Kalotina Machini
Partners HealthCare
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Publication
Featured researches published by Kalotina Machini.
Genome Research | 2015
Laura M. Amendola; Michael O. Dorschner; Peggy D. Robertson; Joseph Salama; Ragan Hart; Brian H. Shirts; Mitzi L. Murray; Mari J. Tokita; Carlos J. Gallego; Daniel Seung Kim; James Bennett; David R. Crosslin; Jane Ranchalis; Kelly L. Jones; Elisabeth A. Rosenthal; Ella R. Jarvik; Andy Itsara; Emily H. Turner; Daniel S. Herman; Jennifer Schleit; Amber A. Burt; Seema M. Jamal; Jenica L. Abrudan; Andrew D. Johnson; Laura K. Conlin; Matthew C. Dulik; Avni Santani; Danielle R. Metterville; Melissa A. Kelly; Ann Katherine M. Foreman
Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.
BMC Medical Genetics | 2014
Heather M. McLaughlin; Ozge Ceyhan-Birsoy; Kurt D. Christensen; Isaac S. Kohane; Joel B. Krier; William J. Lane; Denise Lautenbach; Matthew S. Lebo; Kalotina Machini; Calum A. MacRae; Danielle R. Azzariti; Michael F. Murray; Christine E. Seidman; Jason L. Vassy; Robert C. Green; Heidi L. Rehm
BackgroundThe MedSeq Project is a randomized clinical trial developing approaches to assess the impact of integrating genome sequencing into clinical medicine. To facilitate the return of results of potential medical relevance to physicians and patients participating in the MedSeq Project, we sought to develop a reporting approach for the effective communication of such findings.MethodsGenome sequencing was performed on the Illumina HiSeq platform. Variants were filtered, interpreted, and validated according to methods developed by the Laboratory for Molecular Medicine and consistent with current professional guidelines. The GeneInsight software suite, which is integrated with the Partners HealthCare electronic health record, was used for variant curation, report drafting, and delivery.ResultsWe developed a concise 5–6 page Genome Report (GR) featuring a single-page summary of results of potential medical relevance with additional pages containing structured variant, gene, and disease information along with supporting evidence for reported variants and brief descriptions of associated diseases and clinical implications. The GR is formatted to provide a succinct summary of genomic findings, enabling physicians to take appropriate steps for disease diagnosis, prevention, and management in their patients.ConclusionsOur experience highlights important considerations for the reporting of results of potential medical relevance and provides a framework for interpretation and reporting practices in clinical genome sequencing.
Journal of Genetic Counseling | 2014
Kalotina Machini; Jessica Douglas; Alicia Braxton; Judith Tsipis; Kate Kramer
In recent years, new sequencing technologies known as next generation sequencing (NGS) have provided scientists the ability to rapidly sequence all known coding as well as non-coding sequences in the human genome. As the two emerging approaches, whole exome (WES) and whole genome (WGS) sequencing, have started to be integrated in the clinical arena, we sought to survey health care professionals who are likely to be involved in the implementation process now and/or in the future (e.g., genetic counselors, geneticists and nurse practitioners). Two hundred twenty-one genetic counselors— one third of whom currently offer WES/WGS—participated in an anonymous online survey. The aims of the survey were first, to identify barriers to the implementation of WES/WGS, as perceived by survey participants; second, to provide the first systematic report of current practices regarding the integration of WES/WGS in clinic and/or research across the US and Canada and to illuminate the roles and challenges of genetic counselors participating in this process; and third to evaluate the impact of WES/WGS on patient care. Our results showed that genetic counseling practices with respect to WES/WGS are consistent with the criteria set forth in the ACMG 2012 policy statement, which highlights indications for testing, reporting, and pre/post test considerations. Our respondents described challenges related to offering WES/WGS, which included billing issues, the duration and content of the consent process, result interpretation and disclosure of incidental findings and variants of unknown significance. In addition, respondents indicated that specialty area (i.e., prenatal and cancer), lack of clinical utility of WES/WGS and concerns about interpretation of test results were factors that prevented them from offering this technology to patients. Finally, study participants identified the aspects of their professional training which have been most beneficial in aiding with the integration of WES/WGS into the clinical setting (molecular/clinical genetics, counseling and bioethics) and suggested that counseling aids (to assist them when explaining aspects of these tests to patients) and webinars focused on WES/WGS (for genetic counselors and other health care professionals) would be useful educational tools. Future research should permit us to further enhance our knowledge of pitfalls and benefits associated with the introduction of these powerful technologies in patient care and to further explore the roles and opportunities for genetic counselors in this rapidly evolving field.
