythm 2005;2:1294-1300.
110. Hudson KL. Genetic testing oversight. Science 2006;313:1853
111. Report of the Secretary's Advisory Committee on Genetics, Health, and Society. U.S. system of oversight of genetic testing: a response to the charge of the Secretary of Health and Human Services. Bethesda, MD: Secretary's Advisory Committee on Genetics, Health, and Society; 2008.
112. Genetic Alliance. Letter to the Centers for Medicare and Medicaid Services (CMS) requesting a genetics speciality under the CLinical Laboratory Improvement Amendments (CLIA) June 6, 2006. Available at: http://www. geneticalliance.org/policy.clia.letter. Accessed October 7, 2008.
113. Clinical Data, Inc. Reaffirms support for current regulation of laboratory-developed tests. Business Wire December 16, 2008. Available at: http://investor.clda.com/releasedetail.cfm?ReleaseID=354524. Accessed January 27, 2010.
114. Johnson PC, Haydon DT. Maximum-likelihood estimation of allelic dropout and false allele error rates from microsatellite genotypes in the absence of reference data. Genetics 2007;175:827-842.
115. Carturan E, Tester DJ, Brost BC, Basso C, Thiene G, Ackerman MJ. Postmortem genetic testing for conventional autopsy-negative sudden unexplained death: an evaluation of different DNA extraction protocols and the feasibility of mutational analysis from archival paraffin-embedded heart tissue. Am J Clin Pathol 2008;129:391-397.
116. Dedhia P, Tarale S, Dhongde G, Khadapkar R, Das B. Evaluation of DNA extraction methods and real time PCR optimization on formalin-fixed paraffin-embedded tissues. Asian Pac J Cancer Prev 2007;8:55-59.
117. Gillio-Tos A, De Marco L, Fiano V, et al. Efficient DNA extraction from 25-year-old paraffin-embedded tissues: study of 365 samples. Pathology 2007;39:345-348.
118. Santos MC, Saito CP, Line SR. Extraction of genomic DNA from paraffin-embedded tissue sections of human fetuses fixed and stored in formalin for long periods. Pathol Res Pract 2008;204:633-636.
119. Santos S, Sa D, Bastos E, et al. An efficient protocol for genomic DNA extraction from formalin-fixed paraffin-embedded tissues. Res Vet Sci 2009;86:421-426.
120. Clinical Data. EX-99.1 of 8-K, January 18, 2007. Available at: http://www.sec.gov/Archives/edgar/data/716646/000095013507000224/ b63771cdexv99w1.htm. Accessed June 6, 2008.
121. Medicare and Medicaid programs; Medicare, Medicaid, and Clinical Laboratories Improvement Act (CLIA) patient confidentiality rules\PHS and HCFA. Final rule. Fed Regist 1988; 53: 48645-48648.
122. Schwartz MK. Genetic testing and the Clinical Laboratory Improvement Amendments of 1988: present and future. Clin Chem 1999;45:739-745.
123. Rivers PA, Dobalian A, Germinario FA. A review and analysis of the Clinical Laboratory Improvement Amendment of 1988: compliance plans and enforcement policy. Health Care Manage Rev 2005;30:93-102.
124. Bookman EB, Langehorne AA, Eckfeldt JH, et al. Reporting genetic results in research studies: summary and recommendations of an NHLBI working group. Am J Med Genet A 2006;140:1033-1040.
125. Slaughter LM. The Genetic Information Nondiscrimination Act: why your personal genetics are still vulnerable to discrimination. Surg Clin North Am 2008;88:723-738, vi.
126. Cuomo C, Wagschal G. Lifesaving test held up by paperwork, 2008 Available at: http://abcnews.go.com/GMA/OnCall/story?id=4358619&page=1. Accessed October 22, 2008.
127. Clinical Data, Inc. Signs Contract with Aetna for In-network Coverage of FAMILION® Genetic Tests for Inherited Cardiac Syndromes. Business Wire. October 27, 2008. Available at: http://www.businesswire.com/portal/site/home/ permalink/?ndmViewId=news-view&newsId=20081027005655&newsLang=en. Accessed January 27, 2010.
128. GeneDx. Genetic testing for hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and Long QT syndrome (LQTS) 2009 http://www.genedx.com/ site/cardiomyopathy-genetic-testing. Accessed November 10 2009.
129. Test information sheet: cardiology genetics: hypertrophic cardiomyopathy (HCM) panel, October 15 2009. http://www.genedx.com/ext-upload-files/info-sheet- hcm.pdf. Accessed November 10 2009.
130. PGxHealth. Familion technical specifications, October 2009 http://www.pgxhealth.com/familion/pdf/FAMILION-TechSheet%2009 TS1008.pdf. Accessed November 10 2009.
131. Search results for filings from Bio Reference Laboratories Inc. Available at: http://www.sec.gov/cgi-bin/browse-edgar?company=&match=&CIK= BRLI&filenum=&State=&Country=&SIC=&owner=exclude&Find= Find+Companies&action=getcompany. Accessed November 10, 2009.
132. Clinical Data. Clinical Data, Inc. reports second quarter fiscal 2010 results, 2009. Available at: http://investor.clda.com/releasedetail.cfm? ReleaseID=422745. Accessed November 10, 2009.
133. Kapplinger J, Tester D, Salisbury B, et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rythm 2009;6:1297-1303.
134. Kapa S, Tester D, Salisbury B, et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation 2009;120:1752-1760.
135. MacRae C. Closer look at genetic testing in long-QT syndrome: will DNA diagnostics ever be enough? Circulation 2009;120:1745-1748.
136. Darbar D. Is it time to develop a "pathogenicity" score to distinguish long QT syndrome causing mutations from "background" genetic noise? Hearth Rythm 2009;6:1304-1305.