Publications by authors named "Patrick J Heagerty"

191 Publications

Gestational age, sex, and time affect urine biomarker concentrations in extremely low gestational age neonates.

Pediatr Res 2021 Nov 30. Epub 2021 Nov 30.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center/University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Background: Our understanding of the normative concentrations of urine biomarkers in premature neonates is limited.

Methods: We evaluated urine from 750 extremely low gestational age (GA) neonates without severe acute kidney injury (AKI) to determine how GA affects ten different urine biomarkers at birth and over the first 30 postnatal days. Then, we investigated if the urine biomarkers changed over time at 27, 30, and 34 weeks postmenstrual age (PMA). Next, we evaluated the impact of sex on urine biomarker concentrations at birth and over time. Finally, we evaluated if urine biomarkers were impacted by treatment with erythropoietin (Epo).

Results: We found that all ten biomarker concentrations differ at birth by GA and that some urine biomarker concentrations increase, while others decrease over time. At 27 weeks PMA, 7/10 urine biomarkers differed by GA. By 30 weeks PMA, 5/10 differed, and by 34 weeks PMA, only osteopontin differed by GA. About half of the biomarker concentrations differed by sex, and 4/10 showed different rates of change over time between males vs. females. We found no differences in urine biomarkers by treatment group.

Conclusions: The temporal patterns, GA, and sex differences need to be considered in urine AKI biomarker analyses.

Impact: Urine biomarker concentrations differ by GA at birth. Some urine biomarkers increase, while others decrease, over the first 30 postnatal days. Most urine biomarkers differ by GA at 27 weeks PMA, but are similar by 34 weeks PMA. Some urine biomarkers vary by sex in premature neonates. Urine biomarkers did not differ between neonates randomized to placebo vs. Epo.
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http://dx.doi.org/10.1038/s41390-021-01814-xDOI Listing
November 2021

A Value-of-Information Framework for Personalizing the Timing of Surveillance Testing.

Med Decis Making 2021 Nov 7:272989X211049213. Epub 2021 Nov 7.

The Comparative Health Outcomes, Policy, and Economics Institute, School of Pharmacy, University of Washington, Seattle WA, USA.

Background: Patient surveillance using repeated biomarker measurements presents an opportunity to detect and treat disease progression early. Frequent surveillance testing using biomarkers is recommended and routinely conducted in several diseases, including cancer and diabetes. However, frequent testing involves tradeoffs. Although surveillance tests provide information about current disease status, the complications and costs of frequent tests may not be justified for patients who are at low risk of progression. Predictions based on patients' earlier biomarker values may be used to inform decision making; however, predictions are uncertain, leading to decision uncertainty.

Methods: We propose the Personalized Risk-Adaptive Surveillance (PRAISE) framework, a novel method for embedding predictions into a value-of-information (VOI) framework to account for the cost of uncertainty over time and determine the time point at which collection of biomarker data would be most valuable. The proposed sequential decision-making framework is innovative in that it leverages the patient's longitudinal history, considers individual benefits and harms, and allows for dynamic tailoring of surveillance intervals by considering the uncertainty in current information and estimating the probability that new information may change treatment decisions, as well as the impact of this change on patient outcomes.

Results: When applied to data from cystic fibrosis patients, PRAISE lowers costs by allowing some patients to skip a visit, compared to an "always test" strategy. It does so without compromising expected survival, by recommending less frequent testing among those who are unlikely to be treated at the skipped time point.

Conclusions: A VOI-based approach to patient monitoring is feasible and could be applied to several diseases to develop more cost-effective and personalized strategies for ongoing patient care.

Highlights: In many patient-monitoring settings, the complications and costs of frequent tests are not justified for patients who are at low risk of disease progression. Predictions based on patient history may be used to individualize the timing of patient visits based on evolving risk.We propose Personalized Risk-Adaptive Surveillance (PRAISE), a novel method for personalizing the timing of surveillance testing, where prediction modeling projects the disease trajectory and a value-of-information (VOI)-based pragmatic decision-theoretic framework quantifies patient- and time-specific benefit-harm tradeoffs.A VOI-based approach to patient monitoring could be applied to several diseases to develop more personalized and cost-effective strategies for ongoing patient care.
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http://dx.doi.org/10.1177/0272989X211049213DOI Listing
November 2021

Protocol for a sequential, multiple assignment, randomised trial to test the effectiveness of message-based psychotherapy for depression compared with telepsychotherapy.

BMJ Open 2021 Nov 2;11(11):e046958. Epub 2021 Nov 2.

Department of Biostatistics, University of Washington, Seattle, Washington, USA.

Introduction: Digital mental health tools have become popular alternatives to traditional psychotherapy. One emerging form of digital mental health is message-based care, the use of text messages or asynchronous voice or video messaging to provide psychotherapy. There has been no research into whether this is an effective method of psychotherapy as a stand-alone treatment or in combination with traditional psychotherapy.

Methods And Analysis: This is a sequential, multiple assignment randomised trial to compare message-based care, videoconference-psychotherapy and a combination of the two treatments in 1000 depressed adults. Participants will be recruited through Talkspace, a digital mental health company, and randomised to receive 6 weeks of either message-based care only or videoconference-psychotherapy only. At 6 weeks, participants will be evaluated for their response to treatment. Those with a 50% or more response to treatment will continue with their assigned condition. Those who do not respond will be randomised to either monthly videoconference-psychotherapy or weekly videoconference-psychotherapy plus message-based care. Primary outcomes will be depression and social functioning. We will also explore moderators of treatment outcome.

Ethics And Dissemination: The study received ethics approval from the University of Washington Institutional Review Board. Results of this study will be presented in peer-reviewed journals and at professional conferences.

Trial Registration Number: NCT04513080; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-046958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565526PMC
November 2021

Antibiotics versus Appendectomy for Acute Appendicitis - Longer-Term Outcomes.

N Engl J Med 2021 Oct 25. Epub 2021 Oct 25.

