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New Manuscripts

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interested in publishing original research that is destined to change clinical practice and teaches

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Aut hor Perm issions

son1ething new about the biology of disease. In addition to original research, NEJM publishes reviews,

cases, conuuentary, and other content that is of interest to n1edical professionals.

The dedication of generations of researchers, authors, reviewers, and physician editors has 111ade NEJM the

111ost widely read and respected n1edical journal and website in the world.

Sttb1nitti11g to NEJM

NEJM uses highly rigorous editorial, peer, and statistical review processes to evaluate 111anuscripts for

scientific accuracy, novelty, and ilnportance.

Step 1: Acquaint yourself with NEJM Editorial Policies, Article Types, Presub111ission Options for

Presub111ission Inquiry and Rapid Review, Statistical Reporting Guidelines (if applicable), and key

NEJM Style Elen1ents

Step 2: Prepare Materials for Sub111ission including cover letter (optional), niain text, tables,

figures , supple111entary appendix, clinical trial protocol and statistical analysis plan (if applicable)

Step 3: Sub1nit your nianuscript by clicking on the red button at the top left hand side of this page.

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Presubmission Options

Most NEJM article types are both solicited (invited by NEJM editors) and unsolicited (subnJ.itted at author

discretion via the NEJM online 111anuscript sub111ission syste111).

PRES U BMISSION I NQ UI RY

Authors unsure of the suitability of their 1nanuscript for publication n1ay save considerable ti1ne and effort

by sending a Presubrnission Inquiry to which NEJM editors will endeavor to respond by e1nail within one

(1) week.

INVITED/COMM I SSION ED ART ICLES

Certain article types, including reviews and editorials, are usually solicited by NEJM editors in advance of

subnJ.ission. However, authors interested in proposing ideas for these article types niay also send

Presub111ission Inquiries.

RAPI D REVI EW

NEJM will consider requests for accelerated 111anuscript Rapid Review, especially when research results:

• Deal with urgent public health concerns

• Have potential to dran1atically change clinical practice or to affect n1ortality

• Are ti111ed to inuninent 111eeting presentations

Approval for Rapid Review does not guarantee acceptance of the 1nanuscript, nor does it guarantee

expedited publication ifthe 111anuscript is accepted. Each of these decisions is 1nade separately. NEJM strives to reply to Rapid Reviev.r requests within three (3) business days.

Statistical Reporting Guidelines

Our Statistical Consultants reconunend the following best statistical practices in 1nanuscripts sub1nitted

to the journal. We reconunend that you follow then1 in the design and reporting of research studies.

For all studies:

• The Methods section of all n1anuscripts should contain a brief description of sa1nple size and power considerations for the study, as well as a brief description of the n1ethods for pri1nary and secondary

analyses.

• The Methods section of all n1anuscripts should include a description of how n1issing data have been

handled. Unless n1issingness is rare, a con1plete case analysis is generally not acceptable as the pri1nary analysis and should be replaced by n1ethods that are appropriate, given the n1issingness 111echanisni.

Multiple in1putation or inverse probability case weights can be used when data are n1issing at randon1;

111odel-based n1ethods 111ay be n1ore appropriate v.rhen n1issingness 111ay be infonnative. For the journal's

general approach to the handling of 111issing data in clinical trials please see Ware et al (N Engl J Med

2012;367:1353-1354 ).

• Significance tests should be acco111panied by confidence intervals for estilnated effect sizes, n1easures of

association, or other para111eters of interest. The confidence intervals should be adjusted to 1natch any

adjust111ent n1ade to significance levels in the corresponding test.

• Unless one-sided tests are required by study design, such as in noninferiority clinical trials, all reported P

values should be two-sided. In general, P values larger than 0.01 should be reported to two decitnal places,

and those between 0.01and0.001 to three decitnal places; Pvalues sn1aller than 0.001 should be reported

as P<0.001. Notable exceptions to this policy include P values arising fro111 tests associated with stopping

rules in clinical trials or fro1n geno1ne-wide association studies.

