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Abstract. Background Neutrophil-to-lymphocyte ratio (NLR) has proven its prognostic value in cardiovascular diseases, infections, inflammatory diseases and in several types of cancers. However, no cut-off has been proposed on the basis of reference values coming from healthy population. Methods Routine blood samples were obtained (n = 413) from workers (age: median 38, range: 21–66 years) involved in a health care prevention program, to determine means, standard deviations (SDs), 95% confidence intervals (95% CI), percentiles P2.5 and P97.5. A second independent sample of healthy volunteers is compared (n = 29). Results The mean NLR is 1.65 [±1.96 SD: 0.78–3.53] (95% CI [0.75–0.81] and [3.40–3.66]). In the second cohort (healthy control), the NLR values are in the same range, whichever the used analyzer. No NLR assessed in the validation series is out of the proposed limits. Conclusions We have identified that the normal NLR values in an adult, non-geriatric, population in good health are between 0.78 and 3.53. These data will help to define the normal values of the NLR. Electronic supplementary material The online version of this article (doi:10.1186/s13104-016-2335-5) contains supplementary material, which is available to authorized users. Background phenomenonconcepts↗concepts↗concept_edgesNeutrophil-to-lymphocyte ratio (NLR) is a simple parameter to assess easily the inflammatory status of a subject. It has proven its usefulness in the stratification of mortality in major cardiac events [ 1 , 2 ], as a strong prognostic factor in several types of cancers [ 3 – 10 ], or as a predictor and a marker of inflammatory or infectious pathologies (such is pediatric appendicitis) and postoperative complications [ 11 , 12 ]. object_of_studymechanismsconcepts↗content_tagsHowever, which NLR value is correlated with a higher risk for these patients? Which cut-off value, for the NLR, will discriminate normal from abnormal results? Different values of NLR, with different methods, in different populations (cancerous or not) are cited in the literature. And finally, no universal value is currently available. Therefore, there is a need for reference values to progress in the use of this marker. research_questionThe aim of this study is to determine the limits of the values of the NLR that are observed in an adult, non-geriatric population, without any acute illness and/or chronic debilitating disease. Methods Subjects and data collection With the agreement of the Ethical Committee (ref. 2014/451, Chairperson: Prof. Jean-Marie Maloteaux, av. Hippocrate, 55-14, 1200 Brussels), we performed the following analyses. Blood samples for routine control between October 2011 and 2012 were identified from 413 participants of the health care prevention program for workers. Considering the analysis as retrospective, given the fact that the samples were pre-collected and treated anonymously, the Ethical Committee gave a waiver for individual consent. Consequently, no written informed consent for participation in the study was obtained from participants. Median age was 38 years (range: 21–66 years). limitationsconcepts↗content_tagscontent_tags↗Typically, these subjects were in good health, permitting a full time job without restriction, and without any active disease, including cancer and infectious disease and are representative of the population as a whole. limitationscontent_tagsBlood samples were obtained for routine hematologic control in workers potentially exposed to X-rays or any others ionizing radiation. Samples were treated anonymously, including sex and date of birth. No information was therefore available about habits (e.g. tobacco use) and possible comorbidities (e.g. obesity or vascular disease). Normal controls controlssensescontent_tagsOur goal is to identify the higher boundary observed in a population in good health, but not excluding non-debilitating disease, tobacco use or oral contraception. Therefore, it would be important to compare the results to those obtained in a second, and independent, sample (n = 29) of normal controls, strictly selected on the basis of perfect health, coming from an historical cohort. This cohort was used during the process of the calibration of the blood analyser. The subjects in this second cohort were in the same range of age, but, after interrogation and examination, carefully selected on the basis of the absence of any chronic disease or substance/medications (abuse, including tobacco use). Samples analyses content_tagsAnticoagulated whole blood from routine controls were processed on Sysmex XE2100 [TOA Medical Electronics, Kobe, Japan], Normal controls were analysed on Sysmex XN2000 (TOA Medical electronics Co, Kobe, Japan), Advia 2120 (Bayer