Letters
Annals of Internal Medicine COMMENTS
AND
RESPONSES
2. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165:2671-6. [PMID: 16344427] 3. Bruckert E, Hayem G, Dejager S, Yau C, Be´gaud B. Mild to moderate muscular
N-of-1 (Single-Patient) Trials for Statin-Related Myalgia
symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403-14. [PMID: 16453090]
TO THE EDITOR: In Joy and colleagues’ article (1), placebo and the
4. Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ. The n-of-1 clinical
intervention were each administered for 3 weeks in randomized sequences with intervening 3-week washout periods. However, prior studies suggest that statin-induced myalgia begins within weeks to months of starting therapy, with a mean period of 6 months reported in a review by Hansen and associates (2, 3). In their review, the mean period for resolution of symptoms was 2 months. Therefore, the question that arises is whether the 3-week treatment and intervening washout periods used in this study were long enough for the study participants to develop and resolve, respectively, statin-related myalgia and/or myopathy. Visual analogue scales and a pain inventory were administered once a week during each treatment period. Recall bias thus cannot be excluded, although such bias is likely to be nondifferential for intervention or placebo treatment periods. Future N-of-1 trials may leverage the availability of wireless devices for real-time reporting of symptoms transmitted over secure networks (4). Such real-time reporting can also facilitate the analysis of the data for periodicity of symptoms, such as diurnal variations. Paired t tests were used in the individual-level analysis of each N-of-1 trial. This analytic approach ignores the serial temporal correlation of the reported outcomes, which are likely to be greater between treatment periods that are closer in time (4). In addition, considering that each participant had only 3 paired treatment periods, whether this analysis reasonably satisfied the statistical assumptions that underlie the use of parametric methods was not shown. Intervention, randomization sequence, and results were reported for each patient. However, the baseline characteristics of individual patients were summarized rather than reported at the individual level. Considering that there were only 8 final participants, the presentation of their individual-level baseline characteristics would have facilitated a more robust assessment of the study results vis-a`-vis relating each participant’s baseline characteristics to his or her results. In conclusion, Joy and colleagues have shown the N-of-1 trial method to be a scientifically rigorous and practical approach for individualizing treatment decisions about statin therapy among patients who report statin-related myalgia. Future trials may consider longer treatment and washout periods. They may also use secure wireless technologies for real-time reporting of symptoms.
trial: the ultimate strategy for individualizing medicine? Per Med. 2011;8:161-173.
Oladimeji Akinboro, MD, MPH Linda Williams, MD Daniel Pomerantz, MD, MPH Montefiore New Rochelle Hospital New Rochelle, New York Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0293. References 1. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160:301-10. [PMID: 24737272] doi:10.7326/M13-1921
[PMID: 21695041]
IN RESPONSE: The decision to restrict each treatment exposure and
washout phase to 3 weeks did indeed mean that our N-of-1 trials could not reliably detect statin-related muscle symptoms that took more than 3 weeks to develop and/or resolve. To minimize this circumstance, we chose patients who previously developed myalgia within 3 weeks of starting therapy with a statin and received the same statin in the N-of-1 trial that they associated with myalgia during open-label treatment. We provided our rationale for choosing a 3-week washout period in the article. In Hansen and associates’ review (1), we note that one third of patients reported symptoms within a month of initiating statin therapy. In addition, Cham and coworkers’ study (2) of 354 patients with statin-related muscle symptoms found that myalgia recurred within a median 2 weeks upon statin rechallenge. We believe that our N-of-1 trials reliably assessed possible statin-related myalgia in patients with a shorter history of symptoms. As Akinboro and colleagues suggest, we cannot generalize our findings to patients with a longer history of symptoms. However, we doubt that N-of-1 trials for patients with possible statin-related myalgia that develops or resolves more than 3 weeks after starting or stopping therapy with a statin will be practicable. Parenthetically and on the basis of the few N-of-1 trials that we did, we wonder whether previous cohort studies of patients receiving open-label statin treatment have overestimated the incidence of myalgia that is truly caused by statins and the time needed for resolution. We agree with Akinboro and colleagues that our N-of-1 trials raise the potential for recall bias but that, more important, such bias was equally applicable to placebo and active treatment periods. We also agree that secure wireless technologies for real-time reporting of symptoms are attractive and worth exploring in the context of these trials. We used the paired t test to analyze data from each N-of-1 trial on the basis of published guidelines (3). The assumptions underlying the t test may not be strictly satisfied in our case, but the test is well-known to be robust to violation of assumptions (4). We also note that use of nonparametric tests would yield even less-significant P values than those we obtained by using the t test, thereby providing stronger evidence for our conclusion. The Table shows individual baseline characteristics for patients who completed the N-of-1 trials. Tisha R. Joy, MD Schulich School of Medicine and Dentistry, Western University London, Ontario, Canada Guang Yong Zou, PhD Robarts Research Institute, Western University London, Ontario, Canada © 2014 American College of Physicians 531
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Letters Table. Baseline Characteristics Patient Number
Age, y
Sex
VAS Myalgia Score, mm*
Symptom-Specific VAS Score, mm*
PSS†
PIS†
1 2 3 4 5 6 7 8
56 76 65 62 71 62 78 62
Female Female Female Male Female Female Female Female
0 36 12 2 29 18 12 0
0 37 10 13 0 0 6 0
1.75 4.25 2.00 2.00 4.75 3.00 2.00 3.25
0.00 3.28 1.28 1.29 2.71 2.29 0.00 8.71
PIS ⫽ pain interference score; PSS ⫽ pain severity score; VAS ⫽ visual analogue scale. * The VAS scores range from 0 to 100 mm, with higher scores indicating worse pain or symptomatology. † The PSS and PIS range from 0 to 10, with higher scores indicating worse pain and pain interference, respectively.
