Modeling Longitudinal Data Containing Non-Normal Within Subject Errors

The mission of the National Aeronautics and Space Administrations (NASA) human research program is to advance safe human spaceflight. This involves conducting experiments, collecting data, and analyzing data. The data are longitudinal and result from a relatively few number of subjects; typically 10 20. A longitudinal study refers to an investigation where participant outcomes and possibly treatments are collected at multiple follow-up times. Standard statistical designs such as mean regression with random effects and mixedeffects regression are inadequate for such data because the population is typically not approximately normally distributed. Hence, more advanced data analysis methods are necessary. This research focuses on four such methods for longitudinal data analysis: the recently proposed linear quantile mixed models (lqmm) by Geraci and Bottai (2013), quantile regression, multilevel mixedeffects linear regression, and robust regression. This research also provides computational algorithms for longitudinal data that scientists can directly use for human spaceflight and other longitudinal data applications, then presents statistical evidence that verifies which method is best for specific situations. This advances the study of longitudinal data in a broad range of applications including applications in the sciences, technology, engineering and mathematics fields

Statistical Outlier Detection (SOD): A computer program for detecting outliers in data

There are no author-identified significant results in this report

Designing an Exploration Atmosphere Prebreathe Protocol

Extravehicular activities (EVAs) at remote locations must maximize limited resources such as oxygen (O2) and also minimize the risk of decompression sickness (DCS). A proposed remote denitrogenation (prebreathe) protocol requires astronauts to live in a mildly hypoxic atmosphere at 8.2 psia while periodically performing EVAs at 4.3 psia. Empirical data are required to confirm that the protocol meets the current accept requirements: less than or equal to 15% incidence of Type I DCS, less than or equal to 20% incidence of Grade IV venous gas emboli (VGE), both at 95% statistical confidence, with no Type II DCS symptom during the validation trial. METHODS: A repeated measures statistical design is proposed in which groups of 6 subjects with physical characteristics similar to active-duty astronauts would first become equilibrated to an 8.2 psia atmosphere in a hypobaric chamber containing 34% O2 and 66% N2, over 48 h, and then perform 4 simulated EVAs at 4.3 psia over the next 9 days. In the equilibration phase, subjects undergo a 3-h 100% O2 mask prebreathe prior to and during a 5-min ascent to 8.2 psia to prevent significant tissue N2 supersaturation on reaching 8.2 psia. Masks would be removed once 34% O2 is established at 8.2 psia, and subjects would then equilibrate to this atmosphere for 48 h. The hypoxia is equivalent to breathing air at 1,220 meters (4,000 ft) altitude, just as was experienced in the shuttle 10.2 psia - 26.5% O2 staged denitrogenation protocol and the current ISS campout denitrogenation protocol. For simulated EVAs, each subject dons a mask and breathes 85% O2 and 15% N2 during a 3-min depressurization to 6.0 psia, holds for 15 min, and then completes a 3-min depressurization to 4.3 psia. The simulated EVA period starts when 6.0 psia is reached and continues for a total of 240 min (222 min at 4.3 psia). During this time, subjects will follow a prescribed repetitive activity against loads in the upper and lower body with mean metabolic rate approaching 1500 BTU/hr [378 kcal/hr (O2 consumption about 1.3 l(sub STPD)/min)] in ambulatory subjects. Noninvasive Doppler ultrasound bubble monitoring for VGE in the pulmonary artery will be performed on subjects by 2 Doppler Technicians at about 15 min intervals while at 4.3 psia. At the end of this period, a 15-min repressurization returns all subjects back to 8.2 psia and the cycle is repeated 3 additional times with a day of rest between simulated EVAs. RESULTS: With an assumed 1.5% probability of DCS [P(DCS)] and accounting for within-subject correlation, running the proposed study with 20 subjects has a 95% probability of meeting the accept criterion for DCS. But if the true probability of DCS is 3.0%, then 30 subjects would be needed to achieve about the same probability to meet our accept criterion. These results assume a standard deviation of 1.4 for the between-subjects random component of P(DCS) on a logit scale, which was estimated from a previous study