• Results should be presented with no n1ore precision than is of scientific value and is n1eaningful given the

available san1ple size. For exan1ple, 111easures of association, such as odds ratios, should ordinarily be

reported to two significant digits. Results derived fron1 n1odels should be li1nited to the appropriate

nun1ber of significant digits.

For clinical trials:

• Original and final protocols and statistical analysis plans (SAPs) should be subn1itted along with the

n1anuscript, as well as a table ofan1endn1ents n1ade to the protocol and SAP indicating the date of the

change and its content.

• The analyses of the prilnary outcon1e in n1anuscripts reporting results of clinical trials should n1atch the

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analyses prespecified in the original protocol, except in unusual circu111stances. Analyses that do not

confonu to the protocol should be justified in the Methods section of the n1anuscript. The editors 111ay ask

for additional analyses that are not specified in the protocol.

• When co111paring outco1nes in two or 111ore groups in confinnatory analyses, investigators should use the testing procedures specified in the protocol and SAP to control overall type I error - for exan1ple,

Bonferroni adjusunents or prespecified hierarchical procedures. P values adjusted for n1ultiplicity should

be reported when appropriate and labeled as such in the 1nanuscript. In hierarchical testing procedures, P

values should be reported only until the last con1parison for which the P value was statistically significant.

P values for the first nonsignificant con1parison and for all con1parisons thereafter should not be reported.

For prespecified exploratory analyses, investigators should use 111ethods for controlling false discovery rate

described in the SAP - for exa111ple, Benja1nini- Hochberg procedures.

• When no n1ethod to adjust for 111ultiplicity of inferences or controlling false discovery rate was specified in

the protocol or SAP of a clinical trial, the report of all secondary and exploratory endpoints should be li1nited to point estilnates oftreaunent effects with 95°/o confidence intervals. In such cases, the Methods

section should note that the widths of the intervals have not been adjusted for 111ultiplicity and that the

inferences drawn 1nay not be reproducible. No P values should be reported for these analyses.

• Please see Wang et al (N Engl J Med 2007;357:2189- 2194) on reconunended n1ethods for analyzing subgroups. When the SAP prespecifies an analysis of certain subgroups, that analysis should confonn to

the n1ethod described in the SAP. If the study tean1 believes a post hoc analysis of subgroups is ilnportant,

the rationale for conducting that analysis should be stated. Post hoc analyses should be clearly labeled as

post hoc in the 111anuscript .

x . . •

• Forest plots are often used to present results fro111 an analysis of the consistency of a treat111ent effect

across subgroups of factors of interest. Such plots can be a useful display of estitnated treatn1ent effects

across subgroups, and the editors reco1111nend that they be included for in1portant subgroups. If subgroups are s111all, however, fonnal inferences about the ho1nogeneity oftreatn1ent effects 1nay not be

feasible . A list of P values for treattnent by subgroup interactions is subject to the proble111s of111ultiplicity

and has li111ited value for inference. Therefore, in 1nost cases, no P values for interaction should be

provided in the forest plots.

• If significance tests of safety outcon1es (when not pri1nary outco1nes) are reported along with the treat111ent-specific estitnates, no adjusunent for n1ultiplicity is necessary. Because infonnation contained

in the safety endpoints 111ay signal problen1s within specific organ classes, the editors believe that the type

I error rates larger than 0.05 are acceptable. Editors 111ay request that P values be reported for con1parisons

of the frequency of adverse events a111ong treaunent groups, regardless of whether such con1parisons were

prespecified in the SAP.

• When possible, the editors prefer that absolute event counts or rates be reported before relative risks or hazard ratios. The goal is to provide the reader \¥ith both the actual event frequency and the relative

frequency. Odds ratios should be avoided, as they niay overestin1ate the relative risks in niany settings and

be niisinterpreted.

• Authors should provide a flow diagra111 in CONSORT fonnat. The editors also encourage authors to sub111it

all the relevant infonnation included in the CONSORT checklist. Although all of this infonnation 111ay not be published with the nianuscript, it should be provided in either the nianuscript or a supple111entary

appendix at the tin1e of sub111ission. The CONSORT state1nent, checklist, and flow diagran1 are available

on the CONSORT website.

