Letters
Our assessment of genetic variant reproducibility is not, as Grody and colleagues suggest, at odds with reported diagnostic characteristics of genomic sequencing. We reported that the cross-platform reproducibility of single nucleotide variants was high, as has been previously reported by our group and others.2,3 However, for other, potentially more deleterious variation, namely small insertion-deletion variants, cross-platform concordance, even though higher than has been previously reported, remains low. Others have reported similarly low concordance between platforms3 and analytic pipelines.4 Uncertainty in variant interpretation remains a significant challenge in clinical genomic sequencing, even for patients with syndromic phenotypes,5,6 and is not unique to our experience. The variability in reported diagnostic yield that Grody and colleagues describe is at least partially reflective of this uncertainty. We agree that this challenge is not insurmountable but does need to be addressed with standardized classification criteria and data resources. We agree with Grody and colleagues that these limitations do not preclude important discoveries for individual patients. However, we disagree with Grody and colleagues that a greater focus on quality and standardization is required to bring this exciting technology up to the standards currently demanded from other sequencing and clinical diagnostics. The first step along that road is rigorous assessment of test characteristics of genomic sequencing technology and broad transparency regarding what can be confidently discovered and reported. Frederick Dewey, MD Euan Ashley, MRCP, DPhil Thomas Quertermous, MD Author Affiliations: Stanford Center for Inherited Cardiovascular Disease, Stanford, California. Corresponding Author: Frederick Dewey, MD, Stanford Center for Inherited Cardiovascular Disease, 300 Pasteur Dr, Stanford, CA 94305 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Dewey reported that he is a stockholder and member of the scientific advisory board of Personalis Inc, a privately held genome interpretation company, and received royalties for patented technology related to genome sequencing. Dr Ashley reported being a founder, stockholder, and member of the scientific advisory board of Personalis and receiving royalties for patents related to genome sequencing. Dr Quertermous reported that he is a member of the scientific advisory board of Aviir Inc. 1. UCLA Health School of Medicine. Gene list and coverage. http://pathology .ucla.edu/body.cfm?id=289. Accessed April 20, 2014. 2. Lam HY, Clark MJ, Chen R, et al. Performance comparison of whole-genome sequencing platforms [published correction appears in Nat Biotechnol. 2012;30(6):562]. Nat Biotechnol. 2011;30(1):78-82. 3. Lupski JR, Gonzaga-Jauregui C, Yang Y, et al. Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. Genome Med. 2013;5(6):57. 4. O’Rawe J, Jiang T, Sun G, et al. Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing. Genome Med. 2013;5(3):28. 5. Dorschner MO, Amendola LM, Turner EH, et al. Actionable, pathogenic incidental findings in 1000 participants’ exomes. Am J Hum Genet. 2013;93(4): 631-640.
6. Brownstein CA, Beggs AH, Homer N, et al. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. Genome Biol. 2014;15(3):R53.
Addressing Suicide Risk in Emergency Department Patients To the Editor In their Viewpoint, Dr Olfson and colleagues1 called for “enhanced training of emergency physicians in the management of suicidal patients and patients with deliberate selfharm” due to the “shortages of mental health specialists in emergency medical settings.” Studies show that 1 in 5 emergency department patients may be depressed, yet the diagnosis is often missed for a variety of reasons including that patients do not complain of depression but of somatic depression symptoms.2 Similarly, overt suicidal behavior accounts for 0.6% of emergency department visits but the incidental suicidal ideation that is found in 3% to 11.6% of visits is often missed.3 There are 130 million patient visits to emergency departments each year, so there is much room for improvement.4 There are 27 000 board-certified emergency physicians in the United States, so calling for enhanced training is a start but is unlikely, by itself, to result in substantive improvement in the management of suicidal patients. Good evidence-based research is also needed to answer vexing questions. For example, the benefits of antidepressants to appropriate patients are beyond dispute, but what remains unstudied is whether they should be initiated in the emergency department. Although starting medication earlier in the emergency department rather than later at follow-up intuitively should be beneficial to patients, a randomized clinical trial confirming benefit could prompt emergency medicine physicians to identify more depressed patients in the emergency department. Similarly, consensus on how to assess suicide risk would be helpful. A study comparing measures of suicide risk could help standardize and improve the care of suicidal patients in the emergency department.5 David Hoyer, MD Author Affiliation: Department of Emergency Medicine, University of Texas Health Science Center, Houston. Corresponding Author: David Hoyer, MD, Department of Emergency Medicine, University of Texas Health Science Center, 2026 McDuffie St, Houston, TX 77019 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving compensation for serving on an advisory board for Teva Pharmaceuticals. 1. Olfson M, Marcus SC, Bridge JA. Focusing suicide prevention on periods of high risk. JAMA. 2014;311(11):1107-1108. 2. Hoyer D, David E. Screening for depression in emergency department patients. J Emerg Med. 2012;43(5):786-789. 3. Allen MH, Abar BW, McCormick M, et al. Screening for suicidal ideation and attempts among emergency department medical patients: instrument and results from the Psychiatric Emergency Research Collaboration. Suicide Life Threat Behav. 2013;43(3):313-323. 4. Centers for Disease Control and Prevention. Emergency department visits. http: //www.cdc.gov/nchs/fastats/ervisits.htm. Accessed March 30, 2014.