From University of Washington Medical Center-UW Medicine (G.H.D., D.R.F., E.F., D.C.L., B.B., S.O.L., F.F., L.G.K.), University of Washington (S.E.M., E.C.V., P.J.H., B.A.C.), Swedish Medical Center (K.A.M.), and Harborview Medical Center-UW Medicine (J.C., H.L.E.), Seattle, and Providence Regional Medical Center, Everett (J.G.) - all in Washington; McGovern Medical School, University of Texas Health Science Center (L.S.K.), Lyndon B. Johnson General Hospital, University of Texas (J.H., M.K.L.), and HCA Healthcare Kingwood, University of Houston (M.K.L.) - all in Houston; BC Academic Science Health Network, Vancouver, BC, Canada (D.C.L.); Olive View-UCLA Medical Center (A.K., D.S., G.J.M., D.A.T.), Harbor-UCLA Medical Center (A.H.K., D.A.D.), and UCLA Ronald Reagan Medical Center (D.A.T.), Los Angeles, and the University of California, San Francisco (J.C.) - all in California; Weill Cornell Medical Center (R.J.W.), Tisch Hospital, NYU Langone Medical Center (P.A.-C., W.C., J.V.), Bellevue Hospital Center, NYU School of Medicine (W.C.), and Columbia University Medical Center (N.C., K.F.) - all in New York; Vanderbilt University Medical Center, Nashville (W.H.S., C.M.T.); University of Utah, Salt Lake City (C.M.T.); University of Michigan Medical Center, Ann Arbor (P.K.P., H.B.A.), and Henry Ford Health System, Detroit (J.J., J.H.P.) - both in Michigan; UCHealth, University of Colorado Hospital, Denver (M.S., L.F.); Rush University Medical Center, Chicago (T.P.P., N.S.); Morehouse School of Medicine, Atlanta (P.A.-C.); Maine Medical Center, Portland (B.C., D.W.C.); University of Mississippi Medical Center, Jackson (M.E.K., A.J.); University of Iowa Hospitals and Clinics, Iowa City (B.A.F.); Medical University of South Carolina, Charleston (H.L.E.); and Boston University Medical Center (F.T.D., S.E.S.) and Beth Israel Deaconess Medical Center (C.P., S.R.O.) - both in Boston.

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http://dx.doi.org/10.1056/NEJMc2116018DOI Listing
October 2021

Diffusion Tensor Imaging Changes Do Not Affect Long-Term Neurodevelopment following Early Erythropoietin among Extremely Preterm Infants in the Preterm Erythropoietin Neuroprotection Trial.

Brain Sci 2021 Oct 16;11(10). Epub 2021 Oct 16.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

We aimed to evaluate diffusion tensor imaging (DTI) in infants born extremely preterm, to determine the effect of erythropoietin (Epo) on DTI, and to correlate DTI with neurodevelopmental outcomes at 2 years of age for infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Infants who underwent MRI with DTI at 36 weeks postmenstrual age were included. Neurodevelopmental outcomes were evaluated by Bayley Scales of Infant and Toddler Development (BSID-III). Generalized linear models were used to assess the association between DTI parameters and treatment group, and then with neurodevelopmental outcomes. A total of 101 placebo- and 93 Epo-treated infants underwent MRI. DTI white matter mean diffusivity (MD) was lower in placebo- compared to Epo-treated infants in the cingulate and occipital regions, and occipital white matter fractional isotropy (FA) was lower in infants born at 24-25 weeks vs. 26-27 weeks. These values were not associated with lower BSID-III scores. Certain decreases in clustering coefficients tended to have lower BSID-III scores. Consistent with the PENUT Trial findings, there was no effect on long-term neurodevelopment in Epo-treated infants even in the presence of microstructural changes identified by DTI.
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http://dx.doi.org/10.3390/brainsci11101360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533828PMC
October 2021

Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?

J Pediatr 2021 Oct 7. Epub 2021 Oct 7.

Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To evaluate whether extremely preterm infants regulate iron status via hepcidin.

Study Design: In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo.

Results: The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-27 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002).

Conclusions: Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.
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http://dx.doi.org/10.1016/j.jpeds.2021.09.059DOI Listing
October 2021

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial.

EBioMedicine 2021 Oct 4;72:103605. Epub 2021 Oct 4.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA. Electronic address:

Background: In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks' gestation) infants.

Methods: Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III).

Findings: Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years.

Interpretation: Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice.

Funding: PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).
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http://dx.doi.org/10.1016/j.ebiom.2021.103605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498235PMC
October 2021

Patient, Provider, and Clinic Characteristics Associated with Opioid and Non-Opioid Pain Prescriptions for Patients Receiving Low Back Imaging in Primary Care.

J Am Board Fam Med 2021 Sep-Oct;34(5):950-963

From the Department of Radiology, School of Medicine, University of Washington, Seattle, WA (LSG, KTJ, SKJ, JGJ); Clinical Learning, Evidence, and Research Center, University of Washington, Seattle, WA (LSG, ENM, JAT, KTJ, JLF, PS, SKJ, PJH, JGJ); Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA (ZAM); Department of Biostatistics, University of Washington, Seattle, WA (ENM, PJH); Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA (JAT); Department of Rehabilitation Medicine, University of Washington, Seattle, WA (JAT, JLF); Department of Radiology Mayo Clinic, Rochester, MN (DFK, PHL); Department of Radiology, Henry Ford Hospital, Detroit, MI, (BG); Kaiser Permanente Washington, Seattle, WA (KJS); Rehabilitation Care Services, VA Puget Sound Health Care System, Seattle, WA (PS); Departments of Family Medicine and Internal Medicine, Oregon Health & Science University, Portland, OR (RAD); Division of Research, Kaiser Permanente Northern California, Oakland, CA (ALA).

Background: To describe characteristics of patients, providers, and clinics associated with opioid or non-opioid pain medication prescribing patterns for patients who received lower spine imaging in primary care clinics.

