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[[Cancer]] is a change in the cellular processes that cause a tumour to grow out of control.<ref name="cancer.gov" /> Cancerous cells sometimes have mutations in [[oncogenes]], such as [[KRAS]] and [[CTNNB1]] (β-catenin).<ref>{{Cite journal | last1 = Minamoto | first1 = T. | last2 = Ougolkov | first2 = A. V. | last3 = Mai | first3 = M. | doi = 10.1586/14737159.2.6.565 | title = Detection of oncogenes in the diagnosis of cancers with active oncogenic signaling | journal = Expert Review of Molecular Diagnostics | volume = 2 | issue = 6 | pages = 565–575 | year = 2002 | pmid = 12465453| pmc = }}</ref> Analysing the molecular signature of cancerous cells{{mdash}}the DNA and its levels of expression via [[messenger RNA]]{{mdash}}enables physicians to characterise the cancer and to choose the best therapy for their patients.<ref name="cancer.gov"/> As of 2010, assays that incorporate an array of antibodies against specific protein marker molecules are an emerging technology; there are hopes for these multiplex assays that could measure many markers at once.<ref>{{Cite journal | last1 = Brennan | first1 = D. J. | last2 = O'Connor | first2 = D. P. | last3 = Rexhepaj | first3 = E. | last4 = Ponten | first4 = F. | last5 = Gallagher | first5 = W. M. | title = Antibody-based proteomics: Fast-tracking molecular diagnostics in oncology | doi = 10.1038/nrc2902 | journal = Nature Reviews Cancer | volume = 10 | issue = 9 | pages = 605–617 | year = 2010 | pmid = 20720569| pmc = }}</ref> Other potential future biomarkers include [[miRNA|micro RNA molecules]], which cancerous cells express more of than healthy ones.<ref>{{Cite journal | last1 = Ferracin | first1 = M. | last2 = Veronese | first2 = A. | last3 = Negrini | first3 = M. | doi = 10.1586/erm.10.11 | title = Micromarkers: MiRNAs in cancer diagnosis and prognosis | journal = Expert Review of Molecular Diagnostics | volume = 10 | issue = 3 | pages = 297–308 | year = 2010 | pmid = 20370587}}</ref>
[[Cancer]] is a change in the cellular processes that cause a tumour to grow out of control.<ref name="cancer.gov" /> Cancerous cells sometimes have mutations in [[oncogenes]], such as [[KRAS]] and [[CTNNB1]] (β-catenin).<ref>{{Cite journal | last1 = Minamoto | first1 = T. | last2 = Ougolkov | first2 = A. V. | last3 = Mai | first3 = M. | doi = 10.1586/14737159.2.6.565 | title = Detection of oncogenes in the diagnosis of cancers with active oncogenic signaling | journal = Expert Review of Molecular Diagnostics | volume = 2 | issue = 6 | pages = 565–575 | year = 2002 | pmid = 12465453| pmc = }}</ref> Analysing the molecular signature of cancerous cells{{mdash}}the DNA and its levels of expression via [[messenger RNA]]{{mdash}}enables physicians to characterise the cancer and to choose the best therapy for their patients.<ref name="cancer.gov"/> As of 2010, assays that incorporate an array of antibodies against specific protein marker molecules are an emerging technology; there are hopes for these multiplex assays that could measure many markers at once.<ref>{{Cite journal | last1 = Brennan | first1 = D. J. | last2 = O'Connor | first2 = D. P. | last3 = Rexhepaj | first3 = E. | last4 = Ponten | first4 = F. | last5 = Gallagher | first5 = W. M. | title = Antibody-based proteomics: Fast-tracking molecular diagnostics in oncology | doi = 10.1038/nrc2902 | journal = Nature Reviews Cancer | volume = 10 | issue = 9 | pages = 605–617 | year = 2010 | pmid = 20720569| pmc = }}</ref> Other potential future biomarkers include [[miRNA|micro RNA molecules]], which cancerous cells express more of than healthy ones.<ref>{{Cite journal | last1 = Ferracin | first1 = M. | last2 = Veronese | first2 = A. | last3 = Negrini | first3 = M. | doi = 10.1586/erm.10.11 | title = Micromarkers: MiRNAs in cancer diagnosis and prognosis | journal = Expert Review of Molecular Diagnostics | volume = 10 | issue = 3 | pages = 297–308 | year = 2010 | pmid = 20370587}}</ref>