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JAMA July 16, 2014 Volume 312, Number 3
Copyright 2014 American Medical Association. All rights reserved.
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297
Letters
5. Gray C. Assessment of the suicidal patient in the emergency department. In: Zun LS, Chepenik LG, Mallory MS, eds. Behavioral Emergencies for the Emergency Physician. New York, NY: Cambridge University Press; 2013:60-68.
In Reply We agree with Dr Hoyer that there is ample room for improvement in the emergency care of suicidal patients and that priority should be given to research on emergency assessment and management. We further agree that screening for suicide risk, which seldom occurs in routine emergency care,1 can alert emergency staff to individuals who may be at high risk. In a large, diagnostically mixed research sample, for example, patients who reported a history of suicidal ideation with intent and behavior on the Columbia-Suicide Severity Rating Scale were approximately 9 times more likely than those without such histories to report suicidal behavior during the following 2 months.2 Beyond screening for risk factors, clinical evaluations should focus on detecting warning signs that can serve as targets for clinical intervention such as feeling trapped, escalating drug or alcohol use, recent social withdrawal, or dramatic mood changes.3 Training emergency medicine residents in the evaluation of suicidal patients offers the potential to build their skills in identifying high-risk patients and referring them for appropriate interventions. We do not share Dr Hoyer’s optimism concerning the potential effectiveness of emergency department initiation of antidepressants. Although emergency departments provide important opportunities for linking patients to community mental health services, there are limitations to performing thorough diagnostic evaluations to exclude medical and self-limiting factors, assessing potential risks and benefits of antidepressants, selecting optimal treatments for individual patients, and initiating plans for monitoring treatment safety and effectiveness in an emergency department setting.4 The latency in antidepressant response also argues in favor of initiating antidepressant treatment within the context of an ongoing clinical relationship rather than an emergency department visit. In the Sequenced Treatment Alternatives to Relieve Depression study, only half of the patients with depression who eventually remitted did so during the first 6 weeks of treatment.5 Because antidepressants typically deliver delayed rather than prompt relief, clinical support is especially important during the first few weeks of treatment when the risk of antidepressant nonadherence is greatest.6 Smoothing the transition from emergency department evaluation to outpatient mental health treatment remains a key challenge to ensuring the short-term safety of at-risk patients who are discharged from emergency departments. Research is needed on practical interventions, such as motivational interviewing, safety planning, crisis care coordination, and referrals for same-day intake appointments to engage high-risk emergency patients in outpatient mental health care. Mark Olfson, MD, MPH Steven C. Marcus, PhD Jeffrey A. Bridge, PhD
298
Author Affiliations: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York (Olfson); Center for Health Equity Research and Promotion, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania (Marcus); Research Institute at Nationwide Children's Hospital, Center for Innovation in Pediatric Practice, Columbus, Ohio (Bridge). Corresponding Author: Mark Olfson, MD, MPH, Department of Psychiatry, Columbia University College of Physicians and Surgeons, 1051 Riverside Dr, New York, NY 10032 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Marcus reported receiving a grant from the National Institute of Mental Health (NIMH) and personal fees from the American Foundation for Suicide Prevention. Dr Bridge reported receiving grants from the NIMH, the Centers for Disease Control and Prevention, and the American Foundation for Suicide Prevention; and honoraria from Elsevier. Dr Olfson reported receiving grant support from the American Foundation for Suicide Prevention, the National Institutes of Health, the Agency for Healthcare Research and Quality; and a salary from the New York State Office of Mental Health. 1. Ting SA, Sullivan AF, Miller I, et al; Emergency Department Safety and Follow-up Evaluation (ED-SAFE) Investigators. Multicenter study of predictors of suicide screening in emergency departments. Acad Emerg Med. 2012;19(2): 239-243. 