Methods: In these secondary analyses of the Lumbar Imaging with Reporting of Epidemiology (LIRE) study, a randomized controlled trial conducted in 4 health systems in the United States, we evaluated characteristics associated with receipt of pain medication prescriptions. The outcomes were receipt of prescriptions for opioid or, separately, non-opioid pain medications within 90 days after imaging. Among patients who received opioid or non-opioid prescriptions, we evaluated receipt of multiple prescriptions in the year following imaging. Mixed models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Compared with whites, patients identified as Asian (OR, 0.53; 95% CI, 0.51-0.56), Native Hawaiian/Pacific Islander (OR, 0.73; 95% CI, 0.64-0.83), multiracial (OR, 0.84; 95% CI, 0.71-0.98) or Black (OR, 0.92; 95% CI, 0.89-0.96) had significantly reduced odds for receiving prescriptions for opioids within 90 days. Patients identified as Native American/Alaska Native had greater odds for receiving prescriptions for non-opioid pain medications within 90 days (OR, 1.12; 95% CI, 1.01-1.24). Receipt of pain prescriptions 120 days before imaging was strongly predictive of subsequent receipt of pain prescriptions across all categories.

Conclusions: After adjusting for factors that could affect prescribing, the strongest differences observed in pain-medication prescribing were across racial categories and for patients with previous pain prescriptions. Further research is needed to understand these differences and to optimize prescribing.
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http://dx.doi.org/10.3122/jabfm.2021.05.210033DOI Listing
October 2021

Power and sample size calculation for stepped-wedge designs with discrete outcomes.

Trials 2021 Sep 6;22(1):598. Epub 2021 Sep 6.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Background: Stepped-wedge designs (SWD) are increasingly used to evaluate the impact of changes to the process of care within health care systems. However, to generate definitive evidence, a correct sample size calculation is crucial to ensure such studies are properly powered. The seminal work of Hussey and Hughes (Contemp Clin Trials 28(2):182-91, 2004) provides an analytical formula for power calculations with normal outcomes using a linear model and simple random effects. However, minimal development and evaluation have been done for power calculation with non-normal outcomes on their natural scale (e.g., logit, log). For example, binary endpoints are common, and logistic regression is the natural multilevel model for such clustered data.

Methods: We propose a power calculation formula for SWD with either normal or non-normal outcomes in the context of generalized linear mixed models by adopting the Laplace approximation detailed in Breslow and Clayton (J Am Stat Assoc 88(421):9-25, 1993) to obtain the covariance matrix of the estimated parameters.

Results: We compare the performance of our proposed method with simulation-based sample size calculation and demonstrate its use on a study of patient-delivered partner therapy for STI treatment and a study that assesses the impact of providing additional benchmark prevalence information in a radiologic imaging report. To facilitate adoption of our methods we also provide a function embedded in the R package "swCRTdesign" for sample size and power calculation for multilevel stepped-wedge designs.

Conclusions: Our method requires minimal computational power. Therefore, the proposed procedure facilitates rapid dynamic updates of sample size calculations and can be used to explore a wide range of design options or assumptions.
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http://dx.doi.org/10.1186/s13063-021-05542-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419932PMC
September 2021

Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.

J Pediatr 2021 Dec 26;239:117-125.e6. Epub 2021 Aug 26.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 24-27 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age.

Study Design: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models.

Results: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age.

Conclusions: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.
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http://dx.doi.org/10.1016/j.jpeds.2021.08.040DOI Listing
December 2021

Comparison of Teleintegrated Care and Telereferral Care for Treating Complex Psychiatric Disorders in Primary Care: A Pragmatic Randomized Comparative Effectiveness Trial.

JAMA Psychiatry 2021 Nov;78(11):1189-1199

Department of Psychiatry and Behavioral Sciences, School of Medicine, University of Washington, Seattle.

Importance: Only one-third of patients with complex psychiatric disorders engage in specialty mental health care, and only one-tenth receive adequate treatment in primary care. Scalable approaches are critically needed to improve access to effective mental health treatments in underserved primary care settings.

Objective: To compare 2 clinic-to-clinic interactive video approaches to delivering evidence-based mental health treatments to patients in primary care clinics.

Design, Setting, And Participants: This pragmatic comparative effectiveness trial used a sequential, multiple-assignment, randomized trial (SMART) design with patient-level randomization. Adult patients treated at 24 primary care clinics without on-site psychiatrists or psychologists from 12 federally qualified health centers in 3 states who screened positive for posttraumatic stress disorder and/or bipolar disorder and who were not already receiving pharmacotherapy from a mental health specialist were recruited from November 16, 2016, to June 30, 2019, and observed for 12 months.

Interventions: Two approaches were compared: (1) telepsychiatry/telepsychology-enhanced referral (TER), where telepsychiatrists and telepsychologists assumed responsibility for treatment, and (2) telepsychiatry collaborative care (TCC), where telepsychiatrists provided consultation to the primary care team. TER included an adaptive intervention (phone-enhanced referral [PER]) for patients not engaging in treatment, which involved telephone outreach and motivational interviewing.

Main Outcomes And Measures: Survey questions assessed patient-reported outcomes. The Veterans RAND 12-item Health Survey Mental Component Summary (MCS) score was the primary outcome (range, 0-100). Secondary outcomes included posttraumatic stress disorder symptoms, manic symptoms, depressive symptoms, anxiety symptoms, recovery, and adverse effects.

Results: Of 1004 included participants, 701 of 1000 (70.1%) were female, 660 of 994 (66.4%) were White, and the mean (SD) age was 39.4 (12.9) years. Baseline MCS scores were 2 SDs below the US mean; the mean (SD) MCS scores were 39.7 (14.1) and 41.2 (14.2) in the TCC and TER groups, respectively. There was no significant difference in 12-month MCS score between those receiving TCC and TER (β = 1.0; 95% CI, -0.8 to 2.8; P = .28). Patients in both groups experienced large and clinically meaningful improvements from baseline to 12 months (TCC: Cohen d = 0.81; 95% CI, 0.67 to 0.95; TER: Cohen d = 0.90; 95% CI, 0.76 to 1.04). For patients not engaging in TER at 6 months, there was no significant difference in 12-month MCS score between those receiving PER and TER (β = 2.0; 95% CI, -1.7 to 5.7; P = .29).

