Decreasing human body temperature in the United States since the industrial revolution, Hacker News

Abstract

In the US, the normal, oral temperature of adults is, on average, lower than the canonical ° C established in the 19^{th^{century. We postulated that body temperature has decreased over time. Using measurements from three cohorts – the Union Army Veterans of the Civil War (N=(*********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************, measurement years – the National Health and Nutrition Examination Survey I (N=17, (************************************************************************************************************************************************************************************************************************************************************************************************************; – 1988) , and the Stanford Translational Research Integrated Database Environment (N=(******************************************************************************************************************************************************************************************************************************************************************************************************************************************, 296; 2008 – 2018 – we determined that mean body temperature in men and women, after adjusting for age, height, weight and, in some models date and time of day, has decreased monotonically by 0. 06 ° C per birth decade. A similar decline within the Union Army cohort as between cohorts, makes measurement error an unlikely explanation. This substantive and continuing shift in body temperature — a marker for metabolic rate — provides a framework for understanding changes in human health and longevity over 157 years.}}

Introduction

In (**************************************************************************************************************************************************************************************************************************************, the German physician Carl Reinhold August Wunderlich obtained millions of axillary temperatures from 029, 0 patients in Leipzig, establishing establishing the standard for normal human body temperature of (° C or) ************************************************************************************************************************************************************************************************************************************************************************************************************************************************* 6 ° F (range : (2-) ****************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** 5 ° C [97.2- 99.5 °F] ) (Mackowiak, 2005;Wunderlich and Sequin, 1900. A compilation of (modern studies, however (Sund-Levander et al.,

, reported mean temperature to be uniformly lower than Wunderlich’s estimate. Recently, an analysis of more than 37, 0 British patients with almost 250, 0 temperature measurements, found mean oral temperature to be 36. 6 ° C, confirming this lower value (Obermeyer et al.,

). Remaining unanswered is whether the observed difference between Wunderlich’s and modern averages represents true change or bias from either the method of obtaining temperature (axillary by Wunderlich vs. oral today) or the quality of thermometers and their calibration ( (Mackowiak,

. Wunderlich obtained his measurements in an era when life expectancy was 40 years and untreated chronic infections such as tuberculosis, syphilis, and periodontitis afflicted large proportions of the population (Murray et al. , 2018

;Tampa et al. ., 2015

;Richmond,

. These infectious diseases and other causes of chronic inflammation may well have influenced the ‘normal’ body temperature of that era.

The question of whether mean body temperature is changing over time is not merely a matter of idle curiosity. Human body temperature is a crude surrogate for basal metabolic rate which, in turn, has been linked to both longevity (higher metabolic rate, shorter life span) and body size (lower metabolism, greater body mass). We speculated that the differences observed in temperature between the th^{th^{century and today are real and that the change over time provides important physiologic clues to alterations in human health and longevity since the Industrial Revolution.}}

Results

In men, we analyzed: a) (******************************************************************************************************************************************************************************************************************************************************************************************************************************************************************, measurements from the Union Army Veterans of the Civil War cohort (UAVCW) obtained between 1890 and 1936, b) measurements from the National Health and Nutrition Examination Survey I cohort (NHANES) obtained between and (*****************************************************************************************************************************************************************************************************************************, and c) (**********************************************************************************************************************************************************************************************************************************************************************************************************************, measurements from the Stanford Translational Research Integrated Database Environment cohort (STRIDE) obtained between and (************************ (Table 1

Demographic characteristics (N (%)) and mean (SD)) of cohort participants included in the analyzes.

(******************************** (Total, N (%)

(********************************************************************************************************************************************************************************************************************************************************************************************************************************, 280 ( (%)

************************************** (Observations) ********** (1) 677, () (%)

, () (%) (**************************************** , 309 (2%)280, (******************************************************************************************************************************************************************************************************************************************************************************************************************************************************** (%) (************************************

Age (years) (

( (**

****************************************** (Overall **************************************** (**************************************** (****************************************************************************************************************************************************************************************************************************************************************************************************************************************************** (8 . 90)

**************

(**************************************** (**************************************

************************************** (Overall *****************************************

>(************************************** (**************************************************************************************************************************************************************************************************************************************************** (0%) (************************************** 56 (0%)

2 (0%) (**************************************^(0%)

(************************************** (Sex) ****************************************

(**************************************** (**************************************** (**************************************

**************************6489 (40%) () ************************************** 230, (**************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** (%)

(Ethnicity) ******************************************************

(**************************************^{**************************** (**************************************}

(**********************

Overall, temperature measurements were significantly higher in the UAVCW cohort than in NHANES, and higher in NHANES than in STRIDE ( (Figure 1) ;Figure 1 — figure supplement 1

. In each of the three cohorts, and for both men and women, we observed that temperature decreased with age with a similar magnitude of effect (between −0.0 03 ° C and −0. 45 ° C per year of age,Figure 1As has been previously reported (Eriksson et al.,

), temperature was directly related to weight and inversely related to height, although these associations were not statistically significant in the UAVCW cohort. Analysis using body mass index (BMI) and BMI adjusted for height produced similar results ( (Figure 1 — figure supplement 2

) and analyzes including only white and black subjects ( black subjects) Figure 1 — figure supplement 3

showed similar results to those including subjects of all ethnicities.

