Publications by authors named "Daniel G Whitney"

59 Publications

Critical periods of bone health across the lifespan for individuals with cerebral palsy: Informing clinical guidelines for fracture prevention and monitoring.

Bone 2021 Sep 18;150:116009. Epub 2021 May 18.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.

Background: Skeletal fragility is a major burden for individuals with cerebral palsy (CP), but little is known clinically about when to prevent fractures or monitor bone health for this population. Critical periods of bone health (CPBH) are important windows for intervention to augment bone growth or mitigate bone loss. However, CPBH from the general population may not align with the needs or timing of skeletal fragility for individuals with CP. The objective of this study was to identify discrepancies when evaluating individuals with CP using CPBH across the lifespan from the general population, and propose new CP-specific CPBH.

Methods: Data from 2016 administrative claims databases were used, including the Optum's De-identified Clinformatics® Data Mart Database and a random 20% sample of the Medicare fee-for-service database from the Centers for Medicare and Medicaid Services. Sex-stratified fracture prevalence was compared between individuals with and without CP across the lifespan starting at 2 years of age using age groups to capture important stages of development and 3-4-year age bands in adulthood (up to >80 years). Sex-specific CPBH from the general population included: rapid bone accrual, peak bone mass, menopause, and elderly.

Results: There were 23,861 individuals with CP and 9,976,161 individuals without CP. CPBH from the general population did not align with the timing of skeletal fragility for CP. For example, fractures were rare and decreased throughout the CPBH of peak bone mass for males without CP, but males with CP had a greater relative fracture risk (2.9-5.6-fold higher) and a substantially increased rate of fracture (CP-slope 14× higher than non-CP-slope). For females with CP, fracture risk was increased by 18-21 years, with additional inflection points (e.g., decade before menopause and again by 57-60 years). For males with CP, fracture risk in mid-life exhibited a pattern similar to elderly males without CP.

Conclusions: This study identified discrepancies in evaluating fracture risk for individuals with CP if using established CPBH from the general population. We therefore propose new CP- and sex-specific CPBH for fracture monitoring and prevention.
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http://dx.doi.org/10.1016/j.bone.2021.116009DOI Listing
September 2021

Osteoporosis medication is associated with mortality risk reduction among adults with epilepsy: An observational study.

Authors:
Daniel G Whitney

Bone 2021 Sep 10;150:116003. Epub 2021 May 10.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA; Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Background: Adults with epilepsy have an increased risk of fragility fractures, which contributes to an accelerated rate of premature morbidity and mortality. In the general population, osteoporosis treatment has shown improvements in health and survival, possibly through improving skeletal robustness; however, the effect of osteoporosis medication on survival among adults with epilepsy has not been investigated. The purpose of this propensity score-matched, observational cohort study was to determine if osteoporosis medication was associated with mortality risk among adults with epilepsy. An exploratory analysis then examined the association between the type of osteoporosis medication with mortality.

Methods: Data from 01/01/2012-09/30/2017 was extracted from Optum Clinformatics® Data Mart. Adults ≥50 years of age with epilepsy that were treatment naïve for and initiated osteoporosis medication (EP new users) were the primary group of interest, and were compared to adults with epilepsy that were not prescribed osteoporosis medication (EP no users) and adults without epilepsy that were treatment naïve for and initiated osteoporosis medication (w/o EP new users). Comparison groups were matched 1:4 to EP new users (n = 733; comparison groups, n = 2932) for demographics, glucocorticoid and antiseizure medication, prior 12-month fracture, and the Elixhauser comorbidity index. Crude incidence rate (IR) and IR ratio (IRR and 95% confidence intervals [CI]) was estimated for mortality for up to 3 years of follow-up. For new users, the association between type of osteoporosis medication (bisphosphonates vs. others) and mortality was explored using Cox proportional hazards regression after adjusting for all covariates.

Results: For new users, the majority of the prescribed osteoporosis medications were bisphosphonates (~83%). The incidence of mortality for EP new users was lower compared to EP no users (IRR = 0.69; 95%CI = 0.52-0.93), but elevated compared to w/o EP new users (IRR = 1.42; 95%CI = 1.04-1.94). Comparing bisphosphonates to other medications for new users (P for EP group interaction = 0.089), EP new users showed a lower fully adjusted hazard ratio for mortality (HR = 0.56; 95%CI = 0.30-1.04), but was marginally insignificant (P = 0.066), while w/o EP new users showed no evidence of an association (HR = 1.09; 95%CI = 0.72-1.65).

