Wastewater surveillance provides 10-days forecasting of COVID-19 hospitalizations superior to cases and test positivity: A prediction study.

Background: The public health response to COVID-19 has shifted to reducing deaths and hospitalizations to prevent overwhelming health systems. The amount of SARS-CoV-2 RNA fragments in wastewater are known to correlate with clinical data including cases and hospital admissions for COVID-19. We developed and tested a predictive model for incident COVID-19 hospital admissions in New York State using wastewater data. Methods: Using county-level COVID-19 hospital admissions and wastewater surveillance covering 13.8 million people across 56 counties, we fit a generalized linear mixed model predicting new hospital admissions from wastewater concentrations of SARS-CoV-2 RNA from April 29, 2020 to June 30, 2022. We included covariates such as COVID-19 vaccine coverage in the county, comorbidities, demographic variables, and holiday gatherings. Findings: Wastewater concentrations of SARS-CoV-2 RNA correlated with new hospital admissions per 100,000 up to ten days prior to admission. Models that included wastewater had higher predictive power than models that included clinical cases only, increasing the accuracy of the model by 15%. Predicted hospital admissions correlated highly with observed admissions (r = 0.77) with an average difference of 0.013 hospitalizations per 100,000 (95% CI = [0.002, 0.025]). Interpretation: Using wastewater to predict future hospital admissions from COVID-19 is accurate and effective with superior results to using case data alone. The lead time of ten days could alert the public to take precautions and improve resource allocation for seasonal surges.

Predicting attitudes toward mitigation interventions and social distancing behaviors at the onset of the COVID-19 pandemic in the United States.

Aim: The goal of this research was to assess the influence of adult attachment, personality, and cultural orientation on social distancing and attitudes toward COVID-19 mitigation interventions. Methods: Survey data was collected across two samples (NMTurk = 201, Nsnowball = 242) in the US from April 29 to May 11, 2020. Adult attachment was assessed via the Experiences in Close Relationships Scale-Short Form (ECR-S; Wei, M., Russell, D. W., Mallinckrodt, B., & Vogel, D. L. (2007). The experiences in close relationship scale (ECR)-short form: Reliability, validity, and factor structure. Journal of Personality Assessment, 88(2), 187-204), personality was assessed via the Ten Item Personality Inventory (TIPI; Gosling, S. D., Rentfrow, P. J., & Swann, W. B. (2003). A very brief measure of the Big-Five personality domains. Journal of Research in Personality, 37(6), 504-528), cultural orientation was assessed via the Horizontal and Vertical Individualism and Collectivism Scale (Triandis, H. C., & Galfand, M. J. (1998). Converging measurement of horizontal and vertical individualism and collectivism. Journal of Personality and Social Psychology, 74(1), 118-128), and social distancing and attitudes toward mitigation interventions were assessed via self-report measures developed for this assessment. Results: In the MTurk sample, agreeableness (ß = .19) and conscientiousness (ß = .26) predicted positive mitigation intervention attitudes. Agreeableness (ß = .24) and vertical collectivism (ß = .25) positively predicted social distancing, while attachment anxiety (ß = -.32) and vertical individualism (ß = -.32) negatively predicted social distancing. In our snowball sample, residing primarily in New York, openness (ß = .18) and horizontal collectivism (ß = .16) predicted positive intervention attitudes, while horizontal individualism (ß = -.20) predicted negative attitudes. Social contact in this sample was low and not associated with predictor variables. In both samples, mitigation attitudes and social distancing were only moderately correlated. Implications: Our findings highlight the inherent inconsistency between attitudes and behaviors as well as the potential impact of mandated interventions on both attitudes and behavior.

Correction: A 10+10+30 radio campaign is associated with increased infant vaccination and decreased morbidity in Jimma Zone, Ethiopia: A prospective, quasi-experimental trial.

[This corrects the article DOI: 10.1371/journal.pgph.0001002.].

Wastewater Surveillance for Infectious Disease: A Systematic Review.

