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Postnatal steroid use in bronchopulmonary dysplasia (BPD) decreases lung inflammation but increases impairment (NDI). We hypothesized that increased dose is associated with increased NDI, lower postmenstrual age (PMA) at exposure increases NDI and risk of BPD modifies the effect of PNS.
Steroid dose and timing of exposure beyond 7 days was assessed among 2358 ELBW nested in a prospective trial, with 1667 (84%) survivors examined at 18-22 months PMA. Logistic regression tested the relationship between NDI (Bayley MDI/PDI < 70, disabling cerebral palsy (CP) or sensory impairment), total dose (tertiles < 0.9, 0.9-1.9, ≥ 1.9 mg/kg) and PMA at first dose. Separate logistic regression tested effect modification by BPD severity (Romagnoli Risk > 0.5 as high risk, n=2336 (99%) for days of life 4-7).
366 neonates (16%) were steroid treated (94% dexamethasone). Treated neonates were smaller and less mature. 72% of those treated were high risk for BPD. PNS exposure was associated with NDI/death (61 vs. 44%, p < 0.001). NDI increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg was associated with a 2.0 point reduction in MDI and a 40% risk increase in disabling CP. (OR 1.4, 95% CI: 1.2-1.6). Older PMA did not mitigate the harm. Treatment after 33 weeks PMA was associated with greatest harm (NDI/death OR 2.5, 95% CI: 1.1-5.5) despite not receiving highest dose. The relationship of PNS to NDI was modified by BPD risk, (High risk OR 1.9, 95% CI: 1.4-2.6; Low risk OR 2.9, 95% CI: 1.8-4.8) with those at highest risk experiencing less harm.
Higher PNS dose was associated with increased NDI. There is no “safe” window for PNS use in ELBWs. Neonates with low BPD risk should not be exposed. A randomized trial of PNS for infants at highest risk is warranted.
Postnatal steroid therapy was frequently prescribed during the 1990's to facilitate extubation and reduce bronchopulmonary dysplasia (BPD) by modifying lung inflammation.(1-3) However, multiple reports suggest various short and long term adverse effects, including hyperglycemia, hypertension, gastrointestinal perforation, increased rates of infection, particularly fungal sepsis, cardiac hypertrophy, severe retinopathy of prematurity, reduced head circumference and neurodevelopmental impairment.(4-11) In response to these reports, the American Academy of Pediatrics and Canadian Paediatric Society issued a recommendation discouraging the use of postnatal corticosteroids for the treatment of BPD (12), thus resulting in a dramatic reduction in the use of the therapy. (13) Controversy still exists regarding the possible beneficial effects of lower steroid doses and shorter durations of treatment. A recent study by Doyle, et al. suggests that low-dose dexamethasone after the first week of life shortens the duration of intubation among ventilator dependent, extremely low birth weight (ELBW) infants, without any obvious short-term complications, reopening debate regarding the potential role of low-dose postnatal corticosteroid therapy specifically for infants at high risk for BPD. (14) Furthermore, a recent metaregression reported a significant effect modification by risk for bronchopulmonary dysplasia. With a risk for BPD below 35%, corticosteroid treatment increased the chance of death or cerebral palsy, whereas with the risk for BPD exceeding 65%, it reduced this risk. (15) Currently, no information is available to determine if there is a particular steroid drug, dose or timing of exposure that results in improved short term pulmonary outcomes without adverse long term neurodevelopmental impact. We sought to evaluate the association of postnatal corticosteroid dose, postmenstrual age at time of exposure and the interaction of BPD risk with neurodevelopmental outcomes at 18-22 months among inborn ELBW children born during 2000-2004, enrolled in the NICHD Benchmarking Trial and exposed to postnatal corticosteroids after 7 days age compared to non-exposed ELBW children enrolled in the trial.
This study was a prospective cohort study nested within a randomized controlled trial designed to assess the utility of multimodal quality improvement methods to improve survival free of BPD. (16) Fourteen centers of the NICHD Neonatal Network enrolled 4093 neonates who were born in network centers between March 2001 and May 2004 with a birth weight less than 1250 grams. This study cohort included 2358 infants born at network centers with birth weight less than 1000 grams, of whom 366 (16%) were PNS exposed and 1992 (84%) were not exposed. Demographic characteristics of the study population are included in Table 1. The overall survival rate was 84% and did not differ according to steroid treatment status. Of the 1985 survivors, 306 infants (15%) were steroid treated. Demographic and neonatal characteristics of infants followed (84%) did not differ from those lost to follow up.