Diagnostics, Tarritown, NY, USA), DXH800 (Beckman Coulter, Miami, FL USA), Cell-Dyn Sapphire (Abbott Diagnostics Santa Clara, CA, USA) for the determination of the complete blood cell counts and differential counts of leukocytes. concepts↗concepts↗concepts↗sensescontent_tags↗content_tags↗The absolute neutrophil count was divided by the absolute lymphocyte count to calculate the NLR. Statistical analyses method↗controlsconcepts↗content_tagscontent_tagscontent_tags↗content_tags↗For the statistical analyses, laboratory parameters fit a log-normal distribution. Logarithmic conversion was therefore used for calculating means and 95% confidence limits (95% CI) are presented as arithmetic mean ± 1.96 SD (with their 95% CI). Power analysis shows that, to test the hypothesis that <2.5% of the normal controls would be out of the proposed limits, 28 subjects are needed. It is the reason why we included 29 blood samples of the historical cohort for the external validation. All the analyses were performed with STATISTICA (data analysis software system, version 7, Statsoft Inc. 2004, Tulsa). Results limitationscontent_tagscontent_tagsResults coming from the blood samples of the 413 subjects of the main cohort are presented in Table 1 . Briefly, the mean NLR is 1.65 [±1.96 SD: 0.78–3.53] (95% CI [0.75–0.81] and [3.40–3.66]). In the second cohort (healthy control), the NLR values are in the same range, whichever the used analyzer (Table 1 ). Consequently, no NLR assessed in the validation series is out of the proposed limits. Table 1 Neutrophil-to-lymphocyte ratios obtained in two cohort of subjects (n = 413 and n = 29) on five blood analysers, expressed in mean, SD and lower/upper limits of the mean ± 1.96 SD range (and their 95% CI) Mean SD Lower limit 95% CI Upper limit 95% CI Initial cohort (n = 413) Sysmex XE2100 1.65 1.47 0.78 0.75 0.81 3.53 3.40 3.66 Control cohort (n = 29) Beckman DXH800 1.76 1.42 0.89 0.78 1.02 3.49 3.06 3.97 Siemens 2120i 1.86 1.39 0.97 0.86 1.10 3.54 3.13 4.00 Abbott SAPHYR 1.68 1.42 0.85 0.74 0.96 3.32 2.92 3.79 Sysmex XN2000 1.69 1.37 0.91 0.81 1.03 3.12 2.77 3.52 controlscontent_tagsNLR sample stability over 48 h was assessed; there was no significant variation over this time period and the NLR was then considered stable. Discussion limitationscontent_tagscontent_tagsWe show here that the NLR values, in a sample of 413 active subjects in good health, are between 0.78 and 3.58. We confirm that no normal control (selected on the basis of the absence of any comorbidities and substance abuse, including tobacco) exceeded this range. claim_relationscontent_tagsThere are a lot of examples in the literature of the interest of the NLR as an independent prognostic factor of morbidity and mortality in several conditions, such as cancers and cardiovascular diseases. NLR is also useful in the prediction and the detection of inflammatory and infectious conditions, and their postoperative complications [ 11 , 12 ]. mechanismsconcepts↗concepts↗sensesclaim_relationscontent_tagsNevertheless, none of these studies based their cut-off on data coming from population in good health, and none on data coming from normal controls. Some of these studies chose their cut-off value on the basis of the median, higher quartile or values determined by the use of receiver-operating curves (to predict the occurrence of a condition, e.g. cancer recurrence of infection) [ 13 – 15 ]. mechanismscontent_tagsIn contrast with these studies, we found here limits based on a sample of an active adult population in good health. This value can be used as a cut-off to differentiate patients that are in the range of a population in good health or not [ 16 ]. limitationscontrolscontent_tagsCan it be used in other populations that this from which this sample is coming? Age is certainly a limit, as we tested only adult, non-geriatric, subjects (between 21 and 66 years). Additionally, we did not have the complete documentation of substance use/abuse, like tobacco or oral contraceptive. Ethnic group origins, sex and season of assessment have not been included in the analyses. content_tagsHowever, in the sample of normal control, we see that the 95% CI permits to say that it is very improbable that normal controls will have a NLR value of 3.5. Nevertheless, it seems logical to interpret cautiously this type of parameter (like any other), in a clinical context to adjust the interpretation, even if based on data coming from a comparable population (Additional file 1 ). Conclusions contributionclaim_typesensescontent_tags↗content_tagscontent_tagsWe have identified that normal NLR values in an adult, non-geriatric, population in good health are between 0.78 and 3.53. These data may help the researcher as the clinician searching for a cut-off for the NLR, until now lacking.