Jeffrey L. Mahon, MD, MSc Schulich School of Medicine and Dentistry and Robarts Research Institute, Western University London, Ontario, Canada Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-1921. References 1. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165:2671-6. [PMID: 16344427] 2. Cham S, Evans MA, Denenberg JO, Golomb BA. Statin-associated muscle-related adverse effects: a case series of 354 patients. Pharmacotherapy. 2010;30:541-53. [PMID: 20500044] doi:10.1592/phco.30.6.541 3. Guyatt G, Sackett D, Adachi J, Roberts R, Chong J, Rosenbloom D, et al. A clinician’s guide for conducting randomized trials in individual patients. CMAJ. 1988; 139:497-503. [PMID: 3409138] 4. Heeren T, D’Agostino R. Robustness of the two independent samples t-test when applied to ordinal scaled data. Stat Med. 1987;6:79-90. [PMID: 3576020]
Raising the Bar for the U.S. Preventive Services Task Force TO THE EDITOR: We read Bach’s editorial (1) with great interest.
The U.S. Preventive Services Task Force recommendation on lung cancer screening represents a major synthesis of trial evidence, model-based outcomes, and expert judgment to quantify the tradeoffs of computed tomography screening for the millions of persons at high risk for lung cancer (2, 3). However, Bach states that the Task Force could have been more cautious about relying on modeling for extrapolation well beyond the empirical data to fill in gaps in the evidence (1). Bach questions the net benefit of screening annually over many years. Does he mean that evidence suggests screening 3 times, as was done in NLST (National Lung Screening Trial)? Does he mean that women should receive only 5 breast cancer screenings, because this was the average number in the breast screening trials? Randomized trials are designed to prove the efficacy of an intervention. In translating that evidence to public health, much more is needed— especially to estimate the long-term benefits and harms for the target population. In fact, many would argue that modeling is
essential to translate evidence from trials to population guidelines (4), particularly as we face an ever-increasing pace of technology where questions far exceed our ability to do multiple trials. Our model-based analyses (3) required a joint consideration of many factors, including dose response to smoking and age-specific incidence and death from other causes according to smoking behavior and birth cohort. These factors were superimposed onto more than 1000 schedules of screening examinations using NLST as a guide, something too complex to evaluate without the aid of a model. However, Bach states that we were unable to generate models that parallel the natural history of lung cancer and that our models produced inconsistent mortality benefits in reproducing the early years of NLST. That model variability would produce results that differ in the early years when event rates were low and great variation should not be surprising. Even data monitoring committees place low value on the early years. Bach also points out that the models differed in their predictions of the absolute number of cases of lung cancer and lung cancer deaths prevented. Absolute counts naturally vary considerably and are more difficult to estimate accurately. However, in the ranking of competing scenarios, all 5 models place the 27 scenarios consistently. Moreover, the models reproduce the outcomes observed in the trials (5), and we showed the range of absolute effects in the table on harms and benefits of the advantageous scenario. At the end of the editorial, Bach mentions the term “sharpshooter.” Although this example is dismaying, the analogue is striking. With the models, we indeed draw the target around the greatest cluster of data: On the basis of 200 000 persons enrolled in the screening trials, we can best estimate the screen-detectable preclinical period, test sensitivity, and improvements in prognosis made by screening and early treatment according to sex, age, and histologic characteristics. We therefore hope that clinical researchers will engage more closely with modelers and contribute to deliberations about the best use of models with a deeper understanding of the their development and validation processes. Harry J. de Koning, MD Erasmus Medical Center Rotterdam, the Netherlands Rafael Meza, PhD University of Michigan Ann Arbor, Michigan Sylvia K. Plevritis, PhD NCI Stanford Center for Cancer Systems Biology, Stanford University Stanford, California Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-2316.
References 1. Bach PB. Raising the bar for the U.S. Preventive Services Task Force [Editorial]. Ann Intern Med. 2014;160:365-6. [PMID: 24379087] doi:10.7326/M13-2926 2. Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014; 160:330-8. [PMID: 24378917] doi:10.7326/M13-2771
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Letters 3. de Koning HJ, Meza R, Plevritis SK, ten Haaf K, Munshi VN, Jeon J, et al. Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force. Ann Intern Med. 2014; 160:311-20. [PMID: 24379002] doi:10.7326/M13-2316
Ann Danoff, MD Veterans Affairs New York Harbor Healthcare System and New York University School of Medicine New York, New York
4. Heijnsdijk EA, Wever EM, Auvinen A, Hugosson J, Ciatto S, Nelen V, et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med. 2012;367: 595-605. [PMID: 22894572] doi:10.1056/NEJMoa1201637 5. Meza R, ten Haaf K, Kong CY, Erdogan A, Black WC, Tammemagi MC, et al.
Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0211.
Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials. Cancer. 2014;120:1713-24. [PMID: 24577803] doi:10.1002/cncr.28623
Gender Differences in Time Spent on Parenting and Domestic Responsibilities TO THE EDITOR: As a baby boomer and former K08 awardee who leaked out of the academic pipeline (1) long ago, Jolly and colleagues’ grim observations (2) about ongoing challenges among “Generation X” women to achieve gender equity in academic medical centers and on the home front are disheartening. However, the authors’ efforts to illuminate these unresolved issues and offer a glimmer of hope that one day we may find creative solutions so that women are retained as productive and successful investigators if they wish to be is reassuring. In contrast, I found Cooke and Laine’s editorial (3) deeply disturbing. Although the editorialists acknowledge that “continued differences in standards are inexcusable,” they are much too quick to attribute ongoing gender inequity to “preferences” and “choices” made by women aiming to achieve work–life “balance.” As Jolly and colleagues show (2), these choices are strongly influenced by work and home environments. To deemphasize the experience afforded women in academic medical centers (4) or the effect of the “second shift” (5) on career decisions does a great disservice to the individual women involved. Examples of women not being heard or credited for efforts at work and of pay inequity are commonplace among women in medicine. Also commonplace are descriptions of how a husband “helps” with the child care, followed in the next breath by the acknowledgment that it is still the wife’s job to keep track of the supermarket list and soccer game schedule and gently remind her partner to please pick up the milk. I cannot agree more with Cooke and Laine that I have been personally blessed with a rich and varied professional career. However, I (arguably) took this path by neither choice nor personal failings but rather because the deck was stacked against me. It is regrettable that, like the women of my generation, female members of Generation X must still contend with “accumulated disadvantages” (the converse of “accumulated advantages” described by Gladwell [6]). It seems that we still have an awful lot of work to do. Until all doors are fully opened for each and every one of us (women, men, and persons of all colors and every sexual orientation) and each of us has an equal opportunity for real choice about where on the bus (or in the medical community) we wish to sit, we will all continue to be shortchanged as individuals and as a society. www.annals.org
References 1. Justice AC. Leaky pipes, Faustian dilemmas, and a room of one’s own: can we build a more flexible pipeline to academic success? [Editorial]. Ann Intern Med. 2009;151: 818-9. [PMID: 19949149] doi:10.7326/0003-4819-151-11-200912010-00013 2. Jolly S, Griffith KA, DeCastro R, Stewart A, Ubel P, Jagsi R. Gender differences in time spent on parenting and domestic responsibilities by high-achieving young physician-researchers. Ann Intern Med. 2014;160:344-53. [PMID: 24737273] doi: 10.7326/M13-0974 3. Cooke M, Laine C. A woman physician-researcher’s work is never done [Editorial]. Ann Intern Med. 2014;160:359-60. [PMID: 24737274] doi:10.7326/M14-0218 4. Levine RB, Lin F, Kern DE, Wright SM, Carrese J. Stories from early-career women physicians who have left academic medicine: a qualitative study at a single institution. Acad Med. 2011;86:752-8. [PMID: 21512363] doi:10.1097/ACM .0b013e318217e83b 5. Hochschild AR, Machung A. The Second Shift. New York: Viking Penguin; 1989. 6. Gladwell M. Outliers: The Story of Success. New York: Little, Brown; 2008.
TO THE EDITOR: Perhaps Jolly and colleagues (1) did not conclude
that the observed differences in parenting were due to simple choice—as Cooke and Laine (2) did— because women, like men, make choices within a social context. Dr. Bennett, former Chief of Pediatrics at Harvard Community Health Plan, added a postscript to a “lighthearted” career article included in an anthology in 2002 that states, “In 1961, I was the brainwashed product of my culture’s view of woman’s place in society” (3). At the time, she believed that she was choosing to take primary responsibility at home. However, looking back, she saw how society’s definition of a good wife and mother constrained that choice. That 85.6% of the spouses of women physicians in Jolly and colleagues’ study were employed full-time, whereas only 44.9% of the spouses of their male colleagues were, underlines the enduring strength of traditional gender roles. Although successful, Dr. Bennett emphatically advocated for her younger colleagues. A woman doctor “should be able to experience the joys and responsibilities of marriage and parenthood equally with her male colleague— but not more equally.” Toni Martin, MD Berkeley, California Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0212.
References 1. Jolly S, Griffith KA, DeCastro R, Stewart A, Ubel P, Jagsi R. Gender differences in time spent on parenting and domestic responsibilities by high-achieving young physician-researchers. Ann Intern Med. 2014;160:344-53. [PMID: 24737273] doi: 10.7326/M13-0974 7 October 2014 Annals of Internal Medicine Volume 161 • Number 7 533
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Letters 2. Cooke M, Laine C. A woman physician-researcher’s work is never done [Editorial]. Ann Intern Med. 2014;160:359-60. [PMID: 24737274] doi:10.7326/M14-0218 3. Bennett DR. Postscript. In: Chin EL, ed. This Side of Doctoring: Reflections from Women in Medicine. Thousand Oaks, CA: Sage; 2002:31-2.
Disclosures: Authors have disclosed no conflicts of interest. Forms can
TO THE EDITOR: We read Jolly and colleagues’ article (1) with great
References
interest. As current National Institutes of Health career development awardees who are also mothers with employed spouses, we were not shocked to learn that women of our generation continue to bear a disproportionate burden of domestic work compared with men and that women with children devote less time to research than their male counterparts (with a gap that is roughly equal to the extra time spent doing domestic work). What did shock us were the conclusions drawn by Cooke and Laine (2). They state that the “true measure of a successful life in academic medicine . . . may no longer be measured in grants garnered, papers published, or salary attained but rather in the flexibility to balance” other life goals. At our institutions, grants and papers are the sine qua non of a research-based academic career and promotion from the junior faculty state. To paraphrase Vince Lombardi, grants and papers aren’t everything—they are the only thing. Although other career trajectories are now open in the world of academic medicine, the primarily research-funded academician still needs to produce publications and acquire independent funding to continue in that role and to advance up the academic ladder, regardless of sex. We have each benefited from excellent mentors, both male and female, during our time as career development awardees. The advice that we hear from these mentors is clear: Moving from a K grant to an independently funded research career is challenging and needs to be accomplished during the 5-year K grant timeline. This transition is where many women researchers falter in the academic track by either switching to a different track or not obtaining funding. Not coincidentally, this timeline overlaps with a period during which child rearing is a distraction, albeit an enjoyable and rewarding one. More radical solutions than a paean to “balance” are needed to close the gender gap in academic medicine that continues to include unequal pay and fewer opportunities for promotion among women. Individual women cannot continue to compensate for the inadequacies of systems. Hospitals and universities of the 21st century must consider how best to support women—and, in truth, not only women but anyone with substantial, time-consuming child care duties or other major family responsibilities—so that they can have sustained, productive academic careers. Dena E. Rifkin, MD, MS University of California, San Diego, and Veterans Affairs Healthcare System San Diego, California Nisha Bansal, MD, MAS Kidney Research Institute, University of Washington Seattle, Washington Esther K. Choo, MD, MPH Brown University Providence, Rhode Island
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0213.