Detailed data on postnatal corticosteroid treatments, including timing, corticosteroid type, dose strength and duration were collected prospectively on all enrolled subjects. Corticosteroid dose was normalized to dexamethasone equivalents based on a published comparison of the relative potencies. (17) Total dose exposure was expressed as mg/kg. All decisions to treat with PNS were made at the discretion of the on-site neonatology attending; treatment was not prescribed by protocol. Initial severity of illness was assessed at 24 hours of age using the Score for Neonatal Acute Physiology II – Perinatal Extension. (19) The score evaluates the most severe of 6 physiologic derangements and 3 perinatal factors assessed within the first 24 hours of life and ranges from 1-32, with higher scores being more severe. An additional measure of pulmonary illness severity was calculated using the criteria proposed by Romagnoli, et al. (20) The Romagnoli prediction score uses birth weight along with measures of respiratory illness severity including inspired oxygen concentration and peak inspiratory pressure received at 3 and 5 days of life to generate a predicted risk of BPD.
BPD was assessed at 36 weeks postmenstrual age using a validated physiologic definition that combined respiratory support and oxygen saturation. (21) Secondary outcomes included death before hospital discharge, BPD severity (assessed by a modification of the NIH consensus definition of BPD that included the physiologic definition), duration of mechanical ventilation, duration of continuous positive airway pressure, duration of oxygen supplementation and length of hospital stay. Other measures of common neonatal co-morbidities were specified before the trial began and included: severe intraventricular hemorrhage (Stage III or IV) (22), cystic periventricular leukomalacia, severe retinopathy of prematurity (Stage 3 or more using the International Retinopathy Classification) (23-24), pneumothorax, patent ductus arteriosus, necrotizing enterocolitis (Stage 2 or more by Modified Bell's Criteria) (25) and late onset sepsis, defined as a positive blood culture with clinical signs of sepsis beyond 72 hours of age. All data were abstracted from the neonatal medical record by trained research nurses using standardized definitions. Data were entered remotely with electronic submission. Quality control procedures included range checking, internal comparisons for logic violations, and comparison of expected and observed values.
Neonates were evaluated in a standardized outcome assessment at 18-22 months corrected age conducted by certified examiners. Assessments of pulmonary health, medication use, growth, neurologic examination of muscle tone according to the method described by Amiel-Tison (26) and developmental outcomes (Bayley Scales of Infant Development II) were performed. (27) Cerebral palsy was defined as a persistent disorder of movement and posture appearing in early life and attributable to a nonprogressive disorder of the brain, the result of interference during its development. (28) Cerebral palsy was classified as “moderate” if the child could sit independently or with support, but an assistive device was required for ambulation, and “severe” if the child was unable to sit or walk even with support. The NICHD neuromotor and developmental examiners at each site met annually, followed standardized examination protocols and submitted videos to insure uniform examination techniques throughout the duration of the study. Neurodevelopmental impairment was defined as one or more of the following: moderate or severe cerebral palsy, bilateral blindness, deafness requiring amplification, Bayley MDI and/or PDI < 70. Of the 2358 eligible survivors, 1667 (84%) were evaluated in follow-up.
The study was approved by the Institutional Review Board (IRB) at every institution. One center provided families with a letter of information and all others were given a waiver of consent to collect de-identified data. The main trial was registered at inception with the United States National Library of Medicine trial registry, (www.clinicaltrials.gov ID NCT00067613).
Characteristics, treatments and outcomes were compared between steroid exposed and non-exposed neonates using univariate methods. Continuous variables were compared with students t-test, while dichotomous variables were assessed with chi-squares statistic with correction for multiple comparisons. Total steroid dose was expressed in tertiles with outcomes compared as a function of increasing dosage exposure. Logistic regression adjusted for birth weight, race, sex, antenatal steroids, SGA status, severe intraventricular hemorrhage and maternal education was used to test the relationship between NDI (Bayley MDI < 70, PDI < 70, disabling cerebral palsy (CP) or sensory impairment), total steroid dose (tertiles < 0.9, 0.9-1.9, ≥ 1.9 mg/kg) and PMA at first dose. Separate logistic regression tested effect modification by BPD severity (Romagnoli Risk Probability > 0.5 defined as high risk, n=2336 (99%) for days of life 4-7.