******************************** (************************************** (******************************************************** (**********************************************************

Body temperature measurements by age as observed in three different time periods: 1851 – (UAVCW),************************************************************************************************************************************************************************************************************************ – (NHANES 1), and – (STRIDE).

( (A) *********************************************************** (Unadjusted data (local regression) for temperature measurements , showing a decrease in temperature across age in white men, black men, white women, and black women, in the three cohorts. ( (B) ) Coefficients and standard errors from multivariate linear regression models for each cohort including age, weight, height, ethnicity group and time of day as available. Yellow cells are statistically significant at ap value of********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** (year old men and women with weight (kg and height) cm in each time period / cohort.

******************************

In both STRIDE and a one-third subsample of NHANES, we confirmed the known relationship between later hour of the day and higher temperature: temperature increased 0. ° C per hour of the day in STRIDE compared to 0. (° C in NHANES) (Figure 1) , (Figure 1 — figure supplement 2

, (Figure 1 — figure supplement 4

). The month of the year had a relatively small, though statistically significant, effect on temperature in all three cohorts, but no consistent pattern emerged ( Figure 1 — figure supplement 5

. Using approximated ambient temperature for the date and geographic location of the examination in UAVCW and STRIDE, a rise in ambient temperature of one degree Celsius correlated with 0.0 (degree) p

We explored whether chronic infectious diseases — even in the absence of a diagnosis of fever — might raise temperature in the UAVCW cohort, by assessing the temperatures of men reporting a history of malaria (N=2, 220, syphilis (N=), or hepatitis (N=029), or with active tuberculosis (N=738), pneumonia (N=280 or cystitis (N=1, 320. Only those currently diagnosed with tuberculosis or pneumonia had elevated temperatures compared to the remainder of the UAVCW population [37.22°C (95% CI: 37.20–37.24°C) and 37.06°C (95% CI: 37.03–37.09°C), respectively compared to 37.02 (95% CI: 36.52–37.53)] ( (Supplementary file 1) ). ************

One possible reason for the lower temperature estimates today than in the past is the difference in thermometers or methods of obtaining temperature. To minimize these biases, we examined changes in body temperature by birth decade within each cohort under the assumption that the method of thermometry would not be biased on birth year. Within the UAVCW, we observed a significant birth cohort effect, with temperatures in earlier birth decades consistently higher than those in later cohorts ( (Figure 2) . With each birth decade, temperature decreased by −0. ° C. We then assessed change in temperature over the birth-year span covered by the three cohorts. We observed a steady decrease in body temperature by birth cohort for both men (−0. (° C between birth decades from to 1997; −0.0 ° C per decade (and women) −0. ° C between and 1997; −0.0 029 ° C per decade). Black and white men and women demonstrated similar trends over time ( (Figure 3) ).

(**************************************(******************************************

% level, respectively. ( (C) ************************************************************ () Expected body temperature (and associated) ************************************************************************************************************************************************************************************************************************************************************************************************************************************************************% confidence interval (for************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** (year old men with body weight) ************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** kg and height cm in each birth cohort. These values derive from the regression models presented in B.

******************************                                              (************************************** (************************************************
Modeled body temperature over time in three cohorts by birth year (black and white ethnicity groups).



( (A) Body temperature decreases by birth year in white and black men and women. No data for women were available for the birth years from 1800 to 1920. ( (B) Coefficients (and standard errors) used for the graph from multivariate linear regression including age, body weight, height and birth year. All cells are significant at greater than 103% significance level.