Wastewater surveillance for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to be a valuable source of information regarding SARS-CoV-2 transmission and coronavirus disease 2019 (COVID-19) cases. Although the method has been used for several decades to track other infectious diseases, there has not been a comprehensive review outlining all of the pathogens that have been surveilled through wastewater. Herein we identify the infectious diseases that have been previously studied via wastewater surveillance prior to the COVID-19 pandemic. Infectious diseases and pathogens were identified in 100 studies of wastewater surveillance across 38 countries, as were themes of how wastewater surveillance and other measures of disease transmission were linked. Twenty-five separate pathogen families were identified in the included studies, with the majority of studies examining pathogens from the family Picornaviridae, including polio and nonpolio enteroviruses. Most studies of wastewater surveillance did not link what was found in the wastewater to other measures of disease transmission. Among those studies that did, the value reported varied by study. Wastewater surveillance should be considered as a potential public health tool for many infectious diseases. Wastewater surveillance studies can be improved by incorporating other measures of disease transmission at the population-level including disease incidence and hospitalizations.

High Sensitivity and Specificity of Dormitory-Level Wastewater Surveillance for COVID-19 during Fall Semester 2020 at Syracuse University, New York.

A residential building's wastewater presents a potential non-invasive method of surveilling numerous infectious diseases, including SARS-CoV-2. We analyzed wastewater from 16 different residential locations at Syracuse University (Syracuse, NY, USA) during fall semester 2020, testing for SARS-CoV-2 RNA twice weekly and compared the presence of clinical COVID-19 cases to detection of the viral RNA in wastewater. The sensitivity of wastewater surveillance to correctly identify dormitories with a case of COVID-19 ranged from 95% (95% confidence interval [CI] = 76-100%) on the same day as the case was diagnosed to 73% (95% CI = 53-92%), with 7 days lead time of wastewater. The positive predictive value ranged from 20% (95% CI = 13-30%) on the same day as the case was diagnosed to 50% (95% CI = 40-60%) with 7 days lead time. The specificity of wastewater surveillance to correctly identify dormitories without a case of COVID-19 ranged from 60% (95% CI = 52-67%) on the day of the wastewater sample to 67% (95% CI = 58-74%) with 7 days lead time. The negative predictive value ranged from 99% (95% CI = 95-100%) on the day of the wastewater sample to 84% (95% CI = 77-91%) with 7 days lead time. Wastewater surveillance for SARS-CoV-2 at the building level is highly accurate in determining if residents have a COVID-19 infection. Particular benefit is derived from negative wastewater results that can confirm a building is COVID-19 free.

A 10+10+30 radio campaign is associated with increased infant vaccination and decreased morbidity in Jimma Zone, Ethiopia: A prospective, quasi-experimental trial.

Mass media interventions have the potential to reach large audiences and influence health behaviours and outcomes. To date, no study has evaluated the effect of a radio-only campaign on infant vaccination coverage, timeliness, and related morbidity in a low-income country. We implemented the "10+10+30" radio campaign involving broadcasting a weekly 10-minute radio drama series on vaccination, followed by a 10-minute discussion by community health workers, and then a 30-minute listener phone-in segment in Jimma Zone, Ethiopia for three months. To assess the impact of 10+10+30, which was aired on a community radio station, we recruited mothers of infants up to 5 weeks old in intervention district clusters that were inside the radio station's reception range (n = 328 dyads) and control district clusters that were outside of the range (n = 332 dyads). Intention-to-treat and per-protocol analyses, adjusted for pre-intervention differences between the districts, were conducted to examine the co-primary outcome of Penta-3 vaccination coverage and timeliness as well as those of other vaccines and outcomes related to infant morbidity. Both intention-to-treat and per-protocol analyses revealed higher vaccine coverage (p<0.001) and more timely vaccine administration (p<0.001) in the intervention district relative to the control district, with infants in the intervention district being 39% more likely to receive a Penta 3 vaccination (adjusted RR: 1.39, p<0.001). In addition, adjusted regression analyses of maternal retrospective reports over a two-week period revealed 80% less infant diarrhoea (RR: 0.20, p<0.001), 40% less fever (RR: 0.60, p<0.001) and 58% less cough (RR: 0.42, p<0.001) in the intervention district relative to the control district. This study provides compelling initial evidence that a radio drama integrated with discussion and phone-in components may improve infant vaccination coverage and timeliness, and may reduce infant morbidity. Randomized controlled trials are needed to confirm and extend these findings with other samples.

The association of cultural orientation with adherence to social distancing behaviors during the early COVID-19 pandemic in the United States: A cross-sectional survey.

