Robert J. Reynolds

Mortality and causes of death in persons with Down syndrome in California

This study investigated mortality and causes of death between 1988 and 1999 in 14781 persons (6702 female) with Down syndrome in California, comparing age, sex, ethnicity, and other factors. Mean age at the start of follow-up was 14 years 8 months (SD 14y 10mo). During the study period 600 persons died. The standardized mortality ratio (SMR) for the population was 5.5. Blacks were at greater risk than whites, Hispanics, or Asians (relative risk = 1.5). Mortality declined during the period, especially for children with congenital heart defects. Leukemia (SMR = 17), respiratory illnesses (SMR = 27), congenital anomalies (SMR = 72), and circulatory diseases (SMR = 5.3) accounted for most of the excess mortality. With the exception of leukemia, cancer mortality was not different from that of the general population.

Survival in cerebral palsy in the last 20 years : signs of improvement?

This study investigated the possibility of improved survival in cerebral palsy (CP) over a 20‐year period. Participants were 47 259 persons with CP receiving services from the State of California between 1983 and 2002. The person–year approach was used. This asks whether the probability of dying in a given calendar year changes over the study period after age and severity of disability are taken into account. An appreciable improvement over time was found in children with severe disabilities and in adults who required gastrostomy feeding. In these groups, mortality rates fell by 3.4% per year. Therefore, life expectancies reported in earlier studies should be increased by approximately 5 years if adjustments to 2002 mortality rates are made. For other persons with CP there was, at most, a small improvement over the 20‐year period. The results suggest there have been improvements in the treatment and care of the most medically fragile children. Gastrostomy feeding has become much more widespread over the past two decades, and the improved survival of persons with gastrostomies may reflect better understanding of their requirements.

Change in ambulatory ability of adolescents and young adults with cerebral palsy.

This study aimed to determine the probability that a child with cerebral palsy (CP) will lose or gain ambulatory ability through adolescence and young adulthood. We analyzed retrospectively data from 1987 to 2002 on Californians with CP initially aged 10 years (SD 0.9y; n=7550 [4304 males, 3246 females]) and 25 years (SD 0.8y; n=5721 [3261 males, 2460 females]) who had varying levels of ambulatory ability (initial Gross Motor Function Classification System Levels I‐IV). We used the Aalen‐Johansen estimator to estimate probabilities of transition to other levels of ambulatory ability in the future. Those who walked and climbed stairs without difficulty at age 10 had only a 23% chance of decline (to requiring a handrail to manage stairs, or worse) 15 years later. Those who ambulated with some difficulty but did not use a wheelchair had a significant chance (33%) of improvement (to being able to walk unsteadily alone at least 3m or better) and only a small chance (11%) of becoming non‐ambulatory. Those who used a wheelchair were more likely to lose ambulatory ability (34%) or die (6%). Those who walked and climbed stairs well at age 25 were likely to maintain that ability 15 years later (76%), while those needing support to climb stairs were more likely to lose ability. Improvement in ambulation after age 25 was unlikely. Children and young adults with CP are likely to maintain their ambulatory ability during their next 15 years. Some who ambulate with difficulty at age 10 may improve through adolescence, but those who use a wheelchair are more likely to decline. By age 25 improvement in ambulation is unlikely and decline more likely. Most, however, will not change over the next 15 years.

Coordination and management of multicenter clinical studies in trauma: Experience from the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) Study☆

AIM Early death due to hemorrhage is a major consequence of traumatic injury. Transfusion practices differ among hospitals and it is unknown which transfusion practices improve survival. This report describes the experience of the PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) Study Data Coordination Center in designing and coordinating a study to examine transfusion practices at ten Level 1 trauma centers in the US. METHODS PROMMTT was a multisite prospective observational study of severely injured transfused trauma patients. The clinical sites collected real-time information on the timing and amounts of blood product infusions as well as colloids and crystalloids, vital signs, initial diagnostic and clinical laboratory tests, life saving interventions and other clinical care data. RESULTS Between July 2009 and October 2010, PROMMTT screened 12,561 trauma admissions and enrolled 1245 patients who received one or more blood transfusions within 6h of Emergency Department (ED) admission. A total of 297 massive transfusions were observed over the course of the study at a combined rate of 5.0 massive transfusion patients/week. CONCLUSION PROMMTT is the first multisite study to collect real-time prospective data on trauma patients requiring transfusion. Support from the Department of Defense and collaborative expertise from the ten participating centers helped to demonstrate the feasibility of prospective trauma transfusion studies. The observational data collected from this study will be an invaluable resource for research in trauma surgery and it will guide the design and conduct of future randomized trials.