******************************

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Discussion





In this study, we analyzed (**************************************************************************************************************************************************************************************************************************************************************************, ******************************************************************************************************************************************************************************************************************************************************************************************** (human body temperature measurements from three different cohort populations spanning) ********************************************************************************************************************************************************************************************************************************************************************************************************************************************* years of measurement and birth years. We found that men born in the early th^{century had temperatures 0. ° C higher than men today, with a monotonic decrease of −0. ° C per birth decade. Temperature has also decreased in women by −0. 33 ° C since the s with a similar rate of decline (−0.0 ° C per birth decade). Although one might posit that the differences among cohorts reflect systematic measurement bias due to the varied thermometers and methods used to obtain temperatures, we believe this explanation to be unlikely. We observed similar temporal change within the UAVCW cohort — in which measurement were presumably obtained irrespective of the subject’s birth decade — as we did between cohorts. Additionally, we saw a comparable magnitude of difference in temperature between two modern cohorts using thermometers that would be expected to be similarly calibrated. Moreover, biases introduced by the method of thermometry (axillary presumed in a subset of UAVCW vs. oral for other cohorts) would tend to underestimate change over time since axillary values typically average one degree Celsius lower than oral temperatures ( (Sund-Levander et al.,}

**************************************************************************************************************************************************************************************; (Niven et al., ********************************************************************************************************************************************************************************************). Thus, we believe the observed drop in temperature revers physiologic differences rather than measurement bias. Other findings in our study — for example increased temperature at younger ages, in women, with increased body mass and with later time of day — support a wealth of other studies dating back to the time of Wunderlich ( (Wunderlich and Sequin,) ********************************************************************************************************************************************************************************************************************************** () ; Waalen and Buxbaum , 2014). **********

Resting metabolic rate is the largest component of a typical modern human’s energy expenditure, comprising around (******************************************************************************************************************************************************************************************************************************************************************************************************************************************************************% of daily energy spending for a sedentary individual ( (Heymsfield et al., 2006

). Heat is a byproduct of metabolic processes, the reason nearly all warm-blooded animals have temperatures within a narrow range despite drastic differences in environmental conditions. Over several decades, studies examining whether metabolism is related to body surface area or body weight ( Du Bois, (*****************; (Kleiber,), ultimately, converged on weight-dependent models ( (Mifflin et al.,********************************************************************************************************************************************************************************************** (********************; (Schofield,) ************************************************************************************************************************************************************************************************************************; Nelson et al.,. Since US residents have increased in mass since the mid – (th^{century, we should have correspondingly expected increased body temperature. Thus, we interpret our finding of a decrease in body temperature as indicative of a decrease in metabolic rate independent of changes in anthropometrics. A decline in metabolic rate in recent years is supported in the literature when comparing modern experimental data to those from 1930 ( Frankenfield et al.,
). ************
Although there are many factors that influence resting metabolic rate, change in the population-level of inflammation seems the most plausible explanation for the declined decrease in temperature over time. Economic development, improved standards of living and sanitation, decreased chronic infections from war injuries, improved dental hygiene, the waning of tuberculosis and malaria infections, and the dawn of the antibiotic age together are likely to have increased chronic inflammation since the 19^{th^{century. For example, in the mid – th^{century, 2 –3% of the population would have been living with active tuberculosis ( (Tiemersma et al., ************************************************************************************************************************************************************************************************************}}}
. This figure is consistent with the UAVCW Surgeons’ Certificates that reported cases of active tuberculosis among (**********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************, ********************************************************************************************************************************************************************************************************************************************************* (subjects 3.1) %). That UAVCW veterans who reported either current tuberculosis or pneumonia had a higher temperature (0. ° C and 0. ° C respectively) than those without infecti ous conditions supports this theory ( Supplementary file 1
). Although we would have liked to have compared our modern results to those from a location with a continued high risk of chronic infection, we could identify no such database that included temperature measurements. However, a small study of healthy volunteers from Pakistan — a country with a continued high incidence of tuberculosis and other chronic infections — confirms temperatures more closely approximating the values reported by Wunderlich (mean, median and mode, respectively, of ****************************************************************************************************************************************************************************************************************************************************************************************************************************************************** (° C,********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** ° C, and (° C) ( Adhi et al., ******************************************************************************************************************************************************************************************************^).}

Reduction in inflammation may also explain the continued drop in temperature observed between the two more modern cohorts: NHANES and STRIDE. Although many chronic infections had been conquered before the NHANES study, some — periodontitis as one example (Capilouto and Douglass,

) – continued to decrease over this short period. Moreover, the use of anti-inflammatory drugs including aspirin (Luepker et al., 2018, statins (

************************************************************************ Salami et al.,

) and non-steroidal anti-inflammatory drugs (NSAIDs) (Lamont and Dias, 2011) Increased over this interval, potentially inflammation. NSAIDs have been specifically linked to blunting of body temperature, even in normal volunteers (Murphy et al.,

. In support of declining inflammation in the modern era, a study of NHANES participants demonstrated a 5% decrease in abnormal C-reactive protein levels between and 2010 ( Ong et al ., 2014