NASA'S Standard Measures During Bed Rest: Adaptations in the Cardiovascular System

Bed rest is a well-accepted analog of space flight that has been used extensively to investigate physiological adaptations in a larger number of subjects in a shorter amount of time than can be studied with space flight and without the confounding effects associated with normal mission operations. However, comparison across studies of different bed rest durations, between sexes, and between various countermeasure protocols have been hampered by dissimilarities in bed rest conditions, measurement protocols, and testing schedules. To address these concerns, NASA instituted standard bed rest conditions and standard measures for all physiological disciplines participating in studies conducted at the Flight Analogs Research Unit (FARU) at the University of Texas-Medical Branch. Investigators for individual studies employed their own targeted study protocols to address specific hypothesis-driven questions, but standard measures tests were conducted within these studies on a non-interference basis to maximize data availability while reducing the need to implement multiple bed rest studies to understand the effects of a specific countermeasure. When possible, bed rest standard measures protocols were similar to tests nominally used for medically-required measures or research protocols conducted before and after Space Shuttle and International Space Station missions. Specifically, bed rest standard measures for the cardiovascular system implemented before, during, and after bed rest at the FARU included plasma volume (carbon monoxide rebreathing), cardiac mass and function (2D, 3D and Doppler echocardiography), and orthostatic tolerance testing (15- or 30-minutes of 80 degree head-up tilt). Results to-date indicate that when countermeasures are not employed, plasma volume decreases and the incidence of presyncope during head-up tilt is more frequent even after short-duration bed rest while reductions in cardiac function and mass are progressive as bed rest duration increases. Additionally, while plasma volume loss can be corrected and cardiac mass can be prevented with properly applied countermeasures, orthostatic tolerance is more difficult to protect when supine exercise is the only countermeasure. Similar results have been observed after space flight. Plasma volume, cardiac chamber volume, and orthostatic tolerance recover relatively quickly with resumption of ambulation and normal activity levels after bed rest but restoration of cardiac mass is prolonged

Towards Probablistic Assessment of Hypobaric Decompression Sickness Treatment

INTRODUCTION: Pressure, oxygen (O2), and time are the pillars to effective treatment of decompression sickness (DCS). The NASA DCS Treatment Model links a decrease in computed bubble volume to the resolution of a symptom. The decrease in volume is realized in two stages: a) during the Boyle's Law compression and b) during subsequent dissolution of the gas phase by the O2 window. METHODS: The cumulative distribution of 154 symptoms that resolved during repressurization was described with a log-logistic density function of pressure difference (deltaP as psid) associated with symptom resolution and two other explanatory variables. The 154 symptoms originated from 119 cases of DCS during 969 exposures in 47 different altitude tests. RESULTS: The probability of symptom resolution [P(symptom resolution)] = 1 / (1+exp(- (ln(deltaP) - 1.682 + 1.089AMB - 0.00395SYMPTOM TIME) / 0.633)), where AMB is 1 when the subject ambulated as part of the altitude exposure or else 0 and SYMPTOM TIME is the elapsed time in min from start of the altitude exposure to recognition of a DCS symptom. The P(symptom resolution) was estimated from computed deltaP from the Tissue Bubble Dynamics Model based on the "effective" Boyle's Law change: P2 - P1 (deltaP, psid) = P1V1/V2 - P1, where V1 is the computed volume of a spherical bubble in a unit volume of tissue at low pressure P1 and V2 is computed volume after a change to a higher pressure P2. V2 continues to decrease through time at P2, at a faster rate if 100% ground level O2 was breathed. The computed deltaP is the effective treatment pressure at any point in time as if the entire deltaP was just from Boyle's Law compression. DISCUSSION: Given the low probability of DCS during extravehicular activity and the prompt treatment of a symptom with options through the model it is likely that the symptom and gas phase will resolve with minimum resources and minimal impact on astronaut health, safety, and productivity