Conclusions And Relevance: In this comparative effectiveness trial of patients with complex psychiatric disorders randomized to receive TCC or TER, significantly and substantially improved outcomes were observed in both groups. From a health care system perspective, clinical leadership should implement whichever approach is most sustainable.

Trial Registration: ClinicalTrials.gov Identifier: NCT02738944.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.2318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387948PMC
November 2021

Letter to the Editor re Beachler, et al, 2021.

Pharmacoepidemiol Drug Saf 2021 Dec 16;30(12):1735-1736. Epub 2021 Sep 16.

Department of Biostatistics, University of Washington, Seattle, Washington, USA.

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http://dx.doi.org/10.1002/pds.5342DOI Listing
December 2021

Enteral Iron Supplementation in Infants Born Extremely Preterm and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the Preterm Erythropoietin Neuroprotection Trial Randomized Controlled Trial.

J Pediatr 2021 11 27;238:102-109.e8. Epub 2021 Jul 27.

Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development, third edition (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT).

Study Design: This is a post hoc analysis of a randomized trial that enrolled infants born at 24-28 completed weeks of gestation. All infants in PENUT who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders.

Results: In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7 mg/kg/d (IQR 2.1-5.8 mg/kg/d) at day 60, with a mean of 3.6 mg/kg/d in infants treated with placebo and 4.8 mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P = .03). Greater iron doses were associated with greater motor and language scores but did not reach statistical significance. Results at 90 days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater.

Conclusions: A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in infants born preterm, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo.

Trial Registration: Clinicaltrials.gov: NCT01378273.
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http://dx.doi.org/10.1016/j.jpeds.2021.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629150PMC
November 2021

Appendicular Lean Mass, Grip Strength, and the Development of Knee Osteoarthritis and Knee Pain Among Older Adults.

ACR Open Rheumatol 2021 Aug 10;3(8):566-572. Epub 2021 Jul 10.

California Pacific Medical Center Research Institute and University of California, San Francisco.

Objective: The association of sarcopenia with development of knee osteoarthritis (OA) or knee pain in older adults is uncertain. We examined the relationship of grip strength and appendicular lean mass (ALM) with the likelihood of developing knee OA and knee pain in older adults in the Health ABC (Health, Aging, and Body Composition) Study.

Methods: ALM and grip strength were assessed at baseline by dual-energy x-ray absorptiometry and handheld dynamometry, respectively. Incident clinically diagnosed, symptomatic knee OA, defined as new participant report of physician-diagnosed knee OA and concurrent frequent knee pain, and incident frequent knee pain over 5 years of follow-up were examined. Separate regression analyses, stratified by sex, modeled associations of baseline ALM and grip strength with the likelihood of incident clinically diagnosed, symptomatic knee OA and incident knee pain over follow-up, adjusting for covariates.

Results: Among the 2779 subjects without OA at baseline, 95 men (6.9%) and 158 women (11.3%) developed clinically diagnosed, symptomatic knee OA, and, among the 2182 subjects without knee pain at baseline, 315 men (28.3%) and 385 women (36.1%) developed knee pain over follow-up. Among men only, each SD decrement of ALM was associated with decreasing likelihood of incident knee OA (odds ratio [OR] per SD decrement: 0.68; 95% confidence interval [CI]: 0.47-0.97), and each SD decrement of grip strength was associated with increasing likelihood of incident knee pain (OR per SD decrement: 1.20; 95% CI: 1.01-1.42).

Conclusion: In older men, ALM and grip strength may be associated with the development of knee OA and knee pain, respectively.
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http://dx.doi.org/10.1002/acr2.11302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363849PMC
August 2021

Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines.

JAMA Netw Open 2021 Jul 1;4(7):e2115998. Epub 2021 Jul 1.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle.

Importance: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood.

Objectives: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age.

Design, Setting, And Participants: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020.

Exposures: Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay.

Main Outcomes And Measures: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III).

Results: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure.

Conclusions And Relevance: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.15998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264640PMC
July 2021

Intracranial Hemorrhage and 2-Year Neurodevelopmental Outcomes in Infants Born Extremely Preterm.

J Pediatr 2021 Nov 2;238:124-134.e10. Epub 2021 Jul 2.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To determine the incidence, timing, progression, and risk factors for intracranial hemorrhage (ICH) in infants 24 to 27 weeks of gestational age and to characterize the association between ICH and death or neurodevelopmental impairment (NDI) at 2 years of corrected age.

Study Design: Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial had serial cranial ultrasound scans performed on day 1, day 7-9, and 36 weeks of postmenstrual age to evaluate ICH. Potential risk factors for development of ICH were examined. Outcomes included death or severe NDI as well as Bayley Scales of Infant and Toddler Development, 3rd Edition, at 2 years of corrected age.

Results: ICH was identified in 38% (n = 339) of 883 enrolled infants. Multiple gestation and cesarean delivery reduced the risk of any ICH on day 1. Risk factors for development of bilateral Grade 2, Grade 3, or Grade 4 ICH at day 7-9 included any ICH at day 1; 2 or more doses of prenatal steroids decreased risk. Bilateral Grade 2, Grade 3, or Grade 4 ICH at 36 weeks were associated with previous ICH at day 7-9. Bilateral Grade 2, any Grade 3, and any Grade 4 ICH at 7-9 days or 36 weeks of postmenstrual age were associated with increased risk of death or severe NDI and lower Bayley Scales of Infant and Toddler Development, 3rd Edition, scores.

Conclusions: Risk factors for ICH varied by timing of bleed. Bilateral and increasing grade of ICH were associated with death or NDI in infants born extremely preterm.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551011PMC
November 2021

Expected Organizational Costs for Inserting Prevalence Information Into Lumbar Spine Imaging Reports.