). **********

Changes in ambient temperature may also explain some of the observed change in body temperature over time. Maintaining constant body temperature despite fluctuations in ambient temperature consumes up to – (% of daily energy intake) (Levine,) **************************************************************************************************************************************************************************************************************). Resting metabolic rate (RMR), for which body temperature is a crude proxy, increases when the ambient temperature decreases below or rises above the thermoneutral zone, that is the temperature of the environment at which humans can maintain normal temperature with minimum energy expenditure ( Erikson et al.,

. In the^{th^{century, homes in the US were irregularly and inconsistently heated and never cooled. By the s, however, heating systems reached a broad segment of the population with mean night-time temperature continuing to increase even in the modern era (}}Mavrogianni et al.,

. Air conditioning is now found in more than (% of US homes) (US Energy Information Administration,) *************************************************************************************************************************************************************************************************************

. Thus, the amount of time the population has spent at thermoneutral zones has markedly increased, potentially causing a decrease in RMR, and, by analogy, body temperature.

Some factors known to influence body temperature were not included in our final model due to missing data (ambient temperature and time of day) or complete lack of information (dew point) ( (Obermeyer et al.,

******************************************************************************************************************************************************************************

. Adjusting for ambient temperature, however, would likely have amplified the changes over time due to lack of heating and cooling in the earlier cohorts. Time of day at which measurement was conducted had a more significant effect on temperature ( (Figure 1 — figure supplement 4) ). Based on the distribution of times of day for temperature measurement available to us in STRIDE and NHANES, we estimate that even in the worst case scenario, that is the UAVCW measurements were all were obtained late in the afternoon, adjustment for time of day would have only a small influence (

In summary, normal body temperature is assumed by many, including a great preponderance of physicians, to be 41 ° C. Those who have shown this value to be too high have connected that Wunderlich’s (th century measurements were simply flawed (

Mackowiak,

************; Sund-Levander et al.,). Our investigation indicates that humans in high-income countries have changed physiologically over the last 222 birth years with a mean body temperature 1.6% lower than in the pre-industrial era. The role that this physiologic ‘evolution’ plays in human anthropometrics and longevity is unknown.



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Materials and methods



(Cohorts)       Request a detailed protocol





We compared body temperature measurements from three cohorts. (Cohort 1) ******************************************************************************************************: The Union Army Veterans of the Civil War, 1871 – (UAVCW) is a database from the ‘Early Indictors of Later Work Levels , Disease and Death Study ‘, proposed by the late Nobel Laureate, Robert Fogel in 1990 ( (Fogel and Wimmer,

**************************************************************************************************************************************************************************************

) and continuing today. The study abstracted the Compiled Military Service Records, the Pension Records, Carded Medical Records, the Surgeons’ Certificates (detailed medical records) and information from the US Federal Census for a cluster sample of Union Army companies in the US Civil War. In total, (companies of white and********************************************************************************************************************************************************************************************************************************************************************************************************************************************** companies of black union army veterans were included in the dataset. The Surgeons ’Certificates were obtained at locations throughout the US for veterans seeking pension benefits. These certificates include comprehensive medical histories and physical examinations. Body temperatures in Fahrenheit were hand-written on (****************************************************************************************************************************************************************************************************************************************************************************************************************************************************************, Surgeons’ Certificates from 25, (individuals) mean: 3. 52 examinations per individual; Table 1

). Whether the temperatures were taken orally or in the axilla is unknown; both methods were employed in the^{century although oral temperature was more common ( Salinger and Kalteyer, . Precision of the instruments is also unknown. Inspection of the distribution of reads, however, suggest that it is no better than 0.2 degrees Fahrenheit, consistent with the hashmarks on mercury thermometers ( (Figure 1 — figure supplement 1) ). The UAVCW data — including birth date, temperature, height, weight, location and date of the medical visit, medical history, ongoing medical complaints and findings of physical examinations —are freely available on-line in digital format (The Colored Troops (USCT) original and expanded datasets; (Fogel et al.,}
;Costa, . (Cohort 2) : The National Health and Nutrition Examination Survey (NHANES I) is a multistage, national probability survey conducted between 1971 and 1978 in the US civilian population. A subset of subjects, aged 1 to (years) N =23, (underwent a medical examination) ICPSR study No. 8055), including (******************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************, adults. The major focus of NHANES I was nutrition, and persons with low income, pregnant women and the elderly were consequently oversampled ( Centers for Disease Control, National Center for Health Statistics,