Non-pharmaceutical interventions are one of the major tools to prevent the spread of SARS-CoV-2. Information about these behaviors is disseminated by messaging campaigns. However, people differ in their responses to persuasive messages. Here, we examine whether cultural orientation is associated with adherence to recommended COVID-19 prevention guidelines. Participants (n = 443, 201 from the United States via Amazon Mechanical Turk and 242 from Central New York via a convenience, snowball sample) completed an online survey during April and May 2020. Cultural orientation was measured via the Horizontal and Vertical Individualism and Collectivism Scale. Adherence to limiting social contact was self-reported. Multi-level Poisson regression assessed the association between cultural orientation and social contact behaviors. Those high in horizontal individualist characteristics had a positive association with increased social contact behaviors (RR: 2.20, 95%CI: 1.97-2.47, p<0.001). Those high in vertical collectivist characteristics had a negative association with those behaviors (RR: 0.59, 95%CI: 0.52-0.67, p<0.000). We found an association with cultural orientation and adherence to social contact behaviors during the beginning of the COVID-19 pandemic. In the United States, effective public health messages to promote adherence to preventative behaviors should be tailored to horizontal individualists, those least likely to engage in recommended behaviors.

Comparability of 24-hour composite and grab samples for detection of SARS-2-CoV RNA in wastewater.

Wastewater surveillance is a cost-effective way to monitor pathogen prevalence and transmission patterns in the entire community. Here, we compare 24-hour composite and grab samples collected during September 2020 from several municipalities in New York State to detect SARS-CoV-2. A total of 45 paired samples (90 total samples) from three counties and 14 wastewater treatment plants were available for analysis. The categorical comparison (SARS-CoV-2 genetic material detected and quantifiable, genetic material detected but below the limits of quantification, and genetic material not detected) between the grab and composite samples was quite strong, with 91.1% agreement (kappa P-value < .001). The correlations among the quantifiable grab and composite samples were statistically significant yet modest for SARS2-CoV RNA (Pearson correlation = 0.44, P = .02), crAssphage cDNA (Pearson correlation = 0.36, P = .02), and crAssphage DNA (Pearson correlation = 0.46, P = .002). We found good comparison between grab and 24-hour composite samples for detecting SARS-CoV-2 RNA from municipal wastewater treatment plants. Grab sampling is an efficient and cost-effective method to monitor for the presence of SARS-CoV-2 in the entire community.

Coupling freedom from disease principles and early warning from wastewater surveillance to improve health security.

Infectious disease surveillance is vitally important to maintaining health security, but these efforts are challenged by the pace at which new pathogens emerge. Wastewater surveillance can rapidly obtain population-level estimates of disease transmission, and we leverage freedom from disease principles to make use of nondetection of SARS-CoV-2 in wastewater to estimate the probability that a community is free from SARS-CoV-2 transmission. From wastewater surveillance of 24 treatment plants across upstate New York from May through December of 2020, trends in the intensity of SARS-CoV-2 in wastewater correlate with trends in COVID-19 incidence and test positivity (⍴ > 0.5), with the greatest correlation observed for active cases and a 3-day lead time between wastewater sample date and clinical test date. No COVID-19 cases were reported 35% of the time the week of a nondetection of SARS-CoV-2 in wastewater. Compared to the United States Centers for Disease Control and Prevention levels of transmission risk, transmission risk was low (no community spared) 50% of the time following nondetection, and transmission risk was moderate or lower (low community spread) 92% of the time following nondetection. Wastewater surveillance can demonstrate the geographic extent of the transmission of emerging pathogens, confirming that transmission risk is either absent or low and alerting of an increase in transmission. If a statewide wastewater surveillance platform had been in place prior to the onset of the COVID-19 pandemic, policymakers would have been able to complement the representative nature of wastewater samples to individual testing, likely resulting in more precise public health interventions and policies.

Age at League Entry and Early All-Cause Mortality among National Football League Players.