J Am Coll Radiol 2021 10 30;18(10):1415-1422. Epub 2021 Jun 30.

Department of Health Services, University of Washington, Seattle, Washington.

Background: Modifying physician behavior to more closely align with guideline-based care can be challenging. Few effective strategies resulting in appropriate spine-related health care have been reported. The Lumbar Imaging With Reporting of Epidemiology (LIRE) intervention did not result in reductions in spine care but did in opioid prescriptions written.

Objectives: To estimate organizational resource needs and costs associated with implementing a pragmatic, decision support-type intervention that inserted age- and modality-matched prevalence information for common lumbar spine imaging findings, using site-based resource use data from the LIRE trial.

Research Design: Time and cost estimation associated with implementing the LIRE intervention in a health organization.

Subjects: Providers and patients assessed in the LIRE trial.

Measures: Expected personnel costs required to implement the LIRE intervention.

Results: Annual salaries were converted to daily average per person costs, ranging from $400 to $2,200 per day (base case) for personnel (range: $300-$2,600). Estimated total average cost for implementing LIRE was $5,009 (range: $2,651-$12,020), including conducting pilot testing with providers. Costs associated with a small amount of time for a radiologist (6-12 hours) and imaging-ordering providers (1-8 hours each) account for approximately 75% of the estimated total cost.

Conclusions: The process of implementing an intervention for lumbar spine imaging reports containing age- and modality-appropriate epidemiological benchmarks for common imaging findings required radiologists, imaging-ordering providers, information technology specialists, and limited testing and monitoring. The LIRE intervention seems to be a relatively low-cost, evidence-based, complementary tool that can be easily integrated into the reporting of spine imaging.
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http://dx.doi.org/10.1016/j.jacr.2021.06.010DOI Listing
October 2021

Severe Acute Kidney Injury and Mortality in Extremely Low Gestational Age Neonates.

Clin J Am Soc Nephrol 2021 06 11;16(6):862-869. Epub 2021 Jun 11.

Division of Nephrology, University of Alabama at Birmingham, Children's of Alabama, Birmingham, Alabama.

Background And Objectives: AKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates.

Design, Setting, Participants, & Measurements: The Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin. We included 900 of 941 patients enrolled in Preterm Epo Neuroprotection. Baseline characteristics were compared by primary exposure (severe AKI versus none/stage 1 AKI) using unadjusted logistic regression models. Cox regression models estimated the relationship between severe AKI and death after adjustment for potential confounders. Time-dependent AKI was modeled as a binary outcome and a categorical variable by stage of AKI. We fit Cox models using time-dependent AKI status lagged by <7 days before death. Landmark analyses examined the relationship of death with development of severe AKI.

Results: Severe AKI occurred in 168 of 900 (19%, 95% confidence interval, 17% to 20%) neonates, and stage 3 AKI occurred in 60 (7%, 95% confidence interval, 5% to 8%). Stage 3 AKI occurring 7 days before death (hazard ratio, 3.88; 95% confidence interval, 1.26 to 11.96), intraventricular hemorrhage (hazard ratio, 2.01; 95% confidence interval, 1.01 to 3.99) and sepsis (hazard ratio, 2.85; 95% confidence interval, 1.12 to 7.22) were all independently associated with death. Severe AKI occurring 7 days before death (hazard ratio, 2.21; 95% confidence interval, 0.92 to 5.26) was associated with death but not statistically significant. In a landmark analysis, after adjusting for potential confounders, late (after day 14 and before day 28) severe AKI was strongly associated with higher hazard of death (hazard ratio, 4.57; 95% confidence interval, 1.82 to 11.5).

Conclusions: Severe AKI occurs frequently in extremely low gestational age neonates. Stage 3 AKI is associated with mortality, and this association is present 7 days before death.
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http://dx.doi.org/10.2215/CJN.18841220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216626PMC
June 2021

Severe Acute Kidney Injury and Mortality in Extremely Low Gestational Age Neonates.

Clin J Am Soc Nephrol 2021 06 11;16(6):862-869. Epub 2021 Jun 11.

Division of Nephrology, University of Alabama at Birmingham, Children's of Alabama, Birmingham, Alabama.

Background And Objectives: AKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates.

Design, Setting, Participants, & Measurements: The Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin. We included 900 of 941 patients enrolled in Preterm Epo Neuroprotection. Baseline characteristics were compared by primary exposure (severe AKI versus none/stage 1 AKI) using unadjusted logistic regression models. Cox regression models estimated the relationship between severe AKI and death after adjustment for potential confounders. Time-dependent AKI was modeled as a binary outcome and a categorical variable by stage of AKI. We fit Cox models using time-dependent AKI status lagged by <7 days before death. Landmark analyses examined the relationship of death with development of severe AKI.

Results: Severe AKI occurred in 168 of 900 (19%, 95% confidence interval, 17% to 20%) neonates, and stage 3 AKI occurred in 60 (7%, 95% confidence interval, 5% to 8%). Stage 3 AKI occurring 7 days before death (hazard ratio, 3.88; 95% confidence interval, 1.26 to 11.96), intraventricular hemorrhage (hazard ratio, 2.01; 95% confidence interval, 1.01 to 3.99) and sepsis (hazard ratio, 2.85; 95% confidence interval, 1.12 to 7.22) were all independently associated with death. Severe AKI occurring 7 days before death (hazard ratio, 2.21; 95% confidence interval, 0.92 to 5.26) was associated with death but not statistically significant. In a landmark analysis, after adjusting for potential confounders, late (after day 14 and before day 28) severe AKI was strongly associated with higher hazard of death (hazard ratio, 4.57; 95% confidence interval, 1.82 to 11.5).

Conclusions: Severe AKI occurs frequently in extremely low gestational age neonates. Stage 3 AKI is associated with mortality, and this association is present 7 days before death.
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http://dx.doi.org/10.2215/CJN.18841220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216626PMC
June 2021

Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation.