Three hundred sixty six neonates (16%) were steroid treated. Ninety four percent of those exposed to steroids received dexamethasone, while the remainder received different steroid forms (betamethasone 0.5%, hydrocortisone 8%, mixed steroid exposure 5%, other 4%). The dose of steroid received by those treated averaged 1.99 ± 2.26 mg/kg dexamethasone equivalent units (range 0.04 – 19.8 mg/kg); days treated averaged 10.4 ± 10.8 days (range 1 to 75 days). Treated neonates were smaller (724 vs. 807 grams) and less mature (25.1 vs. 26.6 weeks), (all p < 0.01) than untreated neonates. (Table 1) Seventy two percent of those treated were classified as high risk for BPD by the Romagnoli score (more than 50% predicted risk of BPD).
The acute morbidities experienced by infants in this cohort are shown in Table 2. Infants treated with steroids were more likely to have been diagnosed with a patent ductus arteriosus (60% vs. 48%, p < 0.001). Neonates selected for treatment had significantly poorer pulmonary outcomes. Despite steroid treatment, more of the treated infants were diagnosed with BPD at 36 weeks PMA by the physiologic definition (72% vs. 32%, p < 0.001), remained on ventilators longer (53 ± 28 days vs. 21 ± 28 days, p < 0.001), and had a longer duration of hospitalization (101 ± 13 vs. 81 ± 20 days, p < 0.001). Similar to other reports, treated infants had a higher incidence of severe ROP (39% vs. 17%, p < 0.001) and a higher incidence of late onset sepsis (52% vs. 38%, p< 0.001).
Postnatal steroid exposure was associated with an increased risk of neuodevelopmental impairment or death (61% vs. 44%, p < 0.0001). (Table 3) Higher steroid doses were associated with an increased percentage of survivors with neurodevelopmental impairment; 71% were dead or impaired at the highest dose tertile. The dose effect of postnatal steroids on neurodevelopmental impairment was primarily due to an increase in cerebral palsy. (Figure 1) Each 1 mg/kg steroid dose expsosure was associated with a 2.0 point decrease in MDI and a 40% risk increase in disabling CP, (OR 1.4; 95% CI: 1.2 – 1.6). There was no developmentally “safe” window for postnatal steroid use. The risk of NDI was greater for steroid exposed infants than for those unexposed at every postnatal age evaluated. Older PMA at first dose did not mitigate the harm of steroid exposure. (Figure 2) In fact, treatment after 33 weeks PMA was associated with the greatest harm (NDI/death OR 2.5, 95% CI: 1.1-5.5) despite not having the highest total steroid dose. The relationship of postnatal steroids on NDI was modified by BPD risk (High risk OR 1.9, 95% CI: 1.4-2.6; Low risk OR 2.9, 95% CI: 1.8-4.8). Infants at higher risk of BPD appeared to experience less harm from steroid exposure than those at lower risk. For example, the underlying rates of NDI when steroids were administered were 52% in the High risk group and 53% in the Low risk group. The rates of NDI in the non-exposed groups were 36% in the High risk group and 28% in the Low risk group. Thus, the higher OR for the Low risk group reflects the greater potential relative harm imposed by PNS use (28% to 53%).
The use of postnatal steroids to treat evolving BPD is controversial. While the use of PNS has been reduced following recognition that deleterious effects may outweigh benefits, our data and those of others have shown that ELBW infants continue to be treated with postnatal steroids, primarily dexamethasone. (29-32) In this prospective study which collected detailed data on dosing and timing of open label usage of PNS for evolving or established BPD, we sought to determine the impact of cumulative dose, timing of exposure and the interactions with predicted risk of bronchopulmonary dysplasia. We have shown that there is no safe window of development where PNS exposure is less detrimental to neurodevelopmental outcomes. In addition, increasing dosage exposure is associated with increased risk of lower mental developmental index (loss of 2 points per 1 mg/kg of exposure) and increased risk of cerebral palsy (40% risk increase for each 1 mg/kg of exposure). We hoped to examine the impact of steroid type on outcome; however, of those exposed to PNS after the first week of life, 94% in this cohort were exposed to dexamethasone, thus we were unable to analyze the impact of other steroids. The exclusion of subjects treated prior to seven days of life was necessary in order to determine the effect of postnatal steroids used only for BPD, rather than as treatment for adrenal insufficiency or hypotension.