Relations on this page carry a quotation for the claim. Where a relation was separately evidenced — and so tested against the vocabulary for its type — the row says so; none of 1 relation here carry that mark. The rest are the tagger’s reading of the sentence quoted beside them.
| facet | tag | field | conf. | whose words |
|---|---|---|---|---|
| object_of_study | the neutrophil-to-lymphocyte ratio - A MARKER IN WIDE CLINICAL USE WITH NO REFERENCE RANGE, whose cut-offs had been taken from the diseased populations it was meant to identify | object_of_study | the paper's words | |
| research_question | what values of the NLR occur in an adult, non-geriatric population without acute illness or chronic debilitating disease | research_question | the paper's words | |
| contribution | an upper and lower reference limit for the NLR derived from healthy subjects rather than from patients, with an independent validation cohort | contribution | the paper's words | |
| claim_type | existence | claim_type | the paper's words | |
| phenomenon | a ratio of two routinely-counted cell populations used as an inflammatory index, whose distribution in health had not been described | phenomenon | the paper's words | |
| method | observational-study also in: observational-study | method | the paper's words | |
| mechanisms | THE CUT-OFF WAS DERIVED FROM THE POPULATION IT WAS MEANT TO DISTINGUISH, AND THE PAPER SAYS SO: `none of these studies based their cut-off on data coming from population in good health, and none on data coming from normal controls. Some of these studies chose their cut-off value on the basis of the median, higher quartile or values determined by the use of receiver-operating curves`. A marker whose whole job is separating sick from well, thresholded from the median of the sick | mechanisms[0] | 0.95 | the tagger's words |
| mechanisms | and the field had no single number at all: `Different values of NLR, with different methods, in different populations (cancerous or not) are cited in the literature. And finally, no universal value is currently available`. Three sources of variation named in one sentence - the value, the method and the population | mechanisms[1] | 0.95 | the tagger's words |
| mechanisms | the correction is a change of REFERENCE CLASS, not of statistic: `In contrast with these studies, we found here limits based on a sample of an active adult population in good health`. Same arithmetic, different people, and that is the whole paper | mechanisms[2] | 0.95 | the tagger's words |
| limitations | THE PAPER'S OWN HEADLINE NUMBER IS STATED TWO WAYS. The upper reference limit is the entire contribution, and it appears FIVE TIMES AS 3.53 - abstract, Results, Table 1 and both Conclusions - and ONCE AS 3.58, in the Discussion: `the NLR values, in a sample of 413 active subjects in good health, are between 0.78 and 3.58`. VERIFIED AS THE PUBLISHER'S TEXT, not the pipeline's: `3.58` occurs once in the source XML and `3.53` five times, same file, same renderer | limitations[0] | 0.95 | the tagger's words |
| limitations | AND `HEALTHY` IS DEFINED BY WHAT WAS NOT RECORDED: the samples come from `workers potentially exposed to X-rays or any others ionizing radiation`, anonymised such that `No information was therefore available about habits (e.g. tobacco use) and possible comorbidities (e.g. obesity or vascular disease)`. The reference class for normal is `held a full-time job and nothing was written down` | limitations[1] | 0.95 | the tagger's words |
| limitations | and health is operationalised as EMPLOYABILITY: `these subjects were in good health, permitting a full time job without restriction, and without any active disease ... and are representative of the population as a whole` - a representativeness claim made for a working-age, occupationally-screened sample | limitations[2] | 0.95 | the tagger's words |
| limitations | the paper lists what its own range cannot cover: `Age is certainly a limit, as we tested only adult, non-geriatric, subjects (between 21 and 66 years) ... Ethnic group origins, sex and season of assessment have not been included in the analyses` | limitations[3] | 0.95 | the tagger's words |
| limitations | FIVE ANALYSERS, FIVE MEANS - 1.65, 1.76, 1.86, 1.68, 1.69 - a 13% spread reported as agreement: `the NLR values are in the same range, whichever the used analyzer`. True of the RANGE and not of the mean, and the reference limits come from one instrument | limitations[4] | 0.95 | the tagger's words |
| controls | a second, independent cohort of 29 subjects selected on strict health criteria - no chronic disease, no substance or medication use including tobacco - run on four further analysers eliminates: the objection that the main cohort's limits reflect its own unscreened population: 'no NLR assessed in the validation series is OUT OF THE PROPOSED LIMITS' · outcome: held | controls[0] | 0.95 | the tagger's words |