BMJ Open 2021 04 22;11(4):e043852. Epub 2021 Apr 22.

Department of Biostatistics, University of Washington, Seattle, Washington, USA.

Introduction: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms.

Methods And Analysis: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans.

Ethics And Dissemination: IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor.

Trial Registration Number: NCT02811263; Pre-result.
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http://dx.doi.org/10.1136/bmjopen-2020-043852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070884PMC
April 2021

Complications and healthcare utilization in commercially-insured osteoporotic vertebral compression fracture patients: a comparison of kyphoplasty versus propensity-matched controls.

Spine J 2021 08 26;21(8):1347-1354. Epub 2021 Mar 26.

Department of Radiology, School of Medicine, University of Washington, Seattle, WA, USA; Clinical Learning, Evidence, and Research Center, University of Washington, Seattle, WA, USA.

Background Context: Osteoporotic vertebral fractures (OVFs) can lead to severe pain and reduced function and quality-of-life, but the strength of evidence for treatments remains low, particularly in younger populations.

Purpose: To determine whether patients with OVFs who received kyphoplasty had different patterns of healthcare utilization compared to propensity-matched patients who did not receive vertebral augmentation.

Design: Observational cohort study.

Patient Sample: We identified patients with OVFs from 2007 to 2018 in the IBM MarketScan Commercial Claims and Encounters Databases who received kyphoplasty and compared them to propensity-matched controls who did not receive vertebral augmentation (either kyphoplasty or vertebroplasty).

Outcome Measures: Major medical complications within 30 days, fills of opioids from 1-week through 1-month postaugmentation, and spine-related gross covered payments from 3-days postkyphoplasty through 1-year post-OVF.

Methods: We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs) to compare binary outcomes and median analysis to compare continuous outcomes.

Results: Of the 15,197 OVF patients identified, 1,969 (13%) received kyphoplasty and 1,928 (98%) of these were propensity matched to nonaugmented controls. We did not observe differences in the odds of major medical complications within 30 days (adjusted OR [95% CI]: 1.0 [0.6, 1.8]) but patients who received kyphoplasty were more likely to have filled opioid medications within 30 days (adjusted OR [95% CI]: 1.3 [1.1, 1.5]) and had greater spine-related gross covered payments (kyphoplasty median [95% CI]: $1,340 [$240, $4,850]; nonaugmented: $7,870 [$7,480, $8,270]; adjusted difference in medians [95% CI]: $260 [$190, $2,050]).

Conclusions: In this cohort of patients <65 years, receipt of kyphoplasty was associated with greater likelihood of opioid fills and somewhat greater spine-related gross covered payments, but no difference in major medical complications. In this retrospective study of administrative data, we did not detect advantages of treatment with kyphoplasty compared with nonaugmentation for any of our outcomes.
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http://dx.doi.org/10.1016/j.spinee.2021.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349787PMC
August 2021

A simulation study of statistical approaches to data analysis in the stepped wedge design.

Stat Biosci 2020 Dec 23;12(3):399-415. Epub 2019 Oct 23.

University of Washington, Box 357232, 1959 NE Pacific Street, Seattle, WA 98195, USA.

This paper studies model-based and design-based approaches for the analysis of data arising from a stepped wedge randomized design. Specifically, for different scenarios we compare robustness, efficiency, Type I error rate under the null hypothesis, and power under the alternative hypothesis for the leading analytical options including generalized estimating equations (GEE) and linear mixed model (LMM) based approaches. We find that GEE models with exchangeable correlation structures are more efficient than GEE models with independent correlation structures under all scenarios considered. The model-based GEE Type I error rate can be inflated when applied with a small number of clusters, but this problem can be solved using a design-based approach. As expected, correct model specification is more important for LMM (compared to GEE) since the model is assumed correct when standard errors are calculated. However, in contrast to the model-based results, the design-based Type I error rates for LMM models under scenarios with a random treatment effect show type I error inflation even though the fitted models perfectly match the corresponding data generating scenarios. Therefore, greater robustness can be realized by combining GEE and permutation testing strategies.
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http://dx.doi.org/10.1007/s12561-019-09259-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971509PMC
December 2020

Providing Epidemiological Data in Lumbar Spine Imaging Reports Did Not Affect Subsequent Utilization of Spine Procedures: Secondary Outcomes from a Stepped-Wedge Randomized Controlled Trial.

Pain Med 2021 06;22(6):1272-1280

Clinical Learning, Evidence, and Research Center, University of Washington, Seattle, Washington, USA.

Objective: To evaluate the effect of inserting epidemiological information into lumbar spine imaging reports on subsequent nonsurgical and surgical procedures involving the thoracolumbosacral spine and sacroiliac joints.

Design: Analysis of secondary outcomes from the Lumbar Imaging with Reporting of Epidemiology (LIRE) pragmatic stepped-wedge randomized trial.

Setting: Primary care clinics within four integrated health care systems in the United States.

Subjects: 238,886 patients ≥18 years of age who received lumbar diagnostic imaging between 2013 and 2016.

Methods: Clinics were randomized to receive text containing age- and modality-specific epidemiological benchmarks indicating the prevalence of common spine imaging findings in people without low back pain, inserted into lumbar spine imaging reports (the "LIRE intervention"). The study outcomes were receiving 1) any nonsurgical lumbosacral or sacroiliac spine procedure (lumbosacral epidural steroid injection, facet joint injection, or facet joint radiofrequency ablation; or sacroiliac joint injection) or 2) any surgical procedure involving the lumbar, sacral, or thoracic spine (decompression surgery or spinal fusion or other spine surgery).

Results: The LIRE intervention was not significantly associated with subsequent utilization of nonsurgical lumbosacral or sacroiliac spine procedures (odds ratio [OR] = 1.01, 95% confidence interval [CI] 0.93-1.09; P = 0.79) or any surgical procedure (OR = 0.99, 95 CI 0.91-1.07; P = 0.74) involving the lumbar, sacral, or thoracic spine. The intervention was also not significantly associated with any individual spine procedure.