BACKGROUND: A growing body of research suggests that American football players are exposed to higher cumulative head impact risk as competition level rises. Related literature finds that head impacts absorbed by youth, adolescent, and emerging adult players are associated with elevated risk of long-term health problems (e.g., neurodegenerative disease onset). Most National Football League (NFL) players enter the League as emerging adults (18-24 years old), a period of continued cognitive and overall physical development. However, no prior research has studied the effect of age-at-entry on long-term NFL player health. Hypothesis/Purpose: This study assesses whether early NFL player age-at-entry is associated with increased risk of early all-cause mortality, controlling for player position, BMI, year-of-entry, birth year, and NFL Draft round (expected ability upon League entry). STUDY DESIGN: This retrospective cohort study included 9049 players who entered the NFL from 1970-2017 and subsequently played at least one game. The variables whether deceased, age-at-death, age-at-entry, and controls were collected from Pro Football Reference website, a leading data site for American football that has been used extensively in the literature. Data collection began on 13 July 2017, and follow-up ended on 1 July 2018. Statistical analysis was performed from 10 March 2020 to 3 August 2020. Data was validated by checking a large sub-sample of data points against alternative sources such as NFL.com and NFLsavant.com. METHODS: Cox proportional hazards regression models were used to examine variation in death hazard by NFL player age-at-entry, conditional upon a full set of controls. RESULTS: Conditional on controls, Cox regression results indicate that a one-year increase in age-at-entry was significantly associated with a 14% decreased hazard-of-death (H.R., 0.86; 95% CI, 0.74-0.98). Among relatively young entering players, the increased hazard appears to be concentrated in the first quartile of players by age at League entry (20.2 to 22.3 years). Players not in this quartile exhibited a decreased hazard-of-death (H.R., 0.74; 95% CI, 0.57-0.97) compared with players who entered at a relatively young (first quartile) age. CONCLUSION: An earlier age-at-entry is associated with an increased hazard-of-death among NFL players. Currently, the NFL regulates age-at-entry only indirectly by requiring players to be 3 years removed from high school before becoming NFL Draft-eligible. Implementing a minimum age at entry for NFL players of 22 years and 4 months at beginning of season is expected to result in reduced mortality. What is known about this subject? There are no prior studies on the effects of NFL player age-at-entry on early mortality risk. What this study adds to existing knowledge: This study determines whether entering the NFL at an age of physical and physiological development is related to early mortality risk.

Community-level impacts of sanitation coverage on maternal and neonatal health: a retrospective cohort of survey data.

INTRODUCTION: Access to sanitation facilities (toilets or latrines) greatly improves human health. Low community sanitation coverage may lead to increased exposure to pathogens for households both with and without a sanitation facility. METHODS: We created a retrospective cohort using Demographic and Health Surveys from 1990 through 2018. Using regression with matched women as a random intercept, we assessed the association between community-level sanitation coverage and neonatal mortality (Poisson model, n=1 254 862 live births, 187 datasets), small birth size (logit model, n=1 058 843 live births, 187 datasets) and anaemia (logit model, n=1 304 626 women, 75 datasets). RESULTS: Among women with household sanitation, the incidence of neonatal death (incidence rate ratio: 0.85, 95% CI 0.77 to 0.93), the odds of small birth size (OR: 0.81, 95% CI 0.76 to 0.87) and anaemia (OR: 0.82, 95% CI 0.79 to 0.85) were lower for women in communities with 100% sanitation coverage compared with 1%-30% (p≤0.001 for all). There was no difference in neonatal deaths between women in communities with 31%-99% sanitation coverage compared with 1%-30% (p≥0.05). Among women without household sanitation, there were no differences in neonatal mortality by community sanitation (p≥0.05). The odds of small birth size were decreased (OR: 0.91, 95% CI 0.87 to 0.97, p=0.003) for women in communities with 61%-99% sanitation coverage compared with 1%-30%; there was no association with the other community sanitation categories (p≥0.05). The odds of anaemia were increased (OR: 1.08, 95% CI 1.06 to 1.11, p<0.001) for women living in communities with 0% sanitation coverage compared with 1%-30%, but no association with the other community sanitation categories (p≥0.05). CONCLUSION: Community sanitation coverage is associated with improved maternal and neonatal outcomes, particularly among women with household sanitation. This suggests that the impact of sanitation coverage on maternal and neonatal health is underestimated unless the community-level effects are considered.

Wastewater monitoring, surveillance and epidemiology: a review of terminology for a common understanding.

Response to the COVID-19 (coronavirus disease 2019) pandemic saw an unprecedented uptake in bottom-up efforts to incorporate community wastewater testing to inform public health. While not a new strategy, various specialized scientific advancements were achieved to establish links between wastewater concentrations of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and public health outcomes. Maximizing public health benefit requires collaboration among a broad range of disciplinary experts, each bringing their own historical context to the central goal of protecting human health. One challenge has been a lack of shared terminology. Standardized terminology would provide common ground for this rapidly growing field. Based on the review herein, we recommend categorical usage of the term 'wastewater-based epidemiology' to describe the science of relating microbes, chemicals or other analytes in wastewater to public health. We further recommend the term 'wastewater surveillance' to describe continuous monitoring of health outcomes (either microbes or chemicals) via wastewater. We suggest that 'wastewater tracking' and 'wastewater tracing' be used in more narrow ways, specifically when trying to find the source of a health risk. Finally, we suggest that the phrase 'wastewater monitoring' be abandoned, except in rare circumstances when ensuring wastewater discharge is safe from a public health perspective.