Molecular studies of cancer have proved the significance of driver mutations in the growth and metastasis of tumors.<ref>{{Cite journal|last=Misale|first=Sandra|last2=Yaeger|first2=Rona|last3=Hobor|first3=Sebastijan|last4=Scala|first4=Elisa|last5=Janakiraman|first5=Manickam|last6=Liska|first6=David|last7=Valtorta|first7=Emanuele|last8=Schiavo|first8=Roberta|last9=Buscarino|first9=Michela|date=2012/06|title=Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer|url=https://www.nature.com/articles/nature11156|journal=Nature|language=En|volume=486|issue=7404|pages=532–536|doi=10.1038/nature11156|issn=1476-4687}}</ref>Many technologies for detection of sequence variations have been developed for cancer research. These technologies generally can be grouped into three approaches: polymerase chain reaction (PCR), hybridization, and next-generation sequencing (NGS). <ref>{{Cite journal|date=2016-10-01|title=Diagnostics based on nucleic acid sequence variant profiling: PCR, hybridization, and NGS approaches|url=https://www.sciencedirect.com/science/article/pii/S0169409X16301041|journal=Advanced Drug Delivery Reviews|language=en|volume=105|pages=3–19|doi=10.1016/j.addr.2016.04.005|issn=0169-409X}}</ref>Currently, a lot of PCR and hybridization assays have been approved by FDA as in vitro diagnostics. <ref>{{Cite journal|last=Emmadi|first=Rajyasree|last2=Boonyaratanakornkit|first2=Jerry B.|last3=Selvarangan|first3=Rangaraj|last4=Shyamala|first4=Venkatakrishna|last5=Zimmer|first5=Barbara L.|last6=Williams|first6=Laurina|last7=Bryant|first7=Bonita|last8=Schutzbank|first8=Ted|last9=Schoonmaker|first9=Michele M.|date=2011-11-01|title=Molecular Methods and Platforms for Infectious Diseases Testing|url=http://jmd.amjpathol.org/article/S1525-1578(11)00185-1/fulltext|journal=The Journal of Molecular Diagnostics|language=English|volume=13|issue=6|pages=583–604|doi=10.1016/j.jmoldx.2011.05.011|issn=1525-1578}}</ref>NGS assays, however, are still at an early stage in clinical diagnostics. <ref>FDA-approved next-generation sequencing system could expand clinical genomic testing: experts predict MiSeqDx platform will make genetic testing more affordable for smaller labs. AM. J. Med. Genet. A 164, X-XI.</ref>


==See also==
==See also==

Revision as of 19:09, 10 April 2018

Specialist using "Qiasymphony", an automation platform for molecular diagnostic tests

Molecular diagnostics is a collection of techniques used to analyse biological markers in the genome and proteome—the individual's genetic code and how their cells express their genes as proteins—by applying molecular biology to medical testing. The technique is used to diagnose and monitor disease, detect risk, and decide which therapies will work best for individual patients.[1][2]: foreword 

By analysing the specifics of the patient and their disease, molecular diagnostics offers the prospect of personalised medicine.[3]

These tests are useful in a range of medical specialisms, including infectious disease, oncology, human leucocyte antigen typing (which investigates and predicts immune function), coagulation, and pharmacogenomics—the genetic prediction of which drugs will work best.[4]: v-vii  They overlap with clinical chemistry (medical tests on bodily fluids).