Conclusions: Inserting epidemiological text into spine imaging reports had no effect on nonsurgical or surgical procedure utilization among patients receiving lumbar diagnostic imaging.
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http://dx.doi.org/10.1093/pm/pnab065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185556PMC
June 2021

Effects of Including Epidemiologic Data in Lumbar Spine Imaging Reports on Prescribing Non-Opioid Medications for Pain.

J Gen Intern Med 2021 08 8;36(8):2237-2243. Epub 2021 Feb 8.

Department of Radiology, School of Medicine, University of Washington, Seattle, WA, USA.

Background: Information on the prevalence of common imaging findings among patients without back pain in spine imaging reports might affect pain medication prescribing for patients with back pain. Prior research on inserting this text suggested a small reduction in opioid prescribing.

Objective: To evaluate the effect of epidemiologic information in spine imaging reports on non-opioid pain medication prescribing for primary care patients with back pain.

Design: Post hoc analysis of the Lumbar Imaging with Reporting of Epidemiology cluster-randomized trial.

Participants: A total of 170,680 patients aged ≥ 18 years from four healthcare systems who received thoracolumbar, lumbar, or lumbosacral spine imaging from 2013 to 2016 and had not received a prescription for non-opioid pain medication in the preceding 120 days.

Intervention: Text of age- and modality-specific epidemiologic benchmarks indicating the prevalence of common findings in people without back pain inserted into thoracolumbar, lumbar, or lumbosacral spine imaging reports at intervention clinics.

Main Measures: Primary outcomes: any non-opioid prescription within 90 days after index imaging, overall, and by sub-class (skeletal muscle relaxants, NSAIDs, gabapentinoids, tricyclic antidepressants, benzodiazepines, duloxetine).

Secondary Outcomes: count of non-opioid prescriptions within 90 days, overall, and by sub-class.

Key Results: The intervention was not associated with the likelihood of patients receiving at least one prescription for new non-opioid pain-related medications, overall (adjusted OR, 1.02; 95% CI, 0.97-1.08) or by sub-class. The intervention was not associated with the number of prescriptions for any non-opioid medication (adjusted incidence rate ratio [IRR], 1.02; 95% CI, 0.99-1.04). However, the intervention was associated with more new prescriptions for NSAIDs (IRR, 1.12) and tricyclic antidepressants (IRR, 1.11).

Conclusions: Inserting epidemiologic text in spine imaging reports had no effect on whether new non-opioid pain-related medications were prescribed but was associated with the number of new prescriptions for certain non-opioid sub-classes.

Trial Registration: ClinicalTrials.gov identifier: NCT02015455.
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http://dx.doi.org/10.1007/s11606-021-06627-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342684PMC
August 2021

Cytokine and chemokine responses to injury and treatment in a nonhuman primate model of hypoxic-ischemic encephalopathy treated with hypothermia and erythropoietin.

J Cereb Blood Flow Metab 2021 08 7;41(8):2054-2066. Epub 2021 Feb 7.

Department of Pediatrics, University of Washington, Seattle, WA, USA.

Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h-6h, and significantly lower MCP-4 and MDC at 24 h-72h, respectively. IL-12p40 was lower at 24 h-72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.
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http://dx.doi.org/10.1177/0271678X21991439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327104PMC
August 2021

The Impact of Erythropoietin on Short- and Long-Term Kidney-Related Outcomes in Neonates of Extremely Low Gestational Age. Results of a Multicenter, Double-Blind, Placebo-Controlled Randomized Clinical Trial.

J Pediatr 2021 05 20;232:65-72.e7. Epub 2021 Jan 20.

Department of Pediatrics, University of Washington/Seattle Children's Hospital, Seattle, WA.

Objective: To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22-26 months of corrected gestational age (cGA) compared with those randomized to placebo.

Study Design: We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs.

Results: The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine/cystatin C values at days 0, 7, 9, and 14). At 22-26 months of cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m, 35.8% had urine albumin/creatinine ratio >30 mg/g, 23% had a systolic blood pressure (SBP) >95th percentile for age, and 40% had a diastolic blood pressure (DBP) >95th percentile for age. SBP >90th percentile occurred less often among recipients of erythropoietin (P < .04). This association remained even after controlling for gestational age, site, and sibship (aOR 0.6; 95% CI 0.39-0.92). We did not find statistically significant differences between treatment groups in eGFR, albumin/creatinine ratio, rates of SBP >95th percentile, or DBP >90th or >95th percentiles at the 2 year follow-up visit.

Conclusions: ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin may protect ELGANs against long-term elevated SBP but does not appear to protect from AKI, low eGFR, albuminuria, or elevated DBP at 22-26 months of cGA.
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http://dx.doi.org/10.1016/j.jpeds.2021.01.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093092PMC
May 2021

Association of the Intensity of Diagnostic Evaluation With Outcomes in Incidentally Detected Lung Nodules.

JAMA Intern Med 2021 Apr;181(4):480-489

Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California.

Importance: Whether guideline-concordant lung nodule evaluations lead to better outcomes remains unknown.

Objective: To examine the association between the intensity of lung nodule diagnostic evaluations and outcomes, safety, and health expenditures.

Design, Setting, And Participants: This comparative effectiveness research study analyzed health plan enrollees at Kaiser Permanente Washington in Seattle, Washington, and Marshfield Clinic in Marshfield, Wisconsin, with an incidental lung nodule detected between January 1, 2005, and December 31, 2015. Included patients were 35 years or older, had no high suspicion of infection, had no history of malignant neoplasm, and had no evidence of advanced lung cancer on nodule detection. Data analysis was conducted from January 7 to August 19, 2020.

Exposures: With the 2005 Fleischner Society guidelines (selected for their applicability to the time frame under investigation) as the comparator, 2 other intensities of lung nodule evaluation were defined. Guideline-concordant evaluation followed the guidelines. Less intensive evaluation was the absence of recommended testing, longer-than-recommended surveillance intervals, or less invasive testing than recommended. More intensive evaluation consisted of testing when the guidelines recommended no further testing, shorter-than-recommended surveillance intervals, or more invasive testing than recommended.