We confirmed the prior observation by Doyle and others that the risk of the composite outcome of death or neurodevelopmental impairment was modified by the predicted risk of BPD. (15, 33) Neonates at greater than 50% predicted risk of BPD experienced less harm than those at lower risk (High risk OR 1.9, 95% CI: 1.4-2.6; Low risk OR 2.9, 95% CI: 1.8-4.8). Infants at even higher predicted risk of BPD cross a point where the risk of PNS treatment is offset by the risk of deteriorating pulmonary status and its associated detrimental effects. To assist clinicians faced with the decision of whether or not to treat individual infants with postnatal steroid therapy, we attempted to better define the BPD risk point where the benefit of postnatal steroid therapy might outweigh the harm of its use. Unfortunately, study subjects were not evenly distributed for analysis by either quartiles or deciles of risk. Rather, subject risk status tended to be bimodal in distribution with the majority of subjects classified as either high or low risk for BPD. The percentage of subjects treated with postnatal steroid therapy increased from 6% in the lowest BPD risk quartile to 25% in the highest risk quartile.
A potential shortcoming of this study involves the use of the Romagnoli risk score to classify BPD risk (20). The cohort studied by Romagnoli included infants of 23-34 weeks and 350-1250 grams with a mortality rate of 35%, which is quite different from the cohort in this study. In addition, Romagnoli's prediction was for BPD by oxygen requirement at 28 days rather than by a physiologic definition at 36 weeks postmenstrual age. Its relevance to our cohort is questionable; however, the Romagnoli system was selected because it was the only published model using comparable data with objective risk parameters readily available to clinicians. Controlling for the probability of BPD was necessary to derive odds ratios which internalized the levels of perceived BPD risk, which could not be done using a measure of risk derived directly from our own data. Future research must be done to validate the Romagnoli score and develop additional scoring systems for BPD risk.
Additional outcome studies support the concept of a potentially beneficial effect of postnatal steroid therapy for selected infants at high risk for chronic lung disease. The long-term school age follow-up of preterm infants previously treated at 2 weeks of age with 42 days of dexamethasone, 18 days of dexamethasone or placebo suggests significantly improved neurodevelopmentally intact survival and pulmonary function for those treated with the longest course, suggesting that moderately early corticosteroid treatment may be advantageous for a select group of infants at high risk for BPD. (34) In addition, recently reported increased rates of bronchopulmonary dysplasia and oxygen dependence among very low birth weight infants have been temporally related to the reduction in postnatal steroid use. (30, 35) Although infants at lower risk of BPD should not be exposed to treatment with PNS, our data suggest that there may be a subpopulation that will benefit from PNS treatment.
Since the controversy of PNS use has been aired, many experts have recommended the use of lower doses of dexamethasone based on limited evidence. However, in studies of developing rats and lambs, dexamethasone treatment, even at doses below those used clinically, elicits selective changes in dopaminergic synaptic function, N-methyl-D-aspartate receptors and neural cell development, suggesting that adverse neurobehavioral consequences of glucocorticoid therapy in preterm infants may be inescapable. (36-38) Similar to our results showing worsened outcomes with increasing PNS dose, Powell reported that the risk of cerebral palsy in preterm infants was related to the total cumulative dose of dexamethasone. (39) Doyle and colleagues confirmed that a lower dose was effective in achieving extubation with an improved side effect profile. (14) Unfortunately, the trial was terminated at only 10% of the planned sample size due to limited enrollment, in part because of concerns raised by the position statements of the American Academy of Pediatrics and the Canadian Paediatric Society. (12) Our observational data provide further support that total dose is of critical importance in mediating the detrimental impact of PNS. Further, the prospective data that the detrimental effect of PNS is modified for those with the highest risk of BPD supports a future randomized trial in selected high risk infants.