2. Mundt JC, Greist JH, Jefferson JW, Federico M, Mann JJ, Posner K. Prediction of suicidal behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the electronic Columbia-Suicide Severity Rating Scale. J Clin Psychiatry. 2013;74(9):887-893. 3. Stanley B, Brown GK. Safety planning intervention: a brief intervention to mitigate suicide risk. Cognit Behav Pract. 2012;19:256-264. 4. Dodd S, Malhi GS, Tiller J, et al. A consensus statement for safety monitoring guidelines of treatments for major depressive disorder. Aust N Z J Psychiatry. 2011;45(9):712-725. 5. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. 6. Demyttenaere K. Risk factors and predictors of compliance in depression. Eur Neuropsychopharmacol. 2003;13(suppl 3):S69-S75.
Guidelines for Letters Letters discussing a recent JAMA article should be submitted within 4 weeks of the article's publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 7 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the JAMA article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/public /InstructionsForAuthors.aspx. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http: //manuscripts.jama.com. For technical assistance, please contact [email protected]. Section Editor: Jody W. Zylke, MD, Senior Editor.
JAMA July 16, 2014 Volume 312, Number 3
Copyright 2014 American Medical Association. All rights reserved.
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Our assessment of genetic variant reproducibility is not, as Grody and colleagues suggest, at odds with reported diagnostic characteristics of genomic sequencing. We reported that the cross-platform reproducibility of single nucleotide variants was high, as has been previously reported by our group and others.2,3 However, for other, potentially more deleterious variation, namely small insertion-deletion variants, cross-platform concordance, even though higher than has been previously reported, remains low. Others have reported similarly low concordance between platforms3 and analytic pipelines.4 Uncertainty in variant interpretation remains a significant challenge in clinical genomic sequencing, even for patients with syndromic phenotypes,5,6 and is not unique to our experience. The variability in reported diagnostic yield that Grody and colleagues describe is at least partially reflective of this uncertainty. We agree that this challenge is not insurmountable but does need to be addressed with standardized classification criteria and data resources. We agree with Grody and colleagues that these limitations do not preclude important discoveries for individual patients. However, we disagree with Grody and colleagues that a greater focus on quality and standardization is required to bring this exciting technology up to the standards currently demanded from other sequencing and clinical diagnostics. The first step along that road is rigorous assessment of test characteristics of genomic sequencing technology and broad transparency regarding what can be confidently discovered and reported. Frederick Dewey, MD Euan Ashley, MRCP, DPhil Thomas Quertermous, MD Author Affiliations: Stanford Center for Inherited Cardiovascular Disease, Stanford, California. Corresponding Author: Frederick Dewey, MD, Stanford Center for Inherited Cardiovascular Disease, 300 Pasteur Dr, Stanford, CA 94305 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Dewey reported that he is a stockholder and member of the scientific advisory board of Personalis Inc, a privately held genome interpretation company, and received royalties for patented technology related to genome sequencing. Dr Ashley reported being a founder, stockholder, and member of the scientific advisory board of Personalis and receiving royalties for patents related to genome sequencing. Dr Quertermous reported that he is a member of the scientific advisory board of Aviir Inc. 1. UCLA Health School of Medicine. Gene list and coverage. http://pathology .ucla.edu/body.cfm?id=289. Accessed April 20, 2014. 2. Lam HY, Clark MJ, Chen R, et al. Performance comparison of whole-genome sequencing platforms [published correction appears in Nat Biotechnol. 2012;30(6):562]. Nat Biotechnol. 2011;30(1):78-82. 3. Lupski JR, Gonzaga-Jauregui C, Yang Y, et al. Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. Genome Med. 2013;5(6):57. 4. O’Rawe J, Jiang T, Sun G, et al. Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing. Genome Med. 2013;5(3):28. 5. Dorschner MO, Amendola LM, Turner EH, et al. Actionable, pathogenic incidental findings in 1000 participants’ exomes. Am J Hum Genet. 2013;93(4): 631-640.