Mortality among U.S. astronauts: 1980-2009

INTRODUCTION It has been nearly 20 yr since the first published astronaut mortality analysis. Using astronaut vital data and general population mortality rates, we calculate Standardized Mortality Ratios (SMR) for both total and specific causes of death among astronauts between January 1980 and June 2009 to look for changes in mortality patterns over time. METHODS Astronaut vital data were derived from the Johnson Space Center website and the Astronaut Fact Book. General population mortality rates were taken from the Human Mortality Database and the Centers for Disease Control. SMR were computed as the ratio of observed deaths to expected deaths using indirect standardization to several comparison populations. RESULTS All SMR declined from the 1980s to the 2000s, though astronauts are still at increased risk of accidental death (SMR = 574, 95% C.I. 335-919). Astronauts are at greatly reduced risk of death by cardiovascular disease (SMR = 27, 95% C.I. 9-63) and cancer (SMR = 47, 95% C.I. 19-97), and astronauts are now at decreased risk of all-cause mortality compared with the general population. DISCUSSION The SMR show that mortality from circulatory disease, cancer, and accidents have all declined from previous estimates, though astronauts are still at increased risk of accidental death. Improvements in circulatory disease mortality are likely due to intensive health screening and physical fitness within the Astronaut Corps. Similarly, physical fitness may be contributing to the reduction in cancer mortality. Fewer airplane crashes have contributed to the decreased risk of fatal accidents, which in turn is driving the reduction in all-cause mortality risk.

Survival and mobility in open spina bifida: Comparison of results from the United States and the United Kingdom

The prognosis for survival in spina bifida is an important issue for life-care planners and care-givers. This study documents and compares long-term survival in open spina bifida in California, United States of America, and Cambridge, United Kingdom and investigates the relation between mobility in childhood and long-term survival. Survival after the age 6 years was similar in the two series, with a mortality rate of approximately 1% per year. Data from the California series showed that long-term survival was associated with gross motor function, specifically the ability to crawl or to stand without support. In the Cambridge cohort, mobility at mean age 9 years was a significant predictor of survival at the mean age of 35 years. We conclude that better gross motor function is associated with longer survival in open spina bifida.

Mortality among Soviet and Russian cosmonauts: 1960-2013

INTRODUCTION Though the mortality of U.S. astronauts has been studied repeatedly in the last 20 yr, little is known about the long-term mortality trends of Soviet and Russian cosmonauts. METHODS Using data from 266 cosmonauts accepted into cosmonaut training from 1960 to 2013, we document the causes of death and crude death rates among cosmonauts. Using standardized mortality ratios (SMR), we compared cosmonauts to the general populations of Russia and Ukraine, and to 330 U.S. astronauts. RESULTS Cosmonauts experienced significantly lower all-cause mortality risk compared to the general population. However, cosmonauts were at almost double the risk of all-cause mortality in comparison to U.S. astronauts (SMR = 190, 95% C.I. 154-239). Cosmonauts were also at greater risk of circulatory disease (SMR = 364, 95% C.I. 225-557) and cancer (SMR = 177, 95% C.I. 108-274) compared to U.S. astronauts. Though not statistically significant, cosmonauts experienced fewer fatal accidents (SMR = 88, 95% C.I. = 54-136) than their U.S. counterparts. DISCUSSION Cosmonauts are at much lower risk of all-cause mortality than the general populations of Russia and Ukraine, yet are at greater risk for death by cardiovascular disease and cancer than are U.S. astronauts. This disparity may have common roots with decreases in life expectancy in Russia in recent decades. Further research is needed to understand these trends fully.