. Data abstracted included weight, height, sex, ethnicity, and month and geographic region of examination and, as available, time of day the temperature was obtained. In NHANES, mercury thermometers were used and temperatures were taken orally. Precision, as with the UAVCW cohort, is assumed to be 0.2 ° F. The medical examination was performed by a physician with the help of a nurse. (Cohort 3) : The Stanford Translational Research Integrated Database Environment (STRIDE) extracts electronic medical record information from patient encounters at Stanford Health Care (Stanford, CA). All adult outpatient encounters at Stanford Health Care from (to) with recorded temperature measurements in the electronic medical record are included in this study (N=598, adult outpatient encounters. Temperature measurements were obtained orally with annually-calibrated, digital thermometers with precision of 0.1 ° F and extracted from the dataset along with age, sex, weight, height, primary concern at the visit, prescribed medications, other conditions in the health record with ICD 013 Codes, and year and time of day the temperature was obtained (mean: 3. examinations per individual; Table 1

)

For the UAVCW and STRIDE datasets, any observations having a diagnosis of fever at the time of the medical examination were excluded. From all three datasets, any extreme values of temperature ( (**************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** ° C) were also excluded from the analysis either because they were implausible or because they indicated a diagnosis of fever and would otherwise have been excluded. Improbable values of both body weight (kg (and height

(cm) were also removed. In the UAVCW, we also excluded veterans born after (*********************************************************************************************************************************************************************************************************************************, because they were unlikely to have served in the Union Army.

The use of the STRIDE data was approved as an expedited protocol by the Stanford Institutional Review Board (protocol) and informed consent was waived since the only personal health information abstracted was month of clinic visit. Anonymized data from NHANES and the data from UAVCW are freely available on-line for research use.



********************************************************************************************^{************************************************************************************************ (Data analysis^{******************************************************************************************        Request a detailed protocol}}




Ethnicity categories were defined differently across cohorts. UAVCW included only white and black men. For comparability, we restricted analyzes between the UAVCW and other cohorts to men in these two ethnicity groups. Asians were categorized as ‘Other’ in NHANES and as ‘Asian’ in STRIDE, so were considered as ‘Other ethnicity’ in combined analyzes. We performed analyzes stratified by sex to account for known temperature differences between men and women. The NHANES study uses sample weights to account for its design; these were incorporated into models including NHANES data ( (Centers for Disease Control, National Center for Health Statistics,)

)

To estimate the average body temperature during each of the three time periods, we modeled temperature within each cohort using multivariate linear regression, simultaneously assessing the effects of age, body weight, and height. Measurements in men and women were analyzed separately, by white and black ethnicity groups. We also conducted mixed effects modeling to account for the repeated temperature measurements from some individuals. Because the coefficients were almost identical to those of the linear regression models, we chose to present this more simple statistical method. We also assessed the effects of geography, that is location at which temperature was obtained, on temperature ( (Figure 1 — figure supplement 6) ).

To evaluate temperature changes over time, we predicted body temperature using multivariate linear regression including age, body weight, height and birth decade in the UAVCW cohort (the timeframe of NHANES and STRIDE spanned relatively few years, with insufficient variability to evaluate birth cohort effects within these datasets). To assess change in temperature over the (birth-year span covered by the three cohorts (between years and for men, and between and 1997 for women), we used linear regression with temperature as the outcome and age, weight, height, and birth decade as independent variables, stratifying by ethnicity and sex. The UAVCW cohort was further investigated for reported infectious conditions that might affect temperature. Diagnoses of infectious conditions, either in the medical history (malaria, syphilis, hepatitis) or active at the time of examination (tuberculosis, pneumonia or cystitis), were included in regression models if fever was not listed as part of that record.

Some models included time of day, ambient temperature and month of year. Time of day at which temperature was taken was available for STRIDE and a subset of NHANES. For individuals without time of day, we imputed the time to be (**********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************: 0001 PM (noon). We accounted for ambient temperature using the date and geographic location of examination (available in UAVCW and STRIDE) based on data from the National Centers for Environmental Information (************************************************************************************ NOAA National Centers for Environmental Information, 2020. We used the month of year when each measurement was taken as a random effect. To assess the robustness of our result to the chosen methodology, we repeated the analyzes using linear mixed effect modeling, adjusting for multiple measurements.

Within the UAVCW, minimum ages varied across birth cohorts due to the bias inherent in the cohort structure (for example, it is impossible to be younger than years of age at the time of the pension visit, be born in s, and be a veteran of the Civil War). To avoid instability in the analysis due to having too few people within specific age groups per birth decade, we excluded the lowest 1% of observations in each birth cohort according to age.