Several recent studies have explored the timing of postnatal steroid therapy. In a systematic review of randomized controlled trials of dexamethasone to prevent chronic lung disease, initiation of dexamethasone in the first 15 days of life was associated with a marginally significant reduction in the risk of death and a very significant reduction in chronic lung disease at 36 weeks postconceptional age, with the greatest reduction associated with initiation of therapy in the first 72 hours of life. (40) Despite the apparent benefits of early postnatal steroids, research suggests that many of the short term, yet serious complications of therapy are frequent during early treatment. (1, 41) Other long term randomized controlled studies of children treated with dexamethasone versus placebo have reported significantly higher rates of developmental delay and cerebral palsy among the dexamethasone treated infants. (7, 42) Two large, multicenter trials of early dexamethasone versus placebo for ventilated ELBW infants enrolled by 12 hours age and randomly assigned to receive dexamethasone or placebo for 10-12 days were halted due to serious complications, such as hyperglycemia, gastrointestinal perforation, hypertension and periventricular leukomalacia. (4, 43)
In contrast to “preventative” corticosteroids given shortly after birth to reduce the risk of chronic lung disease, steroids given after 7-10 days of age, termed “moderately early treatment,” reduce time on the ventilator with less risk of neurosensory sequelae. (44-45) A meta-analysis of randomized controlled trials of delayed (> 3 weeks postnatal age) corticosteroid treatment demonstrated an increasing trend in cerebral palsy, which was partly offset by a decreasing trend in death before late follow-up, resulting in no significant difference in the combined rate of death or neurosensory impairment. (3) Our study does not support the use of delayed (> 3 weeks) steroid therapy. In fact, infants exposed to postnatal steroids at older ages demonstrated the greatest risk for neurodevelopmental impairment. We found no difference in the timing of initiation of postnatal steroid therapy between high and low risk subjects in our study, suggesting that steroids were not given to prevent BPD. However, the decision to use postnatal steroid therapy was heavily influenced by study center, ranging from 2% to 35% of center subjects.
The question of the optimal steroid type to be used is unanswered. There is increasing data that dexamethasone, with or without the sulfite preservative, has differential effects on the brain compared to hydrocortisone. (8) Cortisol occupies both mineralocorticoid and glucocorticoid receptors in the brain, binding preferentially to mineralocorticoid receptors at normal physiologic concentrations. (46) Dexamethasone binds only to glucocorticoid receptors. It has been proposed that dexamethasone exerts its adverse effects on the hippocampus by causing a “chemical adrenalectomy”. (47-48) Consistent with this hypothesis, administration of corticosterone to adrenalectomized adult rats was protective against the apoptotic effects of dexamethasone. (49) In a study involving quantitative MRI evaluations and neurocognitive assessments of preterm and term born children, those treated with perinatal hydrocortisone showed no long-term adverse effects on either neurostructural brain development or neurocognitive outcomes. (50) To our knowledge, only a single, uncontrolled retrospective study has compared the effects of dexamethasone and hydrocortisone in the treatment of BPD. (51) Both drugs were effective in reducing days on the ventilator and oxygen, but hydrocortisone had an improved side effect profile with less hyperglycemia, hypertension and adverse growth. Hydrocortisone may also have less impact on brain growth and neurodevelopmental outcome. (51, 52) Together, these data suggest that a randomized trial of PNS treatment, and a comparison of low dose dexamethasone and hydrocortisone among infants with a high risk of BPD is both ethical and necessary to guide the treatment of future high risk preterm infants.