Risk factors for cerebral palsy: current knowledge and future causal inference

McIntyre et al. present a useful systematic review of studies of risk factors for cerebral palsy (CP) in term births. They correctly point out that CP is likely to be the result of a large number of complex causal pathways; many of these may be poorly understood or as yet unknown. The systematic review identified ten risk factors consistently associated with CP and the authors propose the development of a clearinghouse of observational and experimental data that may help researchers pinpoint causal pathways for CP. It is hoped that this may ultimately lead to more effective preventive strategies. To have the best chance at prevention, a clear understanding of the causal pathways to CP will indeed be critical. Some important questions immediately arise. Which, if any, of the risk factors identified by McIntyre et al., or which may be discovered in the future, is truly a cause of CP? Does the presence or severity of any risk factor directly change the probability of a child developing CP? Or is a given risk factor part of a causal chain, influencing other causal factors but having no direct relationship to CP? Might some risk factors be causal in both senses? Until relatively recently, there was simply no rigorous statistical framework for measuring the strength of evidence for causal relationships in medical research, much less for differentiating types of causal relationships. Today, however, a modern and rigorous theory of causality does exist, thanks to a growing body of research by Pearl et al. on the use of directed acyclic graphs, and related methods, in epidemiology. While our own experience with these methods is not vast, we appreciate the value they add in analyzing the impact of an exposure on an outcome. We also understand that if one wishes to measure the causal effect of a given exposure (e.g. neonatal infections) on an outcome (CP), then the following three points, taken from Pearl, are critical: (1) strong predictors of exposure should be excluded from the analysis; (2) factors affecting outcome (or their proxies) are safer and more effective bias reducers than those affecting exposure; and (3) consideration of covariate selection should be grounded in structural assumptions (they cannot be left at the mercy of conventional wisdom, however entrenched). In item 2, one may ponder exactly what Pearl means by ‘safer’. We will return to this. In the modern theory of causality, a directed acyclic graph may be drawn to represent the researchers’ best understanding of the causal relationships between exposures, confounders, and outcome, including possible intermediate causes and unmeasured confounders. From such a graph, and under certain assumptions, one can determine which variables ought to be included in a multivariate analysis in order to minimize the bias in the estimated effects of the exposures of interest. For example, the theory would suggest that if we want to measure the causal effect of neonatal infection on CP, then controlling for birth asphyxia (a factor affecting the outcome, CP) is more likely to reduce bias (i.e. ‘safer’) than controlling for maternal infection (a factor affecting exposure, neonatal infection), which may well increase bias. That controlling for variables more closely associated with exposure than with outcome can amplify bias is a corollary of this causal theory, and is contrary to conventional wisdom. This may be one of the theory’s most significant contributions to modern epidemiology. The call for research into primary prevention in CP is timely. The review by McIntyre et al. provides valuable information for researchers seeking to build a causal framework for CP. Tools (directed acyclic graphs and related methods) to more effectively characterize the causal relationships now exist and are quickly gaining ground in epidemiology. We are hopeful they will soon gain ground in the epidemiology of CP and other developmental disabilities, and that effective new preventive strategies will eventually result.

Mortality Due to Cardiovascular Disease Among Apollo Lunar Astronauts

INTRODUCTION Recent research has postulated increased cardiovascular mortality for astronauts who participated in the Apollo lunar missions. The conclusions, however, are based on small numbers of astronauts, are derived from methods with known weaknesses, and are not consistent with prior research. METHODS Records for NASA astronauts and U.S. Air Force astronauts were analyzed to produce standardized mortality ratios. Lunar astronauts were compared to astronauts who have never flown in space (nonflight astronauts), those who have only flown missions in low Earth orbit (LEO astronauts), and the U.S. general population. RESULTS Lunar astronauts were significantly older at cohort entry than other astronaut group and lunar astronauts alive as of the end of 2015 were significantly older than nonflight astronauts and LEO astronauts. No significant differences in cardiovascular disease (CVD) mortality rates between astronaut groups was observed, though lunar astronauts were noted to be at significantly lower risk of death by CVD than are members of the U.S. general population (SMR = 13, 95% CI = 3-39). DISCUSSION The differences in age structure between lunar and nonlunar astronauts and the deaths of LEO astronauts from external causes at young ages lead to confounding in proportional mortality studies of astronauts. When age and follow-up time are properly taken into account using cohort-based methods, no significant difference in CVD mortality rates is observed. Care should be taken to select the correct study design, outcome definition, exposure classification, and analysis when answering questions involving rare occupational exposures.Reynolds RJ, Day SM. Mortality due to cardiovascular disease among Apollo lunar astronauts. Aerosp Med Hum Perform. 2017; 88(5):492-496.

Extrapolating published survival curves to obtain evidence-based estimates of life expectancy in cerebral palsy.

Studies reporting long‐term survival probabilities for cohorts of persons with cerebral palsy provide evidence‐based information on the life expectancy of those cohorts. Some studies have provided estimates of life expectancy based on extrapolation of such evidence, whereas many others have opted not to do so. Here we review the basic methods of life table analysis necessary for performing such extrapolations, and apply these methods to obtain evidence‐based estimates of life expectancy from several studies that do not report such estimates themselves.