6. Brownstein CA, Beggs AH, Homer N, et al. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. Genome Biol. 2014;15(3):R53.
Addressing Suicide Risk in Emergency Department Patients To the Editor In their Viewpoint, Dr Olfson and colleagues1 called for “enhanced training of emergency physicians in the management of suicidal patients and patients with deliberate selfharm” due to the “shortages of mental health specialists in emergency medical settings.” Studies show that 1 in 5 emergency department patients may be depressed, yet the diagnosis is often missed for a variety of reasons including that patients do not complain of depression but of somatic depression symptoms.2 Similarly, overt suicidal behavior accounts for 0.6% of emergency department visits but the incidental suicidal ideation that is found in 3% to 11.6% of visits is often missed.3 There are 130 million patient visits to emergency departments each year, so there is much room for improvement.4 There are 27 000 board-certified emergency physicians in the United States, so calling for enhanced training is a start but is unlikely, by itself, to result in substantive improvement in the management of suicidal patients. Good evidence-based research is also needed to answer vexing questions. For example, the benefits of antidepressants to appropriate patients are beyond dispute, but what remains unstudied is whether they should be initiated in the emergency department. Although starting medication earlier in the emergency department rather than later at follow-up intuitively should be beneficial to patients, a randomized clinical trial confirming benefit could prompt emergency medicine physicians to identify more depressed patients in the emergency department. Similarly, consensus on how to assess suicide risk would be helpful. A study comparing measures of suicide risk could help standardize and improve the care of suicidal patients in the emergency department.5 David Hoyer, MD Author Affiliation: Department of Emergency Medicine, University of Texas Health Science Center, Houston. Corresponding Author: David Hoyer, MD, Department of Emergency Medicine, University of Texas Health Science Center, 2026 McDuffie St, Houston, TX 77019 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving compensation for serving on an advisory board for Teva Pharmaceuticals. 1. Olfson M, Marcus SC, Bridge JA. Focusing suicide prevention on periods of high risk. JAMA. 2014;311(11):1107-1108. 2. Hoyer D, David E. Screening for depression in emergency department patients. J Emerg Med. 2012;43(5):786-789. 3. Allen MH, Abar BW, McCormick M, et al. Screening for suicidal ideation and attempts among emergency department medical patients: instrument and results from the Psychiatric Emergency Research Collaboration. Suicide Life Threat Behav. 2013;43(3):313-323. 4. Centers for Disease Control and Prevention. Emergency department visits. http: //www.cdc.gov/nchs/fastats/ervisits.htm. Accessed March 30, 2014.
jama.com
JAMA July 16, 2014 Volume 312, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Georgia User on 05/27/2015
297
Letters
5. Gray C. Assessment of the suicidal patient in the emergency department. In: Zun LS, Chepenik LG, Mallory MS, eds. Behavioral Emergencies for the Emergency Physician. New York, NY: Cambridge University Press; 2013:60-68.