Maximum Oxygen Uptake During Long-Duration Space Flight: Preliminary Results

INTRODUCTION: Maximum oxygen uptake (VO2max) is maintained during space flight lasting <15 d, but has not been measured during long-duration missions. This abstract describes pre-flight and in-flight preliminary findings from the International Space Station (ISS) VO2max experiment. METHODS: Seven astronauts (4 M, 3 F: 47 +/- 5 yr, 174 +/- 7 cm, 74.1 +/- 14.7 kg [mean +/- SD]) performed cycle exercise tests to volitional maximum approx.45 d before flight and tests were scheduled every 30 d during flight beginning on flight day (FD) 14. Tests consisted of three 5-min stages designed to elicit 25%, 50%, and 75% of preflight VO2max, followed by 25 W/min increases. VO2 and heart rate (HR) were measured using the ISS Portable Pulmonary Function System (PPFS) (Damec, Odense, DK). Unfortunately the PPFS did not arrive at the ISS in time to support early test sessions for 3 crewmembers. Descriptive statistics are presented for pre-flight vs. late-flight (FD 147 +/- 33 d) comparisons for all subjects (n=7); and pre-flight, early (FD 18 +/- 3) and late-flight (FD 156 +/- 5) data are presented for subjects (n=4) who completed all of these test sessions. RESULTS: When all subjects are considered, average VO2max decreased from pre- to late in-flight (2.98 +/- 0.85 vs. 2.57 +/- 0.50 L/min) while maximum HR late-flight seemed unchanged (178 +/- 9 vs. 175 +/- 8 beats/min). Similarly, for subjects who completed pre-, early, and late flight measurements (n=4), mean VO2max declined from 3.19 +/- 0.75 L/min preflight to 2.43 +/- 0.43 and 2.62 +/- 0.38 L/min early and late-flight, respectively. Maximum HR was 183 +/- 8, 174 +/- 8, and 179 +/- 6 beats/min pre-, early- and late-flight. DISCUSSION: Average VO2max declined during flight and did not appreciably recover as flight duration increased; however much inter-subject variation occurred in these changes

Probabilistic Assessment of Hypobaric Decompression Sickness Treatment Success

The Hypobaric Decompression Sickness (DCS) Treatment Model links a decrease in computed bubble volume from increased pressure (DeltaP), increased oxygen (O2) partial pressure, and passage of time during treatment to the probability of symptom resolution [P(symptom resolution)]. The decrease in offending volume is realized in 2 stages: a) during compression via Boyle's Law and b) during subsequent dissolution of the gas phase via the O2 window. We established an empirical model for the P(symptom resolution) while accounting for multiple symptoms within subjects. The data consisted of 154 cases of hypobaric DCS symptoms along with ancillary information from tests on 56 men and 18 women. Our best estimated model is P(symptom resolution) = 1 / (1+exp(-(ln(Delta P) - 1.510 + 0.795AMB - 0.00308Ts) / 0.478)), where (DeltaP) is pressure difference (psid), AMB = 1 if ambulation took place during part of the altitude exposure, otherwise AMB = 0; and where Ts is the elapsed time in mins from start of the altitude exposure to recognition of a DCS symptom. To apply this model in future scenarios, values of DeltaP as inputs to the model would be calculated from the Tissue Bubble Dynamics Model based on the effective treatment pressure: (DeltaP) = P2 - P1 | = P1V1/V2 - P1, where V1 is the computed volume of a spherical bubble in a unit volume of tissue at low pressure P1 and V2 is computed volume after a change to a higher pressure P2. If 100% ground level O2 (GLO) was breathed in place of air, then V2 continues to decrease through time at P2 at a faster rate. This calculated value of (DeltaP then represents the effective treatment pressure at any point in time. Simulation of a "pain-only" symptom at 203 min into an ambulatory extravehicular activity (EVA) at 4.3 psia on Mars resulted in a P(symptom resolution) of 0.49 (0.36 to 0.62 95% confidence intervals) on immediate return to 8.2 psia in the Multi-Mission Space Exploration Vehicle. The P(symptom resolution) increased to near certainty (0.99) after 2 hrs of GLO at 8.2 psia or with less certainty on immediate pressurization to 14.7 psia [0.90 (0.83 - 0.95)]. Given the low probability of DCS during EVA and the prompt treatment of a symptom with guidance from the model, it is likely that the symptom and gas phase will resolve with minimum resources and minimal impact on astronaut health, safety, and productivity