Historical Analysis of the Risk of Hepatitis E and Its Complications in Pregnant Women in Nepal, 1996-1998.

Hepatitis E (HE) during pregnancy can be fatal; there are no prospective risk estimates for HE and its complications during pregnancy. We followed 2,404 pregnant women for HE and pregnancy outcomes from 1996 to 1998. Subjects from Nepal were enrolled at an antenatal clinic with pregnancy of ≤ 24 weeks. Most women (65.1%) were anti-HE virus negative. There were 16 cases of HE (6.7 per 1,000); three mothers died (18.8%) having had intrauterine fetal death (IUFD). Thirteen mothers survived: five preterm and seven full-term deliveries, one IUFD. HE among seronegative women was the sole cause of maternal death and increased the risk of IUFD (relative risk [RR]: 10.6; 95% confidence interval [CI]: 4.29-26.3) and preterm delivery (RR: 17.1, 95% CI 7.56-38.5). HE vaccination of females in at-risk regions before or as they attain reproductive age would reduce their risk for preterm delivery, IUFD, and maternal death.

Co-quantification of crAssphage increases confidence in wastewater-based epidemiology for SARS-CoV-2 in low prevalence areas.

Wastewater surveillance of SARS-CoV-2 RNA is increasingly being incorporated into public health efforts to respond to the COVID-19 pandemic. In order to obtain the maximum benefit from these efforts, approaches to wastewater monitoring need to be rapid, sensitive, and relatable to relevant epidemiological parameters. In this study, we present an ultracentrifugation-based method for the concentration of SARS-CoV-2 wastewater RNA and use crAssphage, a bacteriophage specific to the human gut, to help account for RNA loss during transit in the wastewater system and sample processing. With these methods, we were able to detect, and sometimes quantify, SARS-CoV-2 RNA from 20 mL wastewater samples within as little as 4.5 hours. Using known concentrations of bovine coronavirus RNA and deactivated SARS-CoV-2, we estimate recovery rates of approximately 7-12% of viral RNA using our method. Results from 24 sewersheds across Upstate New York during the spring and summer of 2020 suggested that stronger signals of SARS-CoV-2 RNA from wastewater may be indicative of greater COVID-19 incidence in the represented service area approximately one week in advance. SARS-CoV-2 wastewater RNA was quantifiable in some service areas with daily positives tests of less than 1 per 10,000 people or when weekly positive test rates within a sewershed were as low as 1.7%. crAssphage DNA concentrations were significantly lower during periods of high flow in almost all areas studied. After accounting for flow rate and population served, crAssphage levels per capita were estimated to be about 1.35 × 1011 and 2.42 × 108 genome copies per day for DNA and RNA, respectively. A negative relationship between per capita crAssphage RNA and service area size was also observed likely reflecting degradation of RNA over long transit times. Our results reinforce the potential for wastewater surveillance to be used as a tool to supplement understanding of infectious disease transmission obtained by traditional testing and highlight the potential for crAssphage co-detection to improve interpretations of wastewater surveillance data.

Routine deworming during antenatal care decreases risk of neonatal mortality and low birthweight: A retrospective cohort of survey data.

BACKGROUND: Soil transmitted helminths (STH) are a common infection among pregnant women in areas with poor access to sanitation. Deworming medications are cheap and safe; however, the health benefit of deworming during pregnancy is not clear. METHODS / PRINCIPAL FINDINGS: We created a retrospective cohort of more than 800,000 births from 95 Demographic and Health Survey datasets to estimate the impact of deworming medicine during routine antenatal care (ANC) on neonatal mortality and low birthweight. We first matched births on the probability of receiving deworming during ANC. We then modeled the birth outcomes with the matched group as a random intercept to estimate the effect of deworming during antenatal care after accounting for various risk factors. We also tested for effect modification of soil transmitted helminth prevalence on the impact of deworming during ANC. Receipt of deworming medication during ANC was associated with a 14% reduction in the risk of neonatal mortality (95% confidence interval = 10-17%, n = 797,772 births), with no difference between high and low transmission countries. In low transmission countries, we found an 11% reduction in the odds of low birth weight (95% confidence interval = 8-13%) for women receiving deworming medicine, and in high transmission countries, we found a 2% reduction in the odds of low birthweight (95% confidence interval = 0-5%). CONCLUSIONS / SIGNIFICANCE: These results suggest a substantial health benefit for deworming during ANC that may be even greater in countries with low STH transmission.