History

Molecular diagnostics uses techniques such as mass spectrometry and gene chips to capture the expression patterns of genes and proteins

The field of molecular biology grew in the late twentieth century, as did its clinical application. In 1980, Yuet Wai Kan et al. suggested a prenatal genetic test for Thalassemia that did not rely upon DNA sequencing—then in its infancy—but on restriction enzymes that cut DNA where they recognised specific short sequences, creating different lengths of DNA strand depending on which allele (genetic variation) the fetus possessed.[5] In the 1980s, the phrase was used in the names of companies such as Molecular Diagnostics Incorporated[6] and Bethseda Research Laboraties Molecular Diagnostics.[7][8]

During the 1990s, the identification of newly discovered genes and new techniques for DNA sequencing led to the appearance of a distinct field of molecular and genomic laboratory medicine; in 1995, the Association for Molecular Pathology (AMP) was formed to give it structure. In 1999, the AMP co-founded The Journal of Medical Diagnostics.[9] Informa Healthcare launched Expert Reviews in Medical Diagnostics in 2001.[1] From 2002 onwards, the HapMap Project aggregated information on the one-letter genetic differences that recur in the human population—the single nucleotide polymorphisms—and their relationship with disease.[2]: ch 37  In 2012, molecular diagnostic techniques for Thalassemia use genetic hybridization tests to identify the specific single nucleotide polymorphism causing an individual's disease.[10]

As the commercial application of molecular diagnostics has become more important, so has the debate about patenting of the genetic discoveries at its heart. In 1998, the European Union's Directive 98/44/ECclarified that patents on DNA sequences were allowable.[11] In 2010 in the US, AMP sued Myriad Genetics to challenge the latter's patents regarding two genes, BRCA1, BRCA2, which are associated with breast cancer. In 2013, the U.S. Supreme Court partially agreed, ruling that a naturally occurring gene sequence could not be patented.[12][13]

Techniques

The Affymetrix 5.0, a microarray chip

Development from research tools

The industrialisation of molecular biology assay tools has made it practical to use them in clinics.[2]: foreword  Miniaturisation into a single handheld device can bring medical diagnostics into the clinic and into the office or home.[2]: foreword  The clinical laboratory requires high standards of reliability; diagnostics may require accreditation or fall under medical device regulations.[14] As of 2011, some US clinical laboratories nevertheless used assays sold for "research use only".[15]

Laboratory processes need to adhere to regulations, for example Clinical Laboratory Improvement Amendments, Health Insurance Portability and Accountability Act, Good Laboratory Practice, and Food and Drug Administration specifications in the United States. Laboratory Information Management Systems help by tracking these processes.[16] Regulation applies to both staff and supplies. As of 2012, twelve US states require molecular pathologists to be licensed; several boards such as the American Board of Medical Genetics and the American Board of Pathology certify technologists, supervisors, and laboratory directors.[17]

Automation and sample barcoding maximise throughput and reduce the possibility of error or contamination during manual handling and results reporting. Single devices to do the assay from beginning to end are now available.[14]

Assays

Main articles: Assay and Biological assay

Molecular diagnostics uses in vitro biological assays such as PCR-ELISA or Fluorescence in situ hybridization.[18][19] The assay detects a molecule, often in low concentrations, that is a marker of disease or risk in a sample taken from a patient. Preservation of the sample before analysis is critical. Manual handling should be minimised.[20] The fragile RNA molecule poses certain challenges. As part of the cellular process of expressing genes as proteins, it offers a measure of gene expression but it is vulnerable to hydrolysis and breakdown by ever-present RNAse enzymes. Samples can be snap-frozen in liquid nitrogen or incubated in preservation agents.[2]: ch 39 

Because molecular diagnostics methods can detect sensitive markers, these tests are less intrusive than a traditional biopsy. For example, because cell-free nucleic acids exist in human plasma, a simple blood sample can be enough to sample genetic information from tumours, transplants or an unborn fetus.[2]: ch 45  Many, but not all, molecular diagnostics methods based on nucleic acids detection use polymerase chain reaction (PCR) to vastly increase the number of nucleic acid molecules, thereby amplifying the target sequence(s) in the patient sample.[2]: foreword  The detection of the marker might use real time PCR, direct sequencing,[2]: ch 17  or microarray chips—prefabricated chips that test many markers at once.[2]: ch 24  The same principle applies to the proteome and the genome. High-throughput protein arrays can use complementary DNA or antibodies to bind and hence can detect many different proteins in parallel.[21] Molecular diagnostic tests vary widely in sensitivity, turn around time, cost, coverage and regulatory approval. They also vary in the level of validation applied in the laboratories using them. Hence, robust local validation in accordance with the regulatory requirements and use of appropriate controls is required especially where the result may be used to inform a patient treatment decision[22].