| controls | a stated power calculation for the validation cohort - 'to test the hypothesis that <2.5% of the normal controls would be out of the proposed limits, 28 subjects are needed. It is the reason why we included 29' eliminates: the objection that n=29 was chosen for convenience; the number is derived and the derivation is printed · outcome: held | controls[1] | 0.95 | the tagger's words |
| controls | NLR sample stability over 48 h eliminates: pre-analytical drift as a source of the observed spread - 'there was no significant variation over this time period and the NLR was then considered stable' · outcome: held | controls[2] | 0.95 | the tagger's words |
| controls | whether the reference limits hold outside an adult, non-geriatric, occupationally-screened, unrecorded-for-smoking population eliminates: nothing, and the paper lists the gaps itself: 'Age is certainly a limit ... we did not have the complete documentation of substance use/abuse ... Ethnic group origins, sex and season of assessment have not been included' · outcome: absent-declared-unreported | controls[3] | 0.95 | the tagger's words |
| concepts | Neutrophil-to-lymphocyte ratio (NLR) also in: Neutrophil-to-lymphocyte ratio (NLR) | concepts[0] | 0.95 | the paper's words |
| concepts | NLR also in: NLR | concepts[1] | 0.95 | the paper's words |
| concepts | parameter also in: parameter | concepts[2] | 0.95 | the paper's words |
| concepts | absolute neutrophil count also in: absolute neutrophil count | concepts[3] | 0.95 | the paper's words |
| concepts | absolute lymphocyte count also in: absolute lymphocyte count | concepts[4] | 0.95 | the paper's words |
| concepts | reference values also in: reference values | concepts[5] | 0.95 | the paper's words |
| concepts | receiver-operating curves also in: receiver-operating curves | concepts[6] | 0.95 | the paper's words |
| concepts | normal controls also in: normal controls | concepts[7] | 0.95 | the paper's words |
| concepts | good health also in: good health | concepts[8] | 0.95 | the paper's words |
| concepts | log-normal distribution also in: log-normal distribution | concepts[9] | 0.95 | the paper's words |
| senses | `normal value` - IN THIS PAPER, THE MEAN +/- 1.96 SD OF A WORKING POPULATION, 0.78 to 3.53. Not a physiological threshold, not an outcome-derived cut-off: a distribution of people who were at work and had blood taken | senses[0] | 0.95 | the tagger's words |
| senses | `normal value` IN THE LITERATURE IT CORRECTS - `the median, higher quartile or values determined by the use of receiver-operating curves`, computed inside the diseased sample. THE SAME PHRASE NAMES A PROPERTY OF THE HEALTHY IN ONE PLACE AND A PROPERTY OF THE SICK IN THE OTHER | senses[1] | 0.95 | the tagger's words |
| senses | `good health` - OPERATIONALLY, EMPLOYABILITY PLUS AN ABSENCE OF RECORDS. `in good health, permitting a full time job without restriction`, with `No information ... about habits ... and possible comorbidities`. The second cohort uses a stricter sense - `carefully selected on the basis of the absence of any chronic disease or substance/medications` - so the paper carries two senses of health and validates one against the other | senses[2] | 0.95 | the tagger's words |
| senses | `NLR` - `The absolute neutrophil count was divided by the absolute lymphocyte count to calculate the NLR`. One sentence, one division, and no cue list the gate holds can see it - `calculated as` is on MEASUREMENT and `to calculate` is not | senses[3] | 0.95 | the tagger's words |
| claim_relations | extends → the prognostic NLR literature in cardiology, oncology and infection, which established the marker's usefulness without ever establishing its normal range | claim_relations[0] | 0.95 | the tagger's words |
| claim_relations | contradicts → the practice of setting an NLR cut-off from the median, upper quartile or ROC of the diseased sample - contradicted as a SOURCE, not as arithmetic | claim_relations[1] | 0.95 | the tagger's words |
| concept_edges | Neutrophil-to-lymphocyte ratio (NLR) —is-a→ parameter strength of the relation: 0.95 · note: 'a SIMPLE parameter to assess easily the inflammatory status of a subject' - the simplicity is the paper's own emphasis and is why the ratio spread through clinical use before anybody established its range also in: Neutrophil-to-lymphocyte ratio (NLR) · parameter | concept_edges[0] | 0.95 | the tagger's words |
| content_tags | THE MARKER HAD NO REFERENCE RANGE AND THE PAPER SAYS SO: `Different values of NLR, with different methods, in different populations (cancerous or not) are cited in the literature. And finally, no universal value is currently available` | content_tags.findings[0] | 0.95 | the tagger's words |
| content_tags | AND THE EXISTING CUT-OFFS CAME FROM THE POPULATION THEY WERE MEANT TO IDENTIFY: `none of these studies based their cut-off on data coming from population in good health ... Some of these studies chose their cut-off value on the basis of the median, higher quartile or values determined by the use of receiver-operating curves` | content_tags.findings[1] | 0.95 | the tagger's words |