Varicella Zoster Virus in Saliva of Patients With Herpes Zoster

Background. VZV DNA is present in saliva of healthy astronauts and patients with Ramsay Hunt syndrome (geniculate zoster). We hypothesized that a prospective analysis of patients with zoster would detect VZV in saliva independent of zoster location. Methods. We treated 54 patients with valacyclovir. On the first treatment day, 7- and 14-days later, pain was scored and saliva examined for VZV DNA. Saliva from six subjects with chronic pain and 14 healthy subjects was similarly studied. Results. Follow-up data was available for 50/54 patients. Pain decreased in 43/50 (86 percent), disappeared in 37 (74 percent), recurred after disappearing in three (6 percent) and increased in four (8 percent). VZV DNA was found in every patient the day treatment was started, decreased in 47/50 (94 percent), transiently increased in three (6 percent) before decreasing, increased in two (4 percent) and disappeared in 41 (82 percent). There was a positive correlation between the presence of VZV DNA and pain, as well as between the VZV DNA copy number and pain (P<0.0005). Saliva of two patients was cultured, and infectious VZV was isolated from one. VZV DNA was present in one patient before rash and in four patients after pain resolved, and not in any control subjects. Conclusion. VZV DNA is present in saliva of zoster patients

Cosmic-ray strangelets in the Earth's atmosphere

If strange quark matter is stable in small lumps, we expect to find such lumps, called ``strangelets'', on Earth due to a steady flux in cosmic rays. Following recent astrophysical models, we predict the strangelet flux at the top of the atmosphere, and trace the strangelets' behavior in atmospheric chemistry and circulation. We show that several strangelet species may have large abundances in the atmosphere; that they should respond favorably to laboratory-scale preconcentration techniques; and that they present promising targets for mass spectroscopy experiments.Comment: 28 pages, 4 figures, revtex

Overestimating Outcome Rates: Statistical Estimation When Reliability Is Suboptimal

To demonstrate how failure to account for measurement error in an outcome (dependent) variable can lead to significant estimation errors and to illustrate ways to recognize and avoid these errors. Data Sources . Medical literature and simulation models. Study Design/Data Collection . Systematic review of the published and unpublished epidemiological literature on the rate of preventable hospital deaths and statistical simulation of potential estimation errors based on data from these studies. Principal Findings . Most estimates of the rate of preventable deaths in U.S. hospitals rely upon classifying cases using one to three physician reviewers (implicit review). Because this method has low to moderate reliability, estimates based on statistical methods that do not account for error in the measurement of a “preventable death” can result in significant overestimation. For example, relying on a majority rule rating with three reviewers per case (reliability ∼0.45 for the average of three reviewers) can result in a 50–100 percent overestimation compared with an estimate based upon a reliably measured outcome (e.g., by using 50 reviewers per case). However, there are statistical methods that account for measurement error that can produce much more accurate estimates of outcome rates without requiring a large number of measurements per case. Conclusion . The statistical principles discussed in this case study are critically important whenever one seeks to estimate the proportion of cases belonging to specific categories (such as estimating how many patients have inadequate blood pressure control or identifying high-cost or low-quality physicians). When the true outcome rate is low (<20 percent), using an outcome measure that has low-to-moderate reliability will generally result in substantially overestimating the proportion of the population having the outcome unless statistical methods that adjust for measurement error are used.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74896/1/j.1475-6773.2006.00661.x.pd