Applications

A microarray chip contains complementary DNA (cDNA) to many sequences of interest. The cDNA fluoresces when it hybridises with a matching DNA fragment in the sample.

Prenatal

See also: Category:Tests during pregnancy

Conventional prenatal tests for chromosomal abnormalities such as Down Syndrome rely on analysing the number and appearance of the chromosomes—the karyotype. Molecular diagnostics tests such as microarray comparative genomic hybridisation test a sample of DNA instead, and because of cell-free DNA in plasma, could be less invasive, but as of 2013 it is still an adjunct to the conventional tests.[23]

Treatment

Main article: Pharmacogenomics

Some of a patient's single nucleotide polymorphisms—slight differences in their DNA—can help predict how quickly they will metabolise particular drugs; this is called pharmacogenomics.[24] For example, the enzyme CYP2C19 metabolises several drugs, such as the anti-clotting agent Clopidogrel, into their active forms. Some patients possess polymorphisms in specific places on the 2C19 gene that make poor metabolisers of those drugs; physicians can test for these polymorphisms and find out whether the drugs will be fully effective for that patient.[25] Advances in molecular biology have helped show that some syndromes that were previously classed as a single disease are actually multiple subtypes with entirely different causes and treatments. Molecular diagnostics can help diagnose the subtype—for example of infections and cancers—or the genetic analysis of a disease with an inherited component, such as Silver-Russell syndrome.[1][26]

Infectious disease

See also: Pathogenomics

Molecular diagnostics are used to identify infectious diseases such as chlamydia,[27] influenza virus[28] and tuberculosis;[29] or specific strains such as H1N1 virus.[30] Genetic identification can be swift; for example a loop-mediated isothermal amplification test diagnoses the malaria parasite and is rugged enough for developing countries.[31] But despite these advances in genome analysis, in 2013 infections are still more often identified by other means—their proteome, bacteriophage, or chromatographic profile.[32] Molecular diagnostics are also used to understand the specific strain of the pathogen—for example by detecting which drug resistance genes it possesses—and hence which therapies to avoid.[32]

Disease risk management

See also: Screening (medicine) and Genetic testing

A patient's genome may include an inherited or random mutation which affects the probability of developing a disease in the future.[24] For example, Lynch syndrome is a genetic disease that predisposes patients to colorectal and other cancers; early detection can lead to close monitoring that improves the patient's chances of a good outcome.[33] Cardiovascular risk is indicated by biological markers and screening can measure the risk that a child will be born with a genetic disease such as Cystic fibrosis.[34] Genetic testing is ethically complex: patients may not want the stress of knowing their risk.[35] In countries without universal healthcare, a known risk may raise insurance premiums.[36]

Cancer

See also: Tumor metabolome

Cancer is a change in the cellular processes that cause a tumour to grow out of control.[24] Cancerous cells sometimes have mutations in oncogenes, such as KRAS and CTNNB1 (β-catenin).[37] Analysing the molecular signature of cancerous cells—the DNA and its levels of expression via messenger RNA—enables physicians to characterise the cancer and to choose the best therapy for their patients.[24] As of 2010, assays that incorporate an array of antibodies against specific protein marker molecules are an emerging technology; there are hopes for these multiplex assays that could measure many markers at once.[38] Other potential future biomarkers include micro RNA molecules, which cancerous cells express more of than healthy ones.[39]

Molecular studies of cancer have proved the significance of driver mutations in the growth and metastasis of tumors.[40]Many technologies for detection of sequence variations have been developed for cancer research. These technologies generally can be grouped into three approaches: polymerase chain reaction (PCR), hybridization, and next-generation sequencing (NGS). [41]Currently, a lot of PCR and hybridization assays have been approved by FDA as in vitro diagnostics. [42]NGS assays, however, are still at an early stage in clinical diagnostics. [43]