In Reply We agree with Dr Hoyer that there is ample room for improvement in the emergency care of suicidal patients and that priority should be given to research on emergency assessment and management. We further agree that screening for suicide risk, which seldom occurs in routine emergency care,1 can alert emergency staff to individuals who may be at high risk. In a large, diagnostically mixed research sample, for example, patients who reported a history of suicidal ideation with intent and behavior on the Columbia-Suicide Severity Rating Scale were approximately 9 times more likely than those without such histories to report suicidal behavior during the following 2 months.2 Beyond screening for risk factors, clinical evaluations should focus on detecting warning signs that can serve as targets for clinical intervention such as feeling trapped, escalating drug or alcohol use, recent social withdrawal, or dramatic mood changes.3 Training emergency medicine residents in the evaluation of suicidal patients offers the potential to build their skills in identifying high-risk patients and referring them for appropriate interventions. We do not share Dr Hoyer’s optimism concerning the potential effectiveness of emergency department initiation of antidepressants. Although emergency departments provide important opportunities for linking patients to community mental health services, there are limitations to performing thorough diagnostic evaluations to exclude medical and self-limiting factors, assessing potential risks and benefits of antidepressants, selecting optimal treatments for individual patients, and initiating plans for monitoring treatment safety and effectiveness in an emergency department setting.4 The latency in antidepressant response also argues in favor of initiating antidepressant treatment within the context of an ongoing clinical relationship rather than an emergency department visit. In the Sequenced Treatment Alternatives to Relieve Depression study, only half of the patients with depression who eventually remitted did so during the first 6 weeks of treatment.5 Because antidepressants typically deliver delayed rather than prompt relief, clinical support is especially important during the first few weeks of treatment when the risk of antidepressant nonadherence is greatest.6 Smoothing the transition from emergency department evaluation to outpatient mental health treatment remains a key challenge to ensuring the short-term safety of at-risk patients who are discharged from emergency departments. Research is needed on practical interventions, such as motivational interviewing, safety planning, crisis care coordination, and referrals for same-day intake appointments to engage high-risk emergency patients in outpatient mental health care. Mark Olfson, MD, MPH Steven C. Marcus, PhD Jeffrey A. Bridge, PhD
298
Author Affiliations: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York (Olfson); Center for Health Equity Research and Promotion, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania (Marcus); Research Institute at Nationwide Children's Hospital, Center for Innovation in Pediatric Practice, Columbus, Ohio (Bridge). Corresponding Author: Mark Olfson, MD, MPH, Department of Psychiatry, Columbia University College of Physicians and Surgeons, 1051 Riverside Dr, New York, NY 10032 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Marcus reported receiving a grant from the National Institute of Mental Health (NIMH) and personal fees from the American Foundation for Suicide Prevention. Dr Bridge reported receiving grants from the NIMH, the Centers for Disease Control and Prevention, and the American Foundation for Suicide Prevention; and honoraria from Elsevier. Dr Olfson reported receiving grant support from the American Foundation for Suicide Prevention, the National Institutes of Health, the Agency for Healthcare Research and Quality; and a salary from the New York State Office of Mental Health. 1. Ting SA, Sullivan AF, Miller I, et al; Emergency Department Safety and Follow-up Evaluation (ED-SAFE) Investigators. Multicenter study of predictors of suicide screening in emergency departments. Acad Emerg Med. 2012;19(2): 239-243. 2. Mundt JC, Greist JH, Jefferson JW, Federico M, Mann JJ, Posner K. Prediction of suicidal behavior in clinical research by lifetime suicidal ideation and behavior ascertained by the electronic Columbia-Suicide Severity Rating Scale. J Clin Psychiatry. 2013;74(9):887-893. 3. Stanley B, Brown GK. Safety planning intervention: a brief intervention to mitigate suicide risk. Cognit Behav Pract. 2012;19:256-264. 4. Dodd S, Malhi GS, Tiller J, et al. A consensus statement for safety monitoring guidelines of treatments for major depressive disorder. Aust N Z J Psychiatry. 2011;45(9):712-725. 5. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917. 6. Demyttenaere K. Risk factors and predictors of compliance in depression. Eur Neuropsychopharmacol. 2003;13(suppl 3):S69-S75.
Guidelines for Letters Letters discussing a recent JAMA article should be submitted within 4 weeks of the article's publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 7 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the JAMA article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/public /InstructionsForAuthors.aspx. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http: //manuscripts.jama.com. For technical assistance, please contact [email protected]. Section Editor: Jody W. Zylke, MD, Senior Editor.
JAMA July 16, 2014 Volume 312, Number 3
Copyright 2014 American Medical Association. All rights reserved.
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