1. Jolly S, Griffith KA, DeCastro R, Stewart A, Ubel P, Jagsi R. Gender differences in time spent on parenting and domestic responsibilities by high-achieving young physician-researchers. Ann Intern Med. 2014;160:344-53. [PMID: 24737273] doi: 10.7326/M13-0974 2. Cooke M, Laine C. A woman physician-researcher’s work is never done [Editorial]. Ann Intern Med. 2014;160:359-60. [PMID: 24737274] doi:10.7326 /M14-0218
IN RESPONSE: We appreciate the insights shared by the authors of
these letters and thank them for providing such rich and vivid examples from women physicians’ lived experiences to complement the data that we presented. We also appreciate the editors’ decision to publish these letters, which reflects their clear commitment to stimulate the sort of healthy discourse and debate that characterize the academic enterprise at its best. We, like the authors of these letters, believe that our findings are a sobering indication of powerful societal constraints on women’s choices even today. However, we are heartened by growing recognition of these issues and institutions’ efforts to support physicians whose careers necessarily develop in this complex social context. Reshma Jagsi, MD, DPhil University of Michigan Ann Arbor, Michigan Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-0974. IN RESPONSE: We regret that Drs. Danoff, Martin, and Rifkin and
colleagues found our editorial disturbing. However, we stand by what we said and think that, in actuality, our positions are not disparate from theirs. We all agree that women in academic medicine struggle to balance work and home, grants and publications remain important (perhaps too important) currency in academic medicine, equal work deserves equal pay, and the number of women in leadership roles should better reflect the number of women in the profession. Further, none of us found Jolly and associates’ findings at all surprising and we all agree that medical academia must consider how best to support physicians to sustain productive academic careers without neglecting their families. In fact, we intended that our editorial promote the development of a portfolio of “radical solutions,” as Dr. Rifkin and colleagues call them, that would go well beyond having more child care at professional meetings. We believe that women in medicine must protect themselves from falling prey to the outdated notion that the only path to a fulfilling, successful career in academic medicine is to do things the way the “old boys” did. Our optimism is fueled by the growing number of female colleagues whom we see carve new paths in academic medicine and institutions that acknowledge the need to support these paths. Navigating a demanding career while nurturing an equally demanding family is not (and never will be) simple—whether a person is male or female, in academic medicine or another field. Successful management of this balancing act will always involve choice, sacri-
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Letters fice, and compromise. As we mentor younger colleagues, we urge them to make the choices that are best for them rather than those that they think others want them to make. As Dr. Martin’s comment illustrates, hearing one’s voice in the midst of various kinds of cultural brainwashing can be difficult.
CORRECTION Correction: Effect of Electronic Health Records on Health Care Costs At the time of publication of “Effect of electronic health records on health care costs: longitudinal comparative evidence from community practices (1),” Dr. Bates did not disclose that he was serving on the board of the nonprofit entity, the Massachusetts eHealth Collaborative. An updated disclosure form reflects this relationship.
Molly Cooke, MD University of California, San Francisco San Francisco, California Christine Laine, MD, MPH Editor in Chief, Annals of Internal Medicine
Reference Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽M14-0218.
ANNALS
OF INTERNAL
1. Adler-Milstein J, Salzberg C, Franz C, Orav EJ, Newhouse JP, Bates DW. Effect of electronic health records on health care costs: longitudinal comparative evidence from community practices. Ann Intern Med. 2013;159:97-104. [PMID: 23856682] doi:10.7326/0003-4819-159-2-201307160-00004
MEDICINE JUNIOR INVESTIGATOR AWARDS
Annals of Internal Medicine and the American College of Physicians recognize excellence among internal medicine trainees and junior investigators with annual awards for original research and scholarly review articles published in Annals in each of the following categories: ● Most outstanding article with a first author in an internal medicine residency program or general medicine or internal medicine subspecialty fellowship program ● Most outstanding article with a first author within 3 years following completion of training in internal medicine or one of its subspecialties Selection of award winners will consider the article’s novelty; methodological rigor; clarity of presentation; and potential to influence practice, policy, or future research. Judges will include Annals Editors and representatives from Annals’ Editorial Board and the American College of Physicians’ Education/Publication Committee. Papers published in the year following submission are eligible for the award in the year of publication. First author status at the time of manuscript submission will determine eligibility. Authors should indicate that they wish to have their papers considered for an award when they submit the manuscript, and they must be able to provide satisfactory documentation of their eligibility if selected for an award. Announcement of awards for a calendar year will occur in January of the subsequent year. We will provide award winners with a framed certificate, a letter documenting the award, and complimentary registration for the American College of Physicians’ annual meeting. Please refer questions to Mary Beth Schaeffer at mschaeffer@acponline .org or visit www.annals.org/public/juniorinvestigatoraward.aspx.
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Annals of Internal Medicine COMMENTS
AND
RESPONSES
2. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165:2671-6. [PMID: 16344427] 3. Bruckert E, Hayem G, Dejager S, Yau C, Be´gaud B. Mild to moderate muscular
N-of-1 (Single-Patient) Trials for Statin-Related Myalgia
symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403-14. [PMID: 16453090]
TO THE EDITOR: In Joy and colleagues’ article (1), placebo and the
4. Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ. The n-of-1 clinical
intervention were each administered for 3 weeks in randomized sequences with intervening 3-week washout periods. However, prior studies suggest that statin-induced myalgia begins within weeks to months of starting therapy, with a mean period of 6 months reported in a review by Hansen and associates (2, 3). In their review, the mean period for resolution of symptoms was 2 months. Therefore, the question that arises is whether the 3-week treatment and intervening washout periods used in this study were long enough for the study participants to develop and resolve, respectively, statin-related myalgia and/or myopathy. Visual analogue scales and a pain inventory were administered once a week during each treatment period. Recall bias thus cannot be excluded, although such bias is likely to be nondifferential for intervention or placebo treatment periods. Future N-of-1 trials may leverage the availability of wireless devices for real-time reporting of symptoms transmitted over secure networks (4). Such real-time reporting can also facilitate the analysis of the data for periodicity of symptoms, such as diurnal variations. Paired t tests were used in the individual-level analysis of each N-of-1 trial. This analytic approach ignores the serial temporal correlation of the reported outcomes, which are likely to be greater between treatment periods that are closer in time (4). In addition, considering that each participant had only 3 paired treatment periods, whether this analysis reasonably satisfied the statistical assumptions that underlie the use of parametric methods was not shown. Intervention, randomization sequence, and results were reported for each patient. However, the baseline characteristics of individual patients were summarized rather than reported at the individual level. Considering that there were only 8 final participants, the presentation of their individual-level baseline characteristics would have facilitated a more robust assessment of the study results vis-a`-vis relating each participant’s baseline characteristics to his or her results. In conclusion, Joy and colleagues have shown the N-of-1 trial method to be a scientifically rigorous and practical approach for individualizing treatment decisions about statin therapy among patients who report statin-related myalgia. Future trials may consider longer treatment and washout periods. They may also use secure wireless technologies for real-time reporting of symptoms.
trial: the ultimate strategy for individualizing medicine? Per Med. 2011;8:161-173.
Oladimeji Akinboro, MD, MPH Linda Williams, MD Daniel Pomerantz, MD, MPH Montefiore New Rochelle Hospital New Rochelle, New York Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0293. References 1. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160:301-10. [PMID: 24737272] doi:10.7326/M13-1921
[PMID: 21695041]
IN RESPONSE: The decision to restrict each treatment exposure and
washout phase to 3 weeks did indeed mean that our N-of-1 trials could not reliably detect statin-related muscle symptoms that took more than 3 weeks to develop and/or resolve. To minimize this circumstance, we chose patients who previously developed myalgia within 3 weeks of starting therapy with a statin and received the same statin in the N-of-1 trial that they associated with myalgia during open-label treatment. We provided our rationale for choosing a 3-week washout period in the article. In Hansen and associates’ review (1), we note that one third of patients reported symptoms within a month of initiating statin therapy. In addition, Cham and coworkers’ study (2) of 354 patients with statin-related muscle symptoms found that myalgia recurred within a median 2 weeks upon statin rechallenge. We believe that our N-of-1 trials reliably assessed possible statin-related myalgia in patients with a shorter history of symptoms. As Akinboro and colleagues suggest, we cannot generalize our findings to patients with a longer history of symptoms. However, we doubt that N-of-1 trials for patients with possible statin-related myalgia that develops or resolves more than 3 weeks after starting or stopping therapy with a statin will be practicable. Parenthetically and on the basis of the few N-of-1 trials that we did, we wonder whether previous cohort studies of patients receiving open-label statin treatment have overestimated the incidence of myalgia that is truly caused by statins and the time needed for resolution. We agree with Akinboro and colleagues that our N-of-1 trials raise the potential for recall bias but that, more important, such bias was equally applicable to placebo and active treatment periods. We also agree that secure wireless technologies for real-time reporting of symptoms are attractive and worth exploring in the context of these trials. We used the paired t test to analyze data from each N-of-1 trial on the basis of published guidelines (3). The assumptions underlying the t test may not be strictly satisfied in our case, but the test is well-known to be robust to violation of assumptions (4). We also note that use of nonparametric tests would yield even less-significant P values than those we obtained by using the t test, thereby providing stronger evidence for our conclusion. The Table shows individual baseline characteristics for patients who completed the N-of-1 trials. Tisha R. Joy, MD Schulich School of Medicine and Dentistry, Western University London, Ontario, Canada Guang Yong Zou, PhD Robarts Research Institute, Western University London, Ontario, Canada © 2014 American College of Physicians 531
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Letters Table. Baseline Characteristics Patient Number
Age, y
Sex
VAS Myalgia Score, mm*
Symptom-Specific VAS Score, mm*
PSS†
PIS†
1 2 3 4 5 6 7 8
56 76 65 62 71 62 78 62
Female Female Female Male Female Female Female Female
0 36 12 2 29 18 12 0
0 37 10 13 0 0 6 0
1.75 4.25 2.00 2.00 4.75 3.00 2.00 3.25
0.00 3.28 1.28 1.29 2.71 2.29 0.00 8.71
PIS ⫽ pain interference score; PSS ⫽ pain severity score; VAS ⫽ visual analogue scale. * The VAS scores range from 0 to 100 mm, with higher scores indicating worse pain or symptomatology. † The PSS and PIS range from 0 to 10, with higher scores indicating worse pain and pain interference, respectively.