Conclusions: Osteoporosis medication initiation was associated with a lower 3-year risk of mortality among adults with epilepsy. The exploratory analysis revealed potential evidence of a unique protective effect of bisphosphonates as compared to other osteoporosis medications on 3-year mortality for adults with epilepsy.
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http://dx.doi.org/10.1016/j.bone.2021.116003DOI Listing
September 2021

Fracture characteristics by age, sex, and ambulatory status among individuals with cerebral palsy: a descriptive study.

Disabil Rehabil 2021 May 7:1-7. Epub 2021 May 7.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA.

Purpose: To evaluate clinically relevant fracture characteristics by age, sex, and ambulatory status among individuals with cerebral palsy.

Methods: Fracture location, energy of fracture, and activities that lead to a fracture were assessed among a clinic-based sample of children (0-17 years;  = 57) and adults (18-70 years;  = 58) with cerebral palsy that sustained a fracture by sex and gross motor function classification system (GMFCS) I-III vs. IV/V.

Results: Proportion of fractures that were low-energy was 67-99% for children and 69-84% for adults. ∼2/3rds of fractures were at the lower extremities, with the distal femur being the most common site for children (44%) and the foot/ankle for adults (40%); however, there were age, sex, and ambulatory effects, such that 43% of adults GMFCS IV/V and 32% of women had a distal femur fracture. GMFCS I-III were more likely to fracture from functionally complex activities, while GMFCS IV/V were more likely to fracture from wheelchair/transfers/limb-stuck and incidental findings.

Conclusions: The majority of fractures were low-energy and occurred in the lower extremities, with effects by age, sex, and GMFCS. Activities that led to a fracture also differed by age and GMFCS, which can be used to design fracture prevention interventions in addition to bolstering skeletal mass and architecture.Implications for rehabilitationSkeletal fragility is a major problem for individuals with cerebral palsy (CP) across the lifespan leading to an increased risk of fragility fractures.Rehabilitation is a prime clinical intervention to prevent fractures from occurring and improving post-fracture healing and function; yet, effective rehabilitation interventions require knowledge of fracture characteristics, such as where fractures are occurring and the activities that lead to the fracture event specific to individuals with CP.Using a clinic-based sample of 0-70 year olds with CP, we describe salient fracture characteristics based on age, sex, and ambulatory status to enhance translation into clinical and rehabilitation practice.
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http://dx.doi.org/10.1080/09638288.2021.1921860DOI Listing
May 2021

The effect of age when initiating anti-seizure medication therapy on fragility fracture risk for children with epilepsy.

Bone 2021 Aug 5;149:115996. Epub 2021 May 5.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.

Background: Anti-seizure medication (ASM) is necessary to manage epilepsy and often prescribed to children and adolescents, but can lead to iatrogenic effects, including bone fragility by altering bone metabolism. Disrupting bone metabolism during crucial developmental stages could have a lasting adverse effect on bone health. Therefore, the objective of this propensity score-matched, observational cohort study was to determine if age when initiating ASM therapy across developmental stages (from pre- to post-puberty) for individuals with epilepsy was associated with an increased risk of fragility fracture.

Methods: Data from 01/01/2011 to 12/31/2018 were extracted from Optum Clinformatics® Data Mart. Children aged 4-21 years at baseline with at least 5 years of continuous health plan enrollment were included to allow for a 1-year baseline and 4-years of follow-up. The primary group of interest included new ASM users (i.e., treatment naïve) with epilepsy. The comparison group, no ASM users without epilepsy, was matched 1:14 to new ASM users with epilepsy for demographics and baseline fracture. To provide a proxy for developmental stages, age was categorized as 4-6 (pre-puberty), 7-10 (early puberty), 11-13 (mid-puberty), 14-17 (late puberty), and 18-21 (post-puberty). Crude incidence rate (IR; per 1000 person years) and IR ratio (IRR and 95% confidence intervals [CI]) were estimated for non-trauma fracture (NTFx) for up to 4-years of follow-up.

Results: Prior to stratifying by age group, the crude NTFx IR (95% CI) of 20.6 (16.5-24.8) for new ASM users with epilepsy (n = 1205) was 34% higher (IRR = 1.34; 95% CI = 1.09-1.66) than the crude NTFx IR (95% CI) of 15.4 (14.4-16.3) for no ASM users without epilepsy. The groups exhibited a different pattern of NTFx incidence with age, with new ASM users showing a more dramatic increase and peaking at 11-13 years, then decreasing with the older age groups. The crude IR and IRR were elevated for new ASM users with epilepsy compared to no ASM users without epilepsy for each age group (10% to 55% higher), but was only statistically significant for 11-13 years (IRR = 1.55; 95% CI = 1.02-2.36).