For observational studies:

The validity of findings fron1 observational studies depends on several in1portant assu111ptions, including

those relating to sa111ple selection, nieasured and un111easured confounding, and the adequacy of 111ethods

used to control for confounding. The Methods section of observational studies should describe how these and other relevant issues were managed in the design and analysis.

• If an observational study included a prespecified SAP with a description of hypotheses to be tested, a

signed and dated version of that plan should be included \Vith the 111anuscript submission. The journal

encourages authors to deposit SAPs for observational studies in one of the online repositories designed for this purpose.

• When appropriate, observational studies should use prespecified accepted 111ethods for controlling fa1nily­

wise error rate or false discovery rate when niultiple tests are conducted. In 111anuscripts reporting

observational studies without a prespecified niethod for error control, su111111ary statistics should be

li111ited to point esti111ates and 95°/o confidence intervals. In such cases, the Methods section should note

that the widths of the intervals have not been adjusted for niultiplicity and that the inferences drawn fro111

the inferences niay not be reproducible. No P values should be reported for these analyses.

• If no prespecified analysis plan exists, the Methods section should provide an outline for the planned 1nethod of analysis, including

o Eligibility criteria for the selection of cases and 1nethod of sa111pling fro111 the data, with a diagran1 as

appropriate. o A description of the association or causal effect to be estin1ated and the rationale for this choice.

o The prespecified niethod of analysis to draw inference about treat1nent or exposure effect or

association.

• Studies reporting the effect of a treatinent or exposure should show the distribution of potential confounders and other variables, stratified by exposure or intervention group. When the analysis depends

on the confounders being balanced by exposure group, differences between groups should be sununarized

with point estin1ates and 95°/o confidence intervals when appropriate.

• Con1plex niodels and their diagnostics can often be best described in a supplen1entary appendix. Authors are encouraged to conduct an analysis that quantifies potential sensitivity to bias fron1 unn1easured

confounding; absent that, authors 111ust provide a discussion of potential biases induced by unn1easured

confounders.

• Authors are encouraged to retest findings in a sin1ilar but independent study or studies to assess the

robustness of their findings.

Key Journal Style Elements

U N ITS O F M EASUREM ENT

Authors should express all n1easuren1ents in conventional units, with Systen1e International (SI) units

U NITS OF MEASUREMEN T

Authors should express all nieasure1nents in conventional units, with Syste1ne International (SI) units

given in parentheses throughout the text. Figures and tables should use conventional units, with

conversion factors given in legends or footnotes. In accordance with the Unifonn Requiren1ents, however,

1nanuscripts containing only SI units will not be returned for that reason.

ABBREV IATIONS

Except for units ofn1easure1nent, abbreviations are strongly discouraged; the first titne an abbreviation

appears, it should be preceded by the words for which it stands.

DRUG NAMES

Generic na111es should be used. When proprietary brands are used in research, include the brand na1ne

and the na1ne of the 111anufacturer in parentheses after the first 1nention of the generic na111e in the

Methods section.

Prepare Materials for Submission

COVER L ETTER

Though cover letters are not required, the NEJM online subnlission syste111 contains a text field through

which itnportant infonnation that is not in the nietadata, such as a 1neeting presentation date or a 111ajor

conflict of interest not in the nianuscript, should be conununicated with initial 111anuscript sub1nissions.

MAN USCRIPT TEXT FILE

Con1pile all text, references, figure legends, and tables into a single double-spaced digital file (preferably

an MS Word docu111ent). NEJM will also accept text (.txt), or Rich Text Fonnat (.rtf) files.