Main Outcomes And Measures: The main outcome was the proportion of patients with lung cancer who had stage III or IV disease, radiation exposure, procedure-related adverse events, and health expenditures 2 years after nodule detection.

Results: Among the 5057 individuals included in this comparative effectiveness research study, 1925 (38%) received guideline-concordant, 1863 (37%) less intensive, and 1269 (25%) more intensive diagnostic evaluations. The entire cohort comprised 2786 female patients (55%), and the mean (SD) age was 67 (13) years. Adjusted analyses showed that compared with guideline-concordant evaluations, less intensive evaluations were associated with fewer procedure-related adverse events (risk difference [RD], -5.9%; 95% CI, -7.2% to -4.6%), lower mean radiation exposure (-9.5 milliSieverts [mSv]; 95% CI, -10.3 mSv to -8.7 mSv), and lower mean health expenditures (-$10 916; 95% CI, -$16 112 to -$5719); no difference in stage III or IV disease was found among patients diagnosed with lung cancer (RD, 4.6%; 95% CI, -22% to +31%). More intensive evaluations were associated with more procedure-related adverse events (RD, +8.1%; 95% CI, +5.6% to +11%), higher mean radiation exposure (+6.8 mSv; 95% CI, +5.8 mSv to +7.8 mSv), and higher mean health expenditures ($20 132; 95% CI, +$14 398 to +$25 868); no difference in stage III or IV disease was observed (RD, -0.5%; 95% CI, -28% to +27%).

Conclusions And Relevance: This study found inconclusive evidence of an association between less intensive diagnostic evaluations and more advanced stage at lung cancer diagnosis compared with guideline-concordant care; higher intensities of diagnostic evaluations were associated with greater procedural complications, radiation exposure, and expenditures. These findings underscore the need for more evidence on better ways to evaluate lung nodules and to avoid unnecessarily intensive diagnostic evaluations of lung nodules.
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http://dx.doi.org/10.1001/jamainternmed.2020.8250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816118PMC
April 2021

Two-wave two-phase outcome-dependent sampling designs, with applications to longitudinal binary data.

Stat Med 2021 04 13;40(8):1863-1876. Epub 2021 Jan 13.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Two-phase outcome-dependent sampling (ODS) designs are useful when resource constraints prohibit expensive exposure ascertainment on all study subjects. One class of ODS designs for longitudinal binary data stratifies subjects into three strata according to those who experience the event at none, some, or all follow-up times. For time-varying covariate effects, exclusively selecting subjects with response variation can yield highly efficient estimates. However, if interest lies in the association of a time-invariant covariate, or the joint associations of time-varying and time-invariant covariates with the outcome, then the optimal design is unknown. Therefore, we propose a class of two-wave two-phase ODS designs for longitudinal binary data. We split the second-phase sample selection into two waves, between which an interim design evaluation analysis is conducted. The interim design evaluation analysis uses first-wave data to conduct a simulation-based search for the optimal second-wave design that will improve the likelihood of study success. Although we focus on longitudinal binary response data, the proposed design is general and can be applied to other response distributions. We believe that the proposed designs can be useful in settings where (1) the expected second-phase sample size is fixed and one must tailor stratum-specific sampling probabilities to maximize estimation efficiency, or (2) relative sampling probabilities are fixed across sampling strata and one must tailor sample size to achieve a desired precision. We describe the class of designs, examine finite sampling operating characteristics, and apply the designs to an exemplar longitudinal cohort study, the Lung Health Study.
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http://dx.doi.org/10.1002/sim.8876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110123PMC
April 2021

Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial.

Pediatr Res 2021 07 11;90(1):109-116. Epub 2021 Jan 11.

Department of Pediatrics, University of Washington, Seattle, WA, USA.

Background: Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population.

Methods: This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions.

Results: Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [-1.34, -0.57]), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group.

Conclusions: Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes.

Impact: Transfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.
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http://dx.doi.org/10.1038/s41390-020-01273-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797706PMC
July 2021

High-Dose Erythropoietin in Extremely Low Gestational Age Neonates Does Not Alter Risk of Retinopathy of Prematurity.

Neonatology 2020 28;117(5):650-657. Epub 2020 Oct 28.

Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.

Introduction: The Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial sought to determine the safety and efficacy of early high-dose Epo as a potential neuroprotective treatment. We hypothesized that Epo would not increase the incidence or severity of retinopathy of prematurity (ROP).

Methods: A total of 941 infants born between 24-0/7 and 27-6/7 weeks' gestation were randomized to 1,000 U/kg Epo or placebo intravenously for 6 doses, followed by subcutaneous or sham injections of 400 U/kg Epo 3 times a week through 32 weeks post-menstrual age. In this secondary analysis of PENUT trial data, survivors were evaluated for ROP. A modified intention-to-treat approach was used to compare treatment groups. In addition, risk factors for ROP were evaluated using regression methods that account for multiples and allow for adjustment for treatment and gestational age at birth.

Results: Of 845 subjects who underwent ROP examination, 503 were diagnosed with ROP with similar incidence and severity between treatment groups. Gestational age at birth, birth weight, prenatal magnesium sulfate, maternal antibiotic exposure, and presence of heart murmur at 2 weeks predicted the development of any ROP, while being on high-frequency oscillator or high-frequency jet ventilation (HFOV/HFJV) at 2 weeks predicted severe ROP.

Conclusion: Early high-dose Epo followed by maintenance dosing through 32 weeks does not increase the risk of any or severe ROP in extremely low gestational age neonates. Gestational age, birth weight, maternal treatment with magnesium sulfate, antibiotic use during pregnancy, and presence of a heart murmur at 2 weeks were associated with increased risk of any ROP. Treatment with HFOV/HFJV was associated with an increased risk of severe ROP.
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http://dx.doi.org/10.1159/000511262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855231PMC
August 2021
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