See also

References

  1. ^ a b c Poste, G. (2001). "Molecular diagnostics: A powerful new component of the healthcare value chain". Expert Review of Molecular Diagnostics. 1 (1): 1–5. doi:10.1586/14737159.1.1.1. PMID 11901792.
  2. ^ a b c d e f g h i Carl A. Burtis; Edward R. Ashwood; David E. Bruns (2012). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Elsevier. ISBN 1-4557-5942-2.
  3. ^ Hamburg, M. A.; Collins, F. S. (2010). "The Path to Personalized Medicine". New England Journal of Medicine. 363 (4): 301–304. doi:10.1056/NEJMp1006304. PMID 20551152.
  4. ^ Grody, Wayne W; Nakamura, Robert M; Strom, Charles M; Kiechle, Frederick L. (2010). Molecular Diagnostics: Techniques and Applications for the Clinical Laboratory. Boston MA: Academic Press Inc. ISBN 978-0-12-369428-7.
  5. ^ Kan, Y. W.; Lee, K. Y.; Furbetta, M.; Angius, A.; Cao, A. (1980). "Polymorphism of DNA Sequence in the β-Globin Gene Region". New England Journal of Medicine. 302 (4): 185–188. doi:10.1056/NEJM198001243020401. PMID 6927915.
  6. ^ Cohn, D. V.; Elting, J. J.; Frick, M.; Elde, R. (1984). "Selective Localization of the Parathyroid Secretory Protein-I/Adrenal Medulla Chromogranin a Protein Family in a Wide Variety of Endocrine Cells of the Rat". Endocrinology. 114 (6): 1963–1974. doi:10.1210/endo-114-6-1963. PMID 6233131.
  7. ^ Persselin, J. E.; Stevens, R. H. (1985). "Anti-Fab antibodies in humans. Predominance of minor immunoglobulin G subclasses in rheumatoid arthritis". Journal of Clinical Investigation. 76 (2): 723–730. doi:10.1172/JCI112027. PMC 423887. PMID 3928684.
  8. ^ Kaplan, G.; Gaudernack, G. (1982). "In vitro differentiation of human monocytes. Differences in monocyte phenotypes induced by cultivation on glass or on collagen". Journal of Experimental Medicine. 156 (4): 1101–1114. doi:10.1084/jem.156.4.1101. PMC 2186821. PMID 6961188.
  9. ^ Fausto, N.; Kaul, K. L. (1999). "Presenting the Journal of Molecular Diagnostics". The Journal of Molecular Diagnostics. 1: 1. doi:10.1016/S1525-1578(10)60601-0.
  10. ^ Atanasovska, B; Bozhinovski, G; Chakalova, L; Kocheva, S; Karanfilski, O; Plaseska-Karanfiska, D (2012). "Molecular Diagnostics of β-Thalassemia". Balkan Journal of Medical Genetics. 15 (Suppl): 61–5. doi:10.2478/v10034-012-0021-z (inactive 15 January 2017). PMC 3776673. PMID 24052746.{{cite journal}}: CS1 maint: DOI inactive as of January 2017 (link)
  11. ^ Sharples, Andrew (23 March 2011). "Gene Patents in Europe Relatively Stable Despite Uncertainty in the U.S." Genetic Engineering and Biotechnology News. Retrieved 13 June 2013.
  12. ^ Bravin, Jess; Kendall, Brent (13 June 2013). "Justices Strike Down Gene Patents". The Wall Street Journal. Retrieved 15 June 2013.
  13. ^ Robert Barnes; Brady Dennis (13 June 2013). "Supreme Court rules human genes may not be patented". The Washington Post. Retrieved 15 June 2013.
  14. ^ a b Gibbs, Jeffrey N (1 August 2008). "Regulatory pathways for molecular diagnosis. Detailing the various options available and what each requires". 24 (14). Genetic Engineering & Biotechnology News. Retrieved 4 September 2013. {{cite journal}}: Cite journal requires |journal= (help)