TITLE PAGE

Create a title page that includes:

• Manuscript title

• Each author's name, highest degree, and affiliation/institution

• Contact information for one (1) corresponding author

ABSTRACT

Provide an abstract of not niore than 250 words with four labeled paragraphs containing the follo\ving:

• Background: Problen1 being addressed in the study

• Methods: How the study was perfor111ed

• Results: Salient results

• Conclusions: What the authors conclude fron1 study results

• Trial registration nun1ber

IDE NTIFYI NG DATA

At appropriate places in the 1nanuscrip t , please provide the following ite1ns:

• If applicable, a state1nent that the research protocol was approved by relevant institutional review boards

or ethics conunittees and that all hu111an participants gave written infonned consent

• Identities of those who analyzed the data ~~~~~~~~~~~~~~~~~~~~-

• For clinical trials, registration ntnnber and registry na111e (see: N EnglJ Med 2004;351:1J50cl)

• For studies containing n1icroarrays, accession ntunbers and repository na111e

RE FE RENCES

References n1ust be double-spaced and ntunbered consecutively as they are cited. References first cited in a

table or figure legend should be nu111bered so they will be in sequence with references cited in the text at the

point where the table or figure is first 1nentioned. List all citation authors when there are six or fewer; \Vhen

there are seven or 1nore, list the first three, followed by et al. The following are san1ple references:

1. Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes n1ellitus

using a glucocorticoid-free inununosuppressive regi111en. N Engl J Med 2000;343:230-8.

2. Goadsby PJ. Pathophysiology of headache. In: Silberstein SD, Lipton RB, Dalessio DJ, eds. Wolff 's

headache and other head pain. 7th ed. Oxford, England: Oxford University Press, 2001:57-72.

3. IZucz111arski RJ, Ogden CL, Granuner-Strawn LM, et al. CDC growth charts: United States. Advance data

fro111 vital and health statistics. No. 314. Hyattsville, Md.: National Center for Health Statistics, 2000.

(DHHS publication no. (PHS) 2000-1250 0 -0431.)

4. Medicare: trends in fees, utilization, and expenditures for iinaging services before and after

iluple111entation of the Deficit Reduction Act of2005. Washington, DC: Govern1nent Accountability

Office, Septe111ber 2008. (http://www.gao.gov/new.ite1ns/d081102r. pdf.)

Ntnubered references to personal conununications, unpublished data, or nianuscripts either "in

preparation" or "sub111itted for publication" are unacceptable. If essential, such n1aterials can be

incorporated at appropriate places in the text.

TABLES

All tables should be included at the end of the 1nanuscript text file . Double-space tables (including

footnotes) and provide a title for each table. For Original Articles, there is nonnally a litnit of five (5)

figures and tables (total) per 1nanuscript. Extensive tables or supplernentary n1aterials will be published as

supple1nental 1uaterials \¥ith the digital version of the article.

Figu res and Ill ustrations

Authors can either insert figures into text files (preferred) or upload figure files separately. Low-resolution

itnages n1ay be subtnitted for peer review, but be aware that NEJM 1nay, at a later stage, request high­

resolution versions that con1ply fully with detailed Technical Guidelines for Figures.

Supplementary Appendix

A 1nanuscript's Supple1uentary Appendix should be paginated, with a table of contents, followed by a list

of investigators (if there is one) , text (such as n1ethods), figures, tables, and then references. Reference

citations in the Appendix and the corresponding list of references should be self-contained with respect to

the Appendix. The Appendix 1nust be subrnitted in two fonnats: PDF and MS Word (or another editable

text fonnat). The Appendix will not be edited for style and \¥ill be presented online as additional

infonnation provided by the authors.

Supplementary Figures and Tables

For outco111e scales, provide in the figure legend or table footnotes the range, sign, and 1ninitually

itnportant difference (ifknown). There n1ust be an infonnative reference citation for the scale. Each figure

should include a title and a legend, which should appear on the san1e page as the figure itself. Tables in the

Supplen1entary Appendix should be labeled Table Sl, Table S2, etc. Each table should be acco111panied by a

title and, if necessary, footnotes.

Trial Protocol and Statistical Analysis Plan (SAP)

Please include a clinical trial's protocol and statistical analysis plan with the sub111ission. The protocol 111ay

be redacted of proprietary infonnation, but nutst include infonnation on the patient flow and outcon1es.

Journal editors 1nay ask for n1ore infor111ation on redacted protocols.

SUBM IT TO NEJM

Click the button below to log in to the NEJM online subn1ission systen1 (ScholarOne Manuscripts) to sub1nit a new 111anuscript. Once logged in, select Start New Sub111ission and follow the

instructions appearing on subsequent screens.

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