Seroprevalence of hepatitis E virus antibodies in adults and children from upstate New York: A cross-sectional study.

Hepatitis E virus (HEV) is a major cause of viral hepatitis around the world, especially in developing countries. Recently, HEV has also been recognized as important cause of hepatitis in Europe and Japan, however, there is a paucity of clinical data from the United States. The overall seroprevalence of HEV antibodies is around 10% in the United States, but considerable variation is seen based on geographic location, year, and assay used. In this study, 63 adults and 417 children from New York State were tested for anti-HEV IgG antibodies using the commercially available Wantai IgG assay. The overall seroprevalence of HEV antibodies among adult participants was 9.52% (95% CI: 3.58-19.59%). Positive adults tended to be older than HEV negative adults, all positive adults were female. Only 3 (0.7%, 95% CI:: 0.15-2.09%) of the children were positive, all positive children were male. These results are consistent with global and United States trends in HEV seroprevalence.

High-throughput wastewater analysis for substance use assessment in central New York during the COVID-19 pandemic.

Wastewater entering sewer networks represents a unique source of pooled epidemiological information. In this study, we coupled online solid-phase extraction with liquid chromatography-high resolution mass spectrometry to achieve high-throughput analysis of health and lifestyle-related substances in untreated municipal wastewater during the coronavirus disease 2019 (COVID-19) pandemic. Twenty-six substances were identified and quantified in influent samples collected from six wastewater treatment plants during the COVID-19 pandemic in central New York. Over a 12 week sampling period, the mean summed consumption rate of six major substance groups (i.e., antidepressants, antiepileptics, antihistamines, antihypertensives, synthetic opioids, and central nervous system stimulants) correlated with disparities in household income, marital status, and age of the contributing populations as well as the detection frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in wastewater and the COVID-19 test positivity in the studied sewersheds. Nontarget screening revealed the covariation of piperine, a nontarget substance, with SARS-CoV-2 RNA in wastewater collected from one of the sewersheds. Overall, this proof-of-the-concept study demonstrated the utility of high-throughput wastewater analysis for assessing the population-level substance use patterns during a public health crisis such as COVID-19.

Association of Professional Football Cumulative Head Impact Index Scores With All-Cause Mortality Among National Football League Players.

Importance: Long-term adverse health outcomes, particularly those associated with repetitive head impacts, are of growing concern among US-style football players in the US and Canada. Objective: To assess whether exposure to repetitive head impacts during a professional football career is associated with an increase in the risk of all-cause mortality. Design, Setting, and Participants: This retrospective cohort study included 13 912 players in the 1969 to 2017 National Football League (NFL) seasons. All cause-mortality up until July 1, 2018, was included. Data collection was performed from July 13, 2017, to July 1, 2018, as reported in the Pro Football Reference. Exposures: The main exposure was a professional football cumulative head impact index (pfCHII). The pfCHII was measured by combining cumulative padded practice time and games played summed during seasons of play reported in the Pro Football Reference and a player position risk adjustment from helmet accelerometer studies. Main Outcomes and Measures: Demographic characteristics except for the pfCHII were calculated for 14 366 players with complete follow-up. The pfCHII was calculated for 13 912 players (eliminating the 454 specials teams players). Cox proportional hazards regression was used to compare hazard ratios (HRs) of death by repetitive head impacts. Analyses were unadjusted and adjusted for birth year, body mass index, and height. Results: Among 14 366 NFL players who had follow-up for analysis, the mean (SD) age was 47.3 (14.8) years, the mean (SD) body mass index was 29.6 (3.9), and 763 of 14 366 players (5.3%) had died. Among 13 912 players in the pfCHII analysis, the median pfCHII was 32.63 (interquartile range, 13.71-66.12). A 1-log increase in pfCHII was significantly associated with an increased hazard of death for the 1969 to 2017 seasons (HR, 2.02; 95% CI, 1.21-3.37; P = .01) after adjustment. The quadratic pfCHII was also statistically significant (HR, 0.91; 95% CI, 0.85-0.98; P = .01), indicating that the hazard of death increased at a decreasing rate, whereas the pfCHII increased. Conclusions and Relevance: The findings suggest that an increase in repetitive head impacts is associated with an increased hazard of death among NFL players. Reduction in repetitive head impacts from playing football or other activities through additional rule and equipment changes may be associated with reduced mortality.