  15. ^ Gibbs, Jeffery N (1 April 2011). "Uncertainty persists with RUO products. FDA may be considering more restrictive approach with research use only assays". 31 (7). Genetic Engineering & Biotechnology News. Retrieved 4 September 2013. {{cite journal}}: Cite journal requires |journal= (help)
  16. ^ Tomiello, Kathryn (21 February 2007). "Regulatory compliance drives LIMS". Design World. Retrieved 7 November 2012.
  17. ^ MacKinnon, A. C.; Wang, Y. L.; Sahota, A.; Yeung, C. C.; Weck, K. E. (2012). "Certification in Molecular Pathology in the United States". The Journal of Molecular Diagnostics. 14 (6): 541–549. doi:10.1016/j.jmoldx.2012.05.004. PMID 22925695.
  18. ^ Molecular Diagnostics: Current Technology and Applications (Horizon Bioscience). 7 July 2006. p. 97. ISBN 1-904933-19-X.
  19. ^ Van Ommen, G. J. B.; Breuning, M. H.; Raap, A. K. (1995). "FISH in genome research and molecular diagnostics". Current Opinion in Genetics & Development. 5 (3): 304–308. doi:10.1016/0959-437X(95)80043-3.
  20. ^ Hammerling, J. A. (2012). "A Review of Medical Errors in Laboratory Diagnostics and Where We Are Today". Laboratory Medicine. 43 (2): 41–44. doi:10.1309/LM6ER9WJR1IHQAUY.
  21. ^ Walter, Gerald; Büssow, Konrad; Lueking, Angelika; Glökler, Jörn (2002). "High-throughput protein arrays: prospects for molecular diagnostics". Trends in Molecular Medicine. 8 (6): 250–253. doi:10.1016/S1471-4914(02)02352-3. PMID 12067604.
  22. ^ Sherwood, James L.; Brown, Helen; Rettino, Alessandro; Schreieck, Amelie; Clark, Graeme; Claes, Bart; Agrawal, Bhuwnesh; Chaston, Ria; Kong, Benjamin S. G. (1 September 2017). "Key differences between 13 KRAS mutation detection technologies and their relevance for clinical practice". ESMO Open. 2 (4): e000235. doi:10.1136/esmoopen-2017-000235. ISSN 2059-7029.
  23. ^ "Advances in Prenatal Molecular Diagnostics Conference (Introduction)". HealthTech. 2013. Retrieved 28 September 2013.
  24. ^ a b c d "Molecular Diagnostics - National Cancer Institute". Cancer.gov. 28 January 2005. Retrieved 26 September 2013.
  25. ^ Desta, Z.; Zhao, X.; Shin, J. G.; Flockhart, D. A. (2002). "Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism". Clinical Pharmacokinetics. 41 (12): 913–958. doi:10.2165/00003088-200241120-00002. PMID 12222994.
  26. ^ Eggermann, T.; Spengler, S.; Gogiel, M.; Begemann, M.; Elbracht, M. (2012). "Epigenetic and genetic diagnosis of Silver–Russell syndrome". Expert Review of Molecular Diagnostics. 12 (5): 459–471. doi:10.1586/erm.12.43. PMID 22702363.
  27. ^ Tong, C. W.; Mallinson, H. (2002). "Moving to nucleic acid-based detection of genital Chlamydia trachomatis". Expert Review of Molecular Diagnostics. 2 (3): 257–266. doi:10.1586/14737159.2.3.257. PMID 12050864.
  28. ^ Deyde, V. M.; Sampath, R.; Gubareva, L. V. (2011). "RT-PCR/electrospray ionization mass spectrometry approach in detection and characterization of influenza viruses". Expert Review of Molecular Diagnostics. 11 (1): 41–52. doi:10.1586/erm.10.107. PMID 21171920.
  29. ^ Pai, M.; Kalantri, S.; Dheda, K. (2006). "New tools and emerging technologies for the diagnosis of tuberculosis: Part I. Latent tuberculosis". Expert Review of Molecular Diagnostics. 6 (3): 413–422. doi:10.1586/14737159.6.3.413. PMID 16706743.
  30. ^ Burkardt, H. J. (2011). "Pandemic H1N1 2009 ('swine flu'): Diagnostic and other challenges". Expert Review of Molecular Diagnostics. 11 (1): 35–40. doi:10.1586/erm.10.102. PMID 21171919.