| content_tags | unlike earlier studies, these limits come from an active adult population in good health | content_tags.findings[2] | 0.95 | the tagger's words |
| content_tags | THE ANSWER: normal NLR is `between 0.78 and 3.53`, mean 1.65, in 413 healthy adults - and no member of the 29-subject validation cohort fell outside it | content_tags.findings[3] | 0.95 | the tagger's words |
| content_tags | the Discussion gives the NLR range as 0.78 to 3.58 | content_tags.findings[4] | 0.95 | the tagger's words |
| content_tags | the main samples came from workers potentially exposed to ionizing radiation, with no information on habits or comorbidities | content_tags.findings[5] | 0.95 | the tagger's words |
| content_tags | and health is operationalised as EMPLOYABILITY: `in good health, permitting a full time job without restriction ... and are representative of the population as a whole` | content_tags.findings[6] | 0.95 | the tagger's words |
| content_tags | THE PAPER CARRIES TWO SENSES OF HEALTH AND VALIDATES ONE AGAINST THE OTHER: the main cohort is `not excluding non-debilitating disease, tobacco use or oral contraception`, the control cohort is `carefully selected on the basis of the absence of any chronic disease or substance/medications` | content_tags.findings[7] | 0.95 | the tagger's words |
| content_tags | normal controls were analysed on four other analysers besides the Sysmex XE2100 used for routine samples | content_tags.findings[8] | 0.95 | the tagger's words |
| content_tags | THE SAMPLE SIZE IS DERIVED AND THE DERIVATION IS PRINTED: `to test the hypothesis that <2.5% of the normal controls would be out of the proposed limits, 28 subjects are needed. It is the reason why we included 29` | content_tags.findings[9] | 0.95 | the tagger's words |
| content_tags | the paper lists what its range cannot cover: `Age is certainly a limit ... Ethnic group origins, sex and season of assessment have not been included in the analyses` | content_tags.findings[10] | 0.95 | the tagger's words |
| content_tags | and it hedges its own use: `it seems logical to interpret cautiously this type of parameter (like any other), in a clinical context to adjust the interpretation, even if based on data coming from a comparable population` | content_tags.findings[11] | 0.95 | the tagger's words |
| content_tags | PRE-ANALYTICAL STABILITY WAS CHECKED: `NLR sample stability over 48 h was assessed; there was no significant variation over this time period` | content_tags.findings[12] | 0.95 | the tagger's words |
| content_tags | and the marker's clinical standing was already established without any of this: `a lot of examples in the literature of the interest of the NLR as an independent prognostic factor of morbidity and mortality in several conditions` | content_tags.findings[13] | 0.95 | the tagger's words |
| content_tags | `The absolute neutrophil count was divided by the absolute lymphocyte count to calculate the NLR` - the paper's only statement of what its own object is, and it is an arithmetic operation written out in prose also in: NLR | content_tags.definitions[0] | 0.95 | the tagger's words |
| content_tags | `between 0.78 and 3.53` in an adult, non-geriatric population in good health - mean +/- 1.96 SD on a log-normal scale, n=413 also in: normal NLR values | content_tags.definitions[1] | 0.95 | the tagger's words |
| content_tags | `permitting a full time job without restriction, and without any active disease, including cancer and infectious disease` - with no data on tobacco or comorbidity also in: good health | content_tags.definitions[2] | 0.95 | the tagger's words |
| content_tags | the upper reference limit - stated five times in the paper, and once as 3.58 value source note: THE DESCRIPTION DRAWS ON THE PAPER BEYOND THIS QUOTE: the 3.58 is the Discussion's version of the upper limit ('are between 0.78 and 3.58.'). The quote gives 3.53; the description records that the paper prints both. | content_tags.quantities[0] | 0.95 | the tagger's words |
| content_tags | the Discussion's version of the same upper limit; the publisher's text, verified against the source XML | content_tags.quantities[1] | 0.95 | the tagger's words |
| content_tags | the lower reference limit, consistent everywhere in the paper | content_tags.quantities[2] | 0.95 | the tagger's words |
| content_tags | subjects in the main cohort, from a workplace health-care prevention programme | content_tags.quantities[3] | 0.95 | the tagger's words |
| content_tags | subjects in the validation cohort - 28 were required by the power calculation | content_tags.quantities[4] | 0.95 | the tagger's words |
| content_tags | log-normal distribution also in: log-normal distribution | content_tags.statistics[0] | 0.95 | the tagger's words |
| content_tags | 95% confidence limits also in: 95% confidence limits | content_tags.statistics[1] | 0.95 | the tagger's words |
| content_tags | the ratio itself - the only variable the paper reports also in: NLR | content_tags.variables[0] | 0.95 | the tagger's words |
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