This work was supported by the National Institute of Child Health and Human Development (U10 HD34216, U10 HD21364, U10 HD27853, U10 HD27851, U01 HD36790, U10 HD27856, U10 HD21397, U10 HD27881, U10 HD27880, U10 HD21415, U10 HD21373, U10 HD21385, U10 HD27871, U10 HD34167 and U10 HD27904) and the NIH General Clinical Research Center (M01 RR8084, M01 RR750, M01 RR997, M01 RR70, M01 RR6022, M01 RR2635, M01 RR2172 and M01 RR1032). The funding agency provided overall oversight for study conduct. All data analyses and interpretation were independent of the funding agency. Study participants were as follows: Advisory committee: M.C. Walsh, MD, MS, A.A. Fanaroff, MD, Case Western Reserve University (Cleveland, OH); A.H. Jobe, MD, PhD, University of Cincinnati (Cincinnati, OH); R.D. Higgins, MD, National Institute of Child Health and Human Development (Bethesda, MD); N.N. Finer, MD, University of California, San Diego (San Diego, CA); W. K. Poole, PhD, Research Triangle Institute (Research Triangle Park, NC); Training committee: Duncan Neuhauser, PhD, Case Western Reserve University (Cleveland, OH); Leslie Clarke, RN, MSN, MBA, Rainbow Babies and Children's Hospital (Cleveland, OH); Lynn Lostocco, RN, MSN, National Association of Children's Hospitals (Warwick RI); Neil N. Finer, MD, University of California, San Diego (San Diego, CA); Intervention centers: S.N. Kazzi, MD, MPH, K. Hayes-Hart, RN, M. Betts, RRT, S. Shankaran, MD, G. Muran, RN, BSN, Wayne State University (Detroit, MI); A.R. Laptook, MD, M. Martin, RN, J. Allen, RRT, University of Texas Southwestern (Dallas, TX); W.A. Engle, MD, L. Miller, RN, R. Hooper, RRT, J.A. Lemons, MD, Indiana University (Indianapolis, IN); W. Rhine, MD, C. Kibler, RN, J. Parker, RRT, D.K. Stevenson, MD, M.B. Ball, BS CCRC, Stanford University (Palo Alto, CA); M.R. Rasmussen, MD, M. Grabarczyk, BSN, C. Joseph, RRT, K. Arnell, BSN, Sharp Mary Birch Hospital for Women (San Diego, CA); G. Heldt, MD, R. Bridge, RN, J. Goodmar, RRT, N.N. Finer, MD, C. Henderson, RCP CRRT, University of California, San Diego (San Diego, CA); S. Buchter, MD, M. Berry, RN, I. Seabrook, RRT, B.J. Stoll, MD, E. Hale, RN, Emory University (Atlanta, GA); Benchmark centers: S. Duara, MD, R. Everett, RN BSN, University of Miami (Miami, Fla); W.A. Carlo, MD, M.V. Collins, RN, University of Alabama (Birmingham, Al); W. Oh, MD, A. Hensman, BSN RNC, Brown University (Providence, RI); Control centers: M.T. O'Shea, MD, MPH, N. Peters, RN, Wake Forest University (Winston-Salem, NC); J.E. Tyson, MD, MPH, G. McDavid, RN, University of Texas (Houston, TX); A.A. Fanaroff, MD, M.C. Walsh, MD, MS, N.S. Newman, BA RN, Case Western Reserve University (Cleveland, OH); D.L. Phelps, MD, R. A. Sinkin, MD, G. Myers, MD, L. Reubens, RN, D. Hust, PNP, R. Jensen, University of Rochester (Rochester, NY); R.A. Ehrenkranz, MD, P. Gettner, RN, Yale University (New Haven, CT); C.M. Cotton, MD MHS, K Auten, RN, Duke University (Durham, NC); E.F. Donovan, MD, C. Grisby, BSN CCRC, University of Cincinnati (Cincinnati, OH); Statistical center: Q. Yao, PhD, W.K. Poole, PhD, Research Triangle Institute (Research Triangle Park, NC). We thank the nursing and medical staff members and parents of the patients in the units for their diligent implementation of this complex trial. We also thank the Neonatal Research Network Research coordinators and study nurses, without whom the trial could not have been completed.
Financial disclosure/Conflict of Interest: none
Deanne Wilson-Costello, Department of Pediatrics, Case Western Reserve University (Cleveland, OH)
Michele C. Walsh, Department of Pediatrics, Case Western Reserve University (Cleveland, OH)
John C. Langer, Department of Statistics, Research Triangle Institute (Research Triangle Park, NC)
Ronnie Guillet, Department of Pediatrics, University of Rochester (Rochester, NY)
Abbot R. Laptook, Department of Pediatrics, University of Texas Southwestern (Dallas, TX)
Barbara J. Stoll, Department of Pediatrics, Emory University (Atlanta, GA)
Seetha Shankaran, Department of Pediatrics, Wayne State University (Detroit, MI)
Neil N. Finer, Department of Pediatrics, University of California, San Diego (San Diego, CA)
Krisa P. Van Meurs, Department of Pediatrics, Stanford University (Palo Alto, CA)
William A. Engle, Department of Pediatrics, Indiana University (Indianapolis, IN)
Abhik Das, Department of Statistics, Research Triangle Institute (Research Triangle Park, NC)