Jeffrey L. Mahon, MD, MSc Schulich School of Medicine and Dentistry and Robarts Research Institute, Western University London, Ontario, Canada Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-1921. References 1. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165:2671-6. [PMID: 16344427] 2. Cham S, Evans MA, Denenberg JO, Golomb BA. Statin-associated muscle-related adverse effects: a case series of 354 patients. Pharmacotherapy. 2010;30:541-53. [PMID: 20500044] doi:10.1592/phco.30.6.541 3. Guyatt G, Sackett D, Adachi J, Roberts R, Chong J, Rosenbloom D, et al. A clinician’s guide for conducting randomized trials in individual patients. CMAJ. 1988; 139:497-503. [PMID: 3409138] 4. Heeren T, D’Agostino R. Robustness of the two independent samples t-test when applied to ordinal scaled data. Stat Med. 1987;6:79-90. [PMID: 3576020]
Raising the Bar for the U.S. Preventive Services Task Force TO THE EDITOR: We read Bach’s editorial (1) with great interest.
The U.S. Preventive Services Task Force recommendation on lung cancer screening represents a major synthesis of trial evidence, model-based outcomes, and expert judgment to quantify the tradeoffs of computed tomography screening for the millions of persons at high risk for lung cancer (2, 3). However, Bach states that the Task Force could have been more cautious about relying on modeling for extrapolation well beyond the empirical data to fill in gaps in the evidence (1). Bach questions the net benefit of screening annually over many years. Does he mean that evidence suggests screening 3 times, as was done in NLST (National Lung Screening Trial)? Does he mean that women should receive only 5 breast cancer screenings, because this was the average number in the breast screening trials? Randomized trials are designed to prove the efficacy of an intervention. In translating that evidence to public health, much more is needed— especially to estimate the long-term benefits and harms for the target population. In fact, many would argue that modeling is
essential to translate evidence from trials to population guidelines (4), particularly as we face an ever-increasing pace of technology where questions far exceed our ability to do multiple trials. Our model-based analyses (3) required a joint consideration of many factors, including dose response to smoking and age-specific incidence and death from other causes according to smoking behavior and birth cohort. These factors were superimposed onto more than 1000 schedules of screening examinations using NLST as a guide, something too complex to evaluate without the aid of a model. However, Bach states that we were unable to generate models that parallel the natural history of lung cancer and that our models produced inconsistent mortality benefits in reproducing the early years of NLST. That model variability would produce results that differ in the early years when event rates were low and great variation should not be surprising. Even data monitoring committees place low value on the early years. Bach also points out that the models differed in their predictions of the absolute number of cases of lung cancer and lung cancer deaths prevented. Absolute counts naturally vary considerably and are more difficult to estimate accurately. However, in the ranking of competing scenarios, all 5 models place the 27 scenarios consistently. Moreover, the models reproduce the outcomes observed in the trials (5), and we showed the range of absolute effects in the table on harms and benefits of the advantageous scenario. At the end of the editorial, Bach mentions the term “sharpshooter.” Although this example is dismaying, the analogue is striking. With the models, we indeed draw the target around the greatest cluster of data: On the basis of 200 000 persons enrolled in the screening trials, we can best estimate the screen-detectable preclinical period, test sensitivity, and improvements in prognosis made by screening and early treatment according to sex, age, and histologic characteristics. We therefore hope that clinical researchers will engage more closely with modelers and contribute to deliberations about the best use of models with a deeper understanding of the their development and validation processes. Harry J. de Koning, MD Erasmus Medical Center Rotterdam, the Netherlands Rafael Meza, PhD University of Michigan Ann Arbor, Michigan Sylvia K. Plevritis, PhD NCI Stanford Center for Cancer Systems Biology, Stanford University Stanford, California Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-2316.
References 1. Bach PB. Raising the bar for the U.S. Preventive Services Task Force [Editorial]. Ann Intern Med. 2014;160:365-6. [PMID: 24379087] doi:10.7326/M13-2926 2. Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014; 160:330-8. [PMID: 24378917] doi:10.7326/M13-2771
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Letters 3. de Koning HJ, Meza R, Plevritis SK, ten Haaf K, Munshi VN, Jeon J, et al. Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force. Ann Intern Med. 2014; 160:311-20. [PMID: 24379002] doi:10.7326/M13-2316
Ann Danoff, MD Veterans Affairs New York Harbor Healthcare System and New York University School of Medicine New York, New York
4. Heijnsdijk EA, Wever EM, Auvinen A, Hugosson J, Ciatto S, Nelen V, et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med. 2012;367: 595-605. [PMID: 22894572] doi:10.1056/NEJMoa1201637 5. Meza R, ten Haaf K, Kong CY, Erdogan A, Black WC, Tammemagi MC, et al.
Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0211.
Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials. Cancer. 2014;120:1713-24. [PMID: 24577803] doi:10.1002/cncr.28623
Gender Differences in Time Spent on Parenting and Domestic Responsibilities TO THE EDITOR: As a baby boomer and former K08 awardee who leaked out of the academic pipeline (1) long ago, Jolly and colleagues’ grim observations (2) about ongoing challenges among “Generation X” women to achieve gender equity in academic medical centers and on the home front are disheartening. However, the authors’ efforts to illuminate these unresolved issues and offer a glimmer of hope that one day we may find creative solutions so that women are retained as productive and successful investigators if they wish to be is reassuring. In contrast, I found Cooke and Laine’s editorial (3) deeply disturbing. Although the editorialists acknowledge that “continued differences in standards are inexcusable,” they are much too quick to attribute ongoing gender inequity to “preferences” and “choices” made by women aiming to achieve work–life “balance.” As Jolly and colleagues show (2), these choices are strongly influenced by work and home environments. To deemphasize the experience afforded women in academic medical centers (4) or the effect of the “second shift” (5) on career decisions does a great disservice to the individual women involved. Examples of women not being heard or credited for efforts at work and of pay inequity are commonplace among women in medicine. Also commonplace are descriptions of how a husband “helps” with the child care, followed in the next breath by the acknowledgment that it is still the wife’s job to keep track of the supermarket list and soccer game schedule and gently remind her partner to please pick up the milk. I cannot agree more with Cooke and Laine that I have been personally blessed with a rich and varied professional career. However, I (arguably) took this path by neither choice nor personal failings but rather because the deck was stacked against me. It is regrettable that, like the women of my generation, female members of Generation X must still contend with “accumulated disadvantages” (the converse of “accumulated advantages” described by Gladwell [6]). It seems that we still have an awful lot of work to do. Until all doors are fully opened for each and every one of us (women, men, and persons of all colors and every sexual orientation) and each of us has an equal opportunity for real choice about where on the bus (or in the medical community) we wish to sit, we will all continue to be shortchanged as individuals and as a society. www.annals.org
References 1. Justice AC. Leaky pipes, Faustian dilemmas, and a room of one’s own: can we build a more flexible pipeline to academic success? [Editorial]. Ann Intern Med. 2009;151: 818-9. [PMID: 19949149] doi:10.7326/0003-4819-151-11-200912010-00013 2. Jolly S, Griffith KA, DeCastro R, Stewart A, Ubel P, Jagsi R. Gender differences in time spent on parenting and domestic responsibilities by high-achieving young physician-researchers. Ann Intern Med. 2014;160:344-53. [PMID: 24737273] doi: 10.7326/M13-0974 3. Cooke M, Laine C. A woman physician-researcher’s work is never done [Editorial]. Ann Intern Med. 2014;160:359-60. [PMID: 24737274] doi:10.7326/M14-0218 4. Levine RB, Lin F, Kern DE, Wright SM, Carrese J. Stories from early-career women physicians who have left academic medicine: a qualitative study at a single institution. Acad Med. 2011;86:752-8. [PMID: 21512363] doi:10.1097/ACM .0b013e318217e83b 5. Hochschild AR, Machung A. The Second Shift. New York: Viking Penguin; 1989. 6. Gladwell M. Outliers: The Story of Success. New York: Little, Brown; 2008.
TO THE EDITOR: Perhaps Jolly and colleagues (1) did not conclude
that the observed differences in parenting were due to simple choice—as Cooke and Laine (2) did— because women, like men, make choices within a social context. Dr. Bennett, former Chief of Pediatrics at Harvard Community Health Plan, added a postscript to a “lighthearted” career article included in an anthology in 2002 that states, “In 1961, I was the brainwashed product of my culture’s view of woman’s place in society” (3). At the time, she believed that she was choosing to take primary responsibility at home. However, looking back, she saw how society’s definition of a good wife and mother constrained that choice. That 85.6% of the spouses of women physicians in Jolly and colleagues’ study were employed full-time, whereas only 44.9% of the spouses of their male colleagues were, underlines the enduring strength of traditional gender roles. Although successful, Dr. Bennett emphatically advocated for her younger colleagues. A woman doctor “should be able to experience the joys and responsibilities of marriage and parenthood equally with her male colleague— but not more equally.” Toni Martin, MD Berkeley, California Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0212.
References 1. Jolly S, Griffith KA, DeCastro R, Stewart A, Ubel P, Jagsi R. Gender differences in time spent on parenting and domestic responsibilities by high-achieving young physician-researchers. Ann Intern Med. 2014;160:344-53. [PMID: 24737273] doi: 10.7326/M13-0974 7 October 2014 Annals of Internal Medicine Volume 161 • Number 7 533
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Letters 2. Cooke M, Laine C. A woman physician-researcher’s work is never done [Editorial]. Ann Intern Med. 2014;160:359-60. [PMID: 24737274] doi:10.7326/M14-0218 3. Bennett DR. Postscript. In: Chin EL, ed. This Side of Doctoring: Reflections from Women in Medicine. Thousand Oaks, CA: Sage; 2002:31-2.
Disclosures: Authors have disclosed no conflicts of interest. Forms can
TO THE EDITOR: We read Jolly and colleagues’ article (1) with great
References
interest. As current National Institutes of Health career development awardees who are also mothers with employed spouses, we were not shocked to learn that women of our generation continue to bear a disproportionate burden of domestic work compared with men and that women with children devote less time to research than their male counterparts (with a gap that is roughly equal to the extra time spent doing domestic work). What did shock us were the conclusions drawn by Cooke and Laine (2). They state that the “true measure of a successful life in academic medicine . . . may no longer be measured in grants garnered, papers published, or salary attained but rather in the flexibility to balance” other life goals. At our institutions, grants and papers are the sine qua non of a research-based academic career and promotion from the junior faculty state. To paraphrase Vince Lombardi, grants and papers aren’t everything—they are the only thing. Although other career trajectories are now open in the world of academic medicine, the primarily research-funded academician still needs to produce publications and acquire independent funding to continue in that role and to advance up the academic ladder, regardless of sex. We have each benefited from excellent mentors, both male and female, during our time as career development awardees. The advice that we hear from these mentors is clear: Moving from a K grant to an independently funded research career is challenging and needs to be accomplished during the 5-year K grant timeline. This transition is where many women researchers falter in the academic track by either switching to a different track or not obtaining funding. Not coincidentally, this timeline overlaps with a period during which child rearing is a distraction, albeit an enjoyable and rewarding one. More radical solutions than a paean to “balance” are needed to close the gender gap in academic medicine that continues to include unequal pay and fewer opportunities for promotion among women. Individual women cannot continue to compensate for the inadequacies of systems. Hospitals and universities of the 21st century must consider how best to support women—and, in truth, not only women but anyone with substantial, time-consuming child care duties or other major family responsibilities—so that they can have sustained, productive academic careers. Dena E. Rifkin, MD, MS University of California, San Diego, and Veterans Affairs Healthcare System San Diego, California Nisha Bansal, MD, MAS Kidney Research Institute, University of Washington Seattle, Washington Esther K. Choo, MD, MPH Brown University Providence, Rhode Island
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0213.
1. Jolly S, Griffith KA, DeCastro R, Stewart A, Ubel P, Jagsi R. Gender differences in time spent on parenting and domestic responsibilities by high-achieving young physician-researchers. Ann Intern Med. 2014;160:344-53. [PMID: 24737273] doi: 10.7326/M13-0974 2. Cooke M, Laine C. A woman physician-researcher’s work is never done [Editorial]. Ann Intern Med. 2014;160:359-60. [PMID: 24737274] doi:10.7326 /M14-0218
IN RESPONSE: We appreciate the insights shared by the authors of
these letters and thank them for providing such rich and vivid examples from women physicians’ lived experiences to complement the data that we presented. We also appreciate the editors’ decision to publish these letters, which reflects their clear commitment to stimulate the sort of healthy discourse and debate that characterize the academic enterprise at its best. We, like the authors of these letters, believe that our findings are a sobering indication of powerful societal constraints on women’s choices even today. However, we are heartened by growing recognition of these issues and institutions’ efforts to support physicians whose careers necessarily develop in this complex social context. Reshma Jagsi, MD, DPhil University of Michigan Ann Arbor, Michigan Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-0974. IN RESPONSE: We regret that Drs. Danoff, Martin, and Rifkin and
colleagues found our editorial disturbing. However, we stand by what we said and think that, in actuality, our positions are not disparate from theirs. We all agree that women in academic medicine struggle to balance work and home, grants and publications remain important (perhaps too important) currency in academic medicine, equal work deserves equal pay, and the number of women in leadership roles should better reflect the number of women in the profession. Further, none of us found Jolly and associates’ findings at all surprising and we all agree that medical academia must consider how best to support physicians to sustain productive academic careers without neglecting their families. In fact, we intended that our editorial promote the development of a portfolio of “radical solutions,” as Dr. Rifkin and colleagues call them, that would go well beyond having more child care at professional meetings. We believe that women in medicine must protect themselves from falling prey to the outdated notion that the only path to a fulfilling, successful career in academic medicine is to do things the way the “old boys” did. Our optimism is fueled by the growing number of female colleagues whom we see carve new paths in academic medicine and institutions that acknowledge the need to support these paths. Navigating a demanding career while nurturing an equally demanding family is not (and never will be) simple—whether a person is male or female, in academic medicine or another field. Successful management of this balancing act will always involve choice, sacri-
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Letters fice, and compromise. As we mentor younger colleagues, we urge them to make the choices that are best for them rather than those that they think others want them to make. As Dr. Martin’s comment illustrates, hearing one’s voice in the midst of various kinds of cultural brainwashing can be difficult.
CORRECTION Correction: Effect of Electronic Health Records on Health Care Costs At the time of publication of “Effect of electronic health records on health care costs: longitudinal comparative evidence from community practices (1),” Dr. Bates did not disclose that he was serving on the board of the nonprofit entity, the Massachusetts eHealth Collaborative. An updated disclosure form reflects this relationship.
Molly Cooke, MD University of California, San Francisco San Francisco, California Christine Laine, MD, MPH Editor in Chief, Annals of Internal Medicine
Reference Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽M14-0218.
ANNALS
OF INTERNAL
1. Adler-Milstein J, Salzberg C, Franz C, Orav EJ, Newhouse JP, Bates DW. Effect of electronic health records on health care costs: longitudinal comparative evidence from community practices. Ann Intern Med. 2013;159:97-104. [PMID: 23856682] doi:10.7326/0003-4819-159-2-201307160-00004
MEDICINE JUNIOR INVESTIGATOR AWARDS
Annals of Internal Medicine and the American College of Physicians recognize excellence among internal medicine trainees and junior investigators with annual awards for original research and scholarly review articles published in Annals in each of the following categories: ● Most outstanding article with a first author in an internal medicine residency program or general medicine or internal medicine subspecialty fellowship program ● Most outstanding article with a first author within 3 years following completion of training in internal medicine or one of its subspecialties Selection of award winners will consider the article’s novelty; methodological rigor; clarity of presentation; and potential to influence practice, policy, or future research. Judges will include Annals Editors and representatives from Annals’ Editorial Board and the American College of Physicians’ Education/Publication Committee. Papers published in the year following submission are eligible for the award in the year of publication. First author status at the time of manuscript submission will determine eligibility. Authors should indicate that they wish to have their papers considered for an award when they submit the manuscript, and they must be able to provide satisfactory documentation of their eligibility if selected for an award. Announcement of awards for a calendar year will occur in January of the subsequent year. We will provide award winners with a framed certificate, a letter documenting the award, and complimentary registration for the American College of Physicians’ annual meeting. Please refer questions to Mary Beth Schaeffer at mschaeffer@acponline .org or visit www.annals.org/public/juniorinvestigatoraward.aspx.
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