Genetics in Medicine | 2017
Ozge Ceyhan-Birsoy; Kalotina Machini; Matthew S. Lebo; Pankaj B. Agrawal; Richard B. Parad; Ingrid A. Holm; Amy L. McGuire; Robert C. Green; Alan H. Beggs; Heidi L. Rehm
Purpose:Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately.Methods:To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project.Results:Here, we present our curated list for 1,514 gene–disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns.Conclusion:Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations.Genet Med advance online publication 12 January 2017
Genetics in Medicine | 2018
Kurt D. Christensen; Jason L. Vassy; Kathryn A. Phillips; Carrie Blout; Danielle R. Azzariti; Christine Y. Lu; Jill O. Robinson; Kaitlyn Lee; Michael P. Douglas; Jennifer M. Yeh; Kalotina Machini; Natasha K. Stout; Heidi L. Rehm; Amy L. McGuire; Robert C. Green; Dmitry Dukhovny
PurposeGreat uncertainty exists about the costs associated with whole-genome sequencing (WGS).MethodsOne hundred cardiology patients with cardiomyopathy diagnoses and 100 ostensibly healthy primary care patients were randomized to receive a family-history report alone or with a WGS report. Cardiology patients also reviewed prior genetic test results. WGS costs were estimated by tracking resource use and staff time. Downstream costs were estimated by identifying services in administrative data, medical records, and patient surveys for 6 months.ResultsThe incremental cost per patient of WGS testing was
Circulation-cardiovascular Genetics | 2017
Allison L. Cirino; Neal K. Lakdawala; Barbara McDonough; Lauren Conner; Dale Adler; Mark Weinfeld; Patrick O’Gara; Heidi L. Rehm; Kalotina Machini; Matthew S. Lebo; Carrie Blout; Robert C. Green; Calum A. MacRae; Christine E. Seidman; Carolyn Y. Ho
5,098 in cardiology settings and
The Lancet Haematology | 2018
William J. Lane; Connie M. Westhoff; Nicholas Gleadall; Maria Aguad; Robin Smeland‐Wagman; Sunitha Vege; Daimon P. Simmons; Helen Mah; Matthew S. Lebo; Klaudia Walter; Nicole Soranzo; Emanuele Di Angelantonio; John Danesh; David J. Roberts; Nicholas A. Watkins; Willem H. Ouwehand; Adam S. Butterworth; Richard M. Kaufman; Heidi L. Rehm; Leslie E. Silberstein; Robert C. Green; David W. Bates; Carrie Blout; Kurt D. Christensen; Allison L. Cirino; Carolyn Y. Ho; Joel B. Krier; Lisa Soleymani Lehmann; Calum A. MacRae; Cynthia C. Morton
5,073 in primary care settings compared with family history alone. Mean 6-month downstream costs did not differ statistically between the control and WGS arms in either setting (cardiology: difference = −
Genetics in Medicine | 2018
Kurt D. Christensen; Barbara A. Bernhardt; Gail P. Jarvik; Lucia A. Hindorff; Jeffrey Ou; Sawona Biswas; Bradford C. Powell; Robert W. Grundmeier; Kalotina Machini; Dean Karavite; Jeffrey W. Pennington; Ian D. Krantz; Jonathan S. Berg; Katrina A.B. Goddard
1,560, 95% confidence interval −
Cold Spring Harb Mol Case Stud | 2018
Jaclyn B. Murry; Kalotina Machini; Ozge Ceyhan-Birsoy; Amy Kritzer; Joel B. Krier; Matthew S. Lebo; Shawn Fayer; Casie A. Genetti; Grace E. VanNoy; Pankaj B. Agrawal; Richard B. Parad; Ingrid A. Holm; Amy L. McGuire; Robert C. Green; Alan H. Beggs; Heidi L. Rehm; Wendi N. Betting; Kurt D. Christensen; Dmitry Dukhovny; Leslie A. Frankel; Chet Graham; Amanda M. Gutierrez; Maegan Harden; Harvey L. Levy; Xingquan Lu; Medha Naik; Tiffany Nguyen; Hayley A. Peoples; Stacey Pereira; Devan Petersen
7,558 to
Annals of Internal Medicine | 2017
Jason L. Vassy; Kurt D. Christensen; Erica Schonman; Carrie Blout; Jill O. Robinson; Joel B. Krier; Pamela M. Diamond; Matthew S. Lebo; Kalotina Machini; Danielle R. Azzariti; Dmitry Dukhovny; David W. Bates; Calum A. MacRae; Michael F. Murray; Heidi L. Rehm; Amy L. McGuire; Robert C. Green
3,866, p = 0.36; primary care: difference =