  31. ^ Han, E. T. (2013). "Loop-mediated isothermal amplification test for the molecular diagnosis of malaria". Expert Review of Molecular Diagnostics. 13 (2): 205–218. doi:10.1586/erm.12.144. PMID 23477559.
  32. ^ a b Tang, Yi-Wei; Procop, Gary W.; Persinga, David H. (1 November 1997). "Molecular diagnostics of infectious diseases". Clinical Chemistry. 43 (11). American Association for Clinical Chemistry: 2021–2038. PMID 9365385.
  33. ^ Van Lier, M. G. F.; Wagner, A.; Van Leerdam, M. E.; Biermann, K.; Kuipers, E. J.; Steyerberg, E. W.; Dubbink, H. J.; Dinjens, W. N. M. (2010). "A review on the molecular diagnostics of Lynch syndrome: A central role for the pathology laboratory". Journal of Cellular and Molecular Medicine. 14 (1–2): 181–197. doi:10.1111/j.1582-4934.2009.00977.x. PMC 3837620. PMID 19929944.
  34. ^ Shrimpton, A. E. (2002). "Molecular diagnosis of cystic fibrosis". Expert Review of Molecular Diagnostics. 2 (3): 240–256. doi:10.1586/14737159.2.3.240. PMID 12050863.
  35. ^ Andorno, R. (2004). "The right not to know: An autonomy based approach". Journal of Medical Ethics. 30 (5): 435–439, discussion 439–40. doi:10.1136/jme.2002.001578. PMC 1733927. PMID 15467071.
  36. ^ Harmon, Amy (2008-02-24) Insurance Fears Lead Many to Shun DNA Tests. New York Times
  37. ^ Minamoto, T.; Ougolkov, A. V.; Mai, M. (2002). "Detection of oncogenes in the diagnosis of cancers with active oncogenic signaling". Expert Review of Molecular Diagnostics. 2 (6): 565–575. doi:10.1586/14737159.2.6.565. PMID 12465453.
  38. ^ Brennan, D. J.; O'Connor, D. P.; Rexhepaj, E.; Ponten, F.; Gallagher, W. M. (2010). "Antibody-based proteomics: Fast-tracking molecular diagnostics in oncology". Nature Reviews Cancer. 10 (9): 605–617. doi:10.1038/nrc2902. PMID 20720569.
  39. ^ Ferracin, M.; Veronese, A.; Negrini, M. (2010). "Micromarkers: MiRNAs in cancer diagnosis and prognosis". Expert Review of Molecular Diagnostics. 10 (3): 297–308. doi:10.1586/erm.10.11. PMID 20370587.
  40. ^ Misale, Sandra; Yaeger, Rona; Hobor, Sebastijan; Scala, Elisa; Janakiraman, Manickam; Liska, David; Valtorta, Emanuele; Schiavo, Roberta; Buscarino, Michela (2012/06). "Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer". Nature. 486 (7404): 532–536. doi:10.1038/nature11156. ISSN 1476-4687. {{cite journal}}: Check date values in: |date= (help)
  41. ^ "Diagnostics based on nucleic acid sequence variant profiling: PCR, hybridization, and NGS approaches". Advanced Drug Delivery Reviews. 105: 3–19. 1 October 2016. doi:10.1016/j.addr.2016.04.005. ISSN 0169-409X.
  42. ^ Emmadi, Rajyasree; Boonyaratanakornkit, Jerry B.; Selvarangan, Rangaraj; Shyamala, Venkatakrishna; Zimmer, Barbara L.; Williams, Laurina; Bryant, Bonita; Schutzbank, Ted; Schoonmaker, Michele M. (1 November 2011). "Molecular Methods and Platforms for Infectious Diseases Testing". The Journal of Molecular Diagnostics. 13 (6): 583–604. doi:10.1016/j.jmoldx.2011.05.011. ISSN 1525-1578.
  43. ^ FDA-approved next-generation sequencing system could expand clinical genomic testing: experts predict MiSeqDx platform will make genetic testing more affordable for smaller labs. AM. J. Med. Genet. A 164, X-XI.
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