Conclusions: Children with epilepsy initiating ASM therapy may be vulnerable to fragility fracture, especially when initiating ASM around the time of puberty. Clinicians should be aware of this age-related association and consider age-appropriate adjunct bone fragility therapies.
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http://dx.doi.org/10.1016/j.bone.2021.115996DOI Listing
August 2021

Obstructive sleep apnea and fractures in children and adolescents.

J Clin Sleep Med 2021 Apr 30. Epub 2021 Apr 30.

Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI.

Study Objectives: To examine, among girls and boys, associations between site-specific extremity fracture and sleep apnea diagnosis or treatment.

Methods: A cross-sectional analysis of claims data from 2016-2018 for children aged 2-18. Children with sleep apnea, continuous positive airway pressure, adenotonsillectomy, and fracture were identified using ICD10, CPT and HCPCS codes. We examined sex-stratified associations between site-specific fracture, sleep apnea and sleep apnea treatment.

Results: Among 2,327,104 children, 9,547 (0.41%) had sleep apnea and nearly 61% were treated. Girls with sleep apnea, treated or untreated, had increased odds of lower, but not upper, extremity fracture compared to those without sleep apnea (treated 1.56, 95% CI 1.11, 2.21; untreated OR 1.63, 95% CI 1.09, 2.44). Only boys untreated for sleep apnea had increased odds of lower extremity fracture in comparison to those without a diagnosis of sleep apnea (OR 1.65, 95% CI 1.20,2.27). Interestingly, boys treated for sleep apnea but not those untreated, in comparison to boys without sleep apnea, had different (reduced) odds of upper extremity fracture (OR 0.74, 95% CI 0.59, 0.95).

Conclusions: These large datasets provide evidence that both boys and girls with untreated sleep apnea have higher odds of lower extremity fractures. However, treatment for sleep apnea was associated with improved odds of lower extremity fracture only in boys. Upper extremity data were less clear. These data are cross-sectional and cannot show causality, but they suggest that treatment for sleep apnea may lower risk for extremity fractures in boys.
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http://dx.doi.org/10.5664/jcsm.9318DOI Listing
April 2021

Loss of function of lysosomal acid lipase (LAL) profoundly impacts osteoblastogenesis and increases fracture risk in humans.

Bone 2021 Jul 7;148:115946. Epub 2021 Apr 7.

Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA; Center for Bone Biology, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address:

Lysosomal acid lipase (LAL) is essential for cholesteryl ester (CE) and triacylglycerol (TAG) hydrolysis in the lysosome. Clinically, an autosomal recessive LIPA mutation causes LAL deficiency (LALD), previously described as Wolman Disease or Cholesteryl Ester Storage Disease (CESD). LAL-D is associated with ectopic lipid accumulation in the liver, small intestine, spleen, adrenal glands, and blood. Considering the importance of unesterified cholesterol and fatty acids in bone metabolism, we hypothesized that LAL is essential for bone formation, and ultimately, skeletal health. To investigate the role of LAL in skeletal homeostasis, we used LAL-deficient () mice, in vitro osteoblast cultures, and novel clinical data from LAL-D patients. Both male and female LAL mice demonstarted lower trabecular and cortical bone parameters , which translated to reduced biomechanical properties. Further histological analyses revealed that LAL mice had fewer osteoblasts, with no change in osteoclast or marrow adipocyte numbers. In studying the cell-autonomous role of LAL, we observed impaired differentiation of LAL calvarial osteoblasts and in bone marrow stromal cells treated with the LAL inhibitor lalistat. Consistent with LAL's role in other tissues, lalistat resulted in profound lipid puncta accumulation and an altered intracellular lipid profile. Finally, we analyzed a large de-identified national insurance database (i.e. 2016/2017 Optum Clinformatics®) which revealed that adults (≥18 years) with CESD (n = 3076) had a higher odds ratio (OR = 1.21; 95% CI = 1.03-1.41) of all-cause fracture at any location compared to adults without CESD (n = 13.7 M) after adjusting for demographic variables and osteoporosis. These data demonstrate that alterations in LAL have significant clinical implications related to fracture risk and that LAL's modulation of lipid metabolism is a critical for osteoblast function.
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http://dx.