All analyzes were performed using R statistical software version 3.3.0. and packages easyGgplot2, lme4, merTools, and ggplot2 for statistical analysis and graphs ( (www.r-project.org) ). ********

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References

              (1)                          (2)                          (3)                          (4)                          (5)                          (6)                          (7)                          (8)                          (9)                                                 (******************************************************************************************************                                                 (******************************************************************************************************                         (****************************************************************************************************                         (****************************************************************************************************                         (**************************************************************************************************

Fever: Basic Mechanisms and Management

                                                           PA Mackowiak

(

) History of clinical thermometry, Fever: Basic Mechanisms and Management, Philadelphia, Lippincott Williams & Wilkins.^{(******************************************************************************************************************Google Scholar
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Predicting basal metabolic rate, new standards and review of previous work
                                                           WN Schofield

(}

Human Nutrition. Clinical Nutrition (****************************************************

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Decision letter





Thank you for submitting your article “Decreasing human body temperature in the United States since the Industrial Revolution” for consideration by (eLife) ********************************************************************************************************************************. Your article has been reviewed by two peer reviewers, and the evaluation has been overseen by Mark Jit as the Reviewing Editor and Eduardo Franco as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Jill Waalen (Reviewer # 1); Frank Rühli (Reviewer # 2).

The Reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission. We believe that the manuscript is basically acceptable for publication, but would like you to address some minor textual comments raised by the reviewers.

We find that this is an interesting and well-written manuscript using measurements of mean body temperature among 3 US cohorts with data collected in 3 distinct time periods to support the hypothesis that mean population body temperature has decreased over the time from to (********************************************************************************************************************************************************************************************************. We highly appreciate this work due to its relevant yet unique research topic, solid data sets and straight-forward analysis.

Given the differences in measurement practices, data collection, and environmental conditions over that time period, the paper has tackled a question that is inherently unprovable in regard to cause-effect. However, the arguments are cogent enough (eg, the same known temperature trends corresponding to age seen in all cohorts) and the data supportive enough (eg, the same known temperature trends corresponding to age seen in all cohorts), that it is worth its thought- provocation.

We would like the following textual changes to be made to the manuscript:

1) The last sentence of the Abstract states that understanding the trend of decreasing mean population body temperature “provides a framework for understanding changes in body habitus and human longevity over the last 216 years. ” There are two problems with this:

a) The study spans 1862 – 2019, which is (years.)

b) Given that body temperature is defined as a biomarker for metabolic rate, discussion regarding body habitus in different parts of the manuscript are a bit difficult to reconcile: 1) lower metabolism is associated with greater body mass (Introduction, last paragraph); 2) Increased body mass is associated with increased body temperature (Discussion, second paragraph).

Given the above, please change the line in the Abstract to: “provides a framework for understanding changes in human health and longevity over the last years “(or … since the Civil War ….)

2) Given the relative paucity of published medical research on the UAVCW cohort (there appears to be only a few PubMed listings), it would be helpful to give more detail about the medical data included for this cohort and how it was obtained:

a) From the brief description in the Materials and methods section, it is not clear how many times an individual may have been examined, for example. Were they tested on a regular basis for pension benefits and disqualified based on some findings? It is stated in the first paragraph of the subsection “Cohorts”, that measures could have been obtained on multiple occasions from individual veterans, which, of course, introduces that problem of lack of independence of measures, but need to have some idea of how big a problem this would be (not likely to be big, but would be good to have numbers).

b) Also, were the examinations done at one location for all veterans (relevant to correlating body temperature with ambient temperature)? This is implied in the third paragraph of the Results, but would be helpful to state explicitly in the Materials and methods.

c) A “Table 1” with basic characteristics of the three cohorts would also be helpful in this regard, given the likely differences, for example, in ranges of height, weight, age, and other covariates. This would be helpful, for example, in understanding why height and weight were not statistically significantly associated in the UAVCW (Results, second paragraph) – perhaps a narrower range in the other cohorts?

3) It is implied in the third paragraph of the subsection “Data Analysis”, that fever was recorded and that these records were excluded in at least some of the models. This raises the question of whether “febrile” subjects were excluded in all cohorts and, if so, what cut-offs were used to define fever in the different cohorts?

4) Given that the changes in mean temperature of interest are relatively small (less than 1 degree), more information regarding the measurement is of interest:

a) In what scale were the measurements in each cohort originally made (Celsius or Fahrenheit)? To what precision level were they recorded?

b) Is it known how thermometers were calibrated for the measures in the respective cohorts (particularly UAVCW)?

5) Please use the term “ethnicity” rather than “race” since we assume this is what is actually being recorded from the cohorts.

6) Discussion, first paragraph: “that” should be “than”



(******************************************************************************************************** https : //doi.org/ (************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************. / eLife. 01575879. sa1

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Author response





We believe that the manuscript is basically acceptable for publication, but would like you to address some minor textual comments raised by the reviewers.

We find that this is an interesting and well-written manuscript using measurements of mean body temperature among 3 US cohorts with data collected in 3 distinct time periods to support the hypothesis that mean population body temperature has decreased over th e time from 1871 to 2019. We highly appreciate this work due to its relevant yet unique research topic, solid data sets and straight-forward analysis.

Given the differences in measurement practices, data collection, and environmental conditions over that time period, the paper has tackled a question that is inherently unprovable in regard to cause-effect. However, the arguments are cogent enough (eg, the same known temperature trends corresponding to age seen in all cohorts) and the data supportive enough (eg, the same known temperature trends corresponding to age seen in all cohorts), that it is worth its thought- provocation,

We would like the following textual changes to be made to the manuscript:

1) The last sentence of the Abstract states that understanding the trend of decreasing mean population body temperature “provides a framework for understanding changes in body habitus and human longevity over the last 216 years. ” There are two problems with this:

a) The study spans 1862 – 2019, which is (years.)

b) Given that body temperature is defined as a biomarker for metabolic rate, discussion regarding body habitus in different parts of the manuscript are a bit difficult to reconcile: 1) lower metabolism is associated with greater body mass (Introduction, last paragraph); 2) Increased body mass is associated with increased body temperature (Discussion, second paragraph).

Given the above, please change the line in the Abstract to: “provides a framework for understanding changes in human health and longevity over the last years “(or … since the Civil War ….)



We have revised the last sentence of the Abstract to read: “This substantive and continuing shift in body temperature — a marker for metabolic rate — provides a framework for understanding changes in human health and longevity over 172 years ”. We feel this version is most understandable to the reader.



2) Given the relative paucity of published medical research on the UAVCW cohort (there appears to be only a few PubMed listings), it would be helpful to give more detail about the medical data included for this cohort and how it was obtained:



We have provided more information on this cohort in the Materials and methods section and added two citations, including one for UAdata.org

which provides detailed information and the raw data .

a) From the brief description in the Materials and methods section, it is not clear how many times an individual may have been examined, for example. Were they tested on a regular basis for pension benefits and disqualified based on some findings? It is stated in the first paragraph of the subsection “Cohorts”, that measures could have been obtained on multiple occasions from individual veterans, which, of course, introduces that problem of lack of independence of measures, but need to have some idea of how big a problem this would be (not likely to be big, but would be good to have numbers).



As shown in Table 1, each veteran was tested a mean of 3.5 times ((****************************************************************************************************************************************************************************************************************************************************************************************************************************************************************, examinations for (********************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************, (individuals), often years apart. In STRIDE, temperature measurements were obtained. times per individual over time. The NHANES subjects ’temperatures were tested just once. We repeated our analyzes using mixed effects models to account for repeated measurements and the coefficients were unchanged from the linear regression models. We decided to use the linear regression for simplicity of interpretation. We’ve added a sentence in this regard to the Materials and methods section.



b) Also, were the examinations done at one location for all veterans (relevant to correlating body temperature with ambient temperature)? This is implied in the third paragraph of the Results, but would be helpful to state explicitly in the Materials and methods.



The examinations were conducted at medical examination boards at different locations throughout the country. Veterans may have traveled long distances to have their examinations done. We evaluated whether these locations were associated with variation in temperature since ambient temperature varies considerably throughout the United States. This analysis is now included in the supplement (Figure 1 — figure supplement 6). We did not have the location for NHANES (just large regions) and all the STRIDE samples were obtained at our clinics in Northern California. Because of the murkiness of the location data (how long did they reside in these areas, for example, and lack of detailed ambient temperature data for each site), we elected not to include this information in the overall analysis.



c) A “Table 1” with basic characteristics of the three cohorts would also be helpful in this regard, given the likely differences, for example, in ranges of height, weight, age, and other covariates. This would be helpful, for example, in understanding why height and weight were not statistically significantly associated in the UAVCW (Results, second paragraph) – perhaps a narrower range in the other cohorts?



Thank you for this suggestion. We have added means and standard deviations to Table 1 so the reader can better interpret the data.



3) It is implied in the third paragraph of the subsection “Data Analysis, that fever was recorded and that these records were excluded in at least some of the models. This raises the question of whether “febrile” subjects were excluded in all cohorts and, if so, what cut-offs were used to define fever in the different cohorts?



From all three datasets, any values greater than 42 ºC were excluded from the analysis because they indicated a diagnosis of fever (subsection “Cohorts”, second paragraph). Temperatures less than 50C were also excluded as being implausible. In addition, in both the UAVCW and STRIDE databases, anyone with a physician diagnosis of fever at that visit was excluded from analysis (see the aforementioned paragraph); we excluded them irrespective of the temperature measurement at the visit. Because NHANES did not collect acute illness diagnoses (subjects were volunteers coming to participate in the Nutrition survey and could reschedule for illness), similar information is not available for that cohort.



4) Given that the changes in mean temperature of interest are relatively small (less than 1 degree), more information regarding the measurement is of interest:

a) In what scale were the measurements in each cohort originally made (Celsius or Fahrenheit)? To what precision level were they recorded?



The UAVCW Surgeons’ Certificates were recorded in Fahrenheit. The precision level is variable (some report to one decimal, others do not) and a histogram of temperature measurements suggests poor precision; temperatures disproportionately fall at a relatively small number of values across the range. The NHANES were collected with mercury thermometers. Because these have hashmarks at 0.2 degree intervals, a disproportionate number of values were “even”. Thus, they should be considered to have 0.2 degree precision as seen in the histogram. We have included Figure 1 — figure supplement 1, that presents the distribution of temperature in each of the three cohorts. Reassuringly, inspection of these curves supports the change in mean temperatures over time. Lack of precision, of course, tends to result in negative findings. However, we cannot exclude the possibility that physicians in the UAVCW cohort reported biased values based on prior knowledge of “normal temperature”. Yet this bias would fail to explain the cohort effect within the UAVCW cohort.



b) Is it known how thermometers were calibrated for the measures in the respective cohorts (particularly UAVCW)?



It is not known how or whether thermometers were calibrated for UAVCW or NHANES. For STRIDE, thermometers are calibrated annually by Clinical Technology and Biomedical Engineering within the Stanford Hospitals and Clinics.



5) Please use the term “ethnicity” rather than “race” since we assume this is what is actually being recorded from the cohorts.



Done.



6) Discussion, first paragraph: “that” should be “than”



Done.



https://doi.org/ (**************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************. ************************************************************************************************************************************************************************************ / eLife. (************************************************************************************************************************************************************************. sa2

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Article and author information



       (Author details)    Myroslava Protsiv      (******************************************************************************************** Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, School of Medicine, Stanford, United States

Contribution

        Data curation, Software, Formal analysis, Validation, Visualization, Methodology, Writing — original draft

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        No competing interests declared

               (******************************************

“This ORCID iD identifies the author of this article. : “    ^{************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** – 03 – –}

**************    (********************************************************************************************************************    (********************************************************************************************************************     (************************************************************************************************************************************************    Trevor Hastie

     (********************************************** Department of Statistics, Stanford University, Stanford, United States              Department of Biomedical Data Science, Stanford University, School of Medicine, Stanford, United States^{(************** (Contribution) **********************************************************************************************************************************************}Formal analysis, Visualization, Methodology, Writing — review and editing



Competing interests

        No competing interests declared

**************

   (Julie Parsonnet)      (**********************************************Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, School of Medicine, Stanford, United States            Division of Epidemiology, Department of Health Research and Policy, Stanford University, School of Medicine, Stanford, United States         (************** (Contribution) **********************************************************************************************************************************************         Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Project administration, Writing — review and editing

(For correspondence)

[email protected]**************************************************************************************************

Competing interests

        No competing interests declared

              (******************************************

“This ORCID iD identifies the author of this article. : “    ^{************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************** – 0002 – –}
**************(**********************************************************************************************************************************************

Funding



       (******** Stanford Center for Clinical and Translational Research and Education (SPECTRUM award)

The Funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.



(Acknowledgment) **************************************************************************************************

We thank Professor Dora Costa, University of California, Los Angeles and Dr Louis Nguyen, Harvard Medical School for sharing their expertise and knowledge of the Union Army data. Thank you also to Dr. Philip Mackowiak, University of Maryland, for providing feedback on study design, analysis and interpretation. We also thank Michelle Bass, PhD, and Yelena Nazarenko for their support of the STRIDE clinical databases.

(Ethics) **************************************************************************************************

Human subjects: The use of the STRIDE data was approved as an expedited protocol by the Stanford Institutional Review Board (protocol 41667 and informed consent was waived since the only personal health information abstracted was month of clinic visit. Anonymized data from NHANEs and the data from UAVCW are freely available on-line for research use.

(Senior Editor)

            Eduardo Franco, McGill University, Canada      (**********************

(Reviewing Editor)

           Mark Jit, London School of Hygiene & Tropical Medicine, and Public Health England, United Kingdom     (**********************

(Reviewers) **************************************************************************************************

            (Jill Waalen, The Scripps Research Institute, United States) **************************************************************************************************************              (Frank Rühli)      (**********************

(Publication history)

            (Received: June) ************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************************, **************************************************************************************************************************************************************************************************

             Accepted: December 1, (**********************************************************************************************************************              (Version of Record published:******************************************************************************************************************************** (January 7, ************************************************************************************************************************************************************************************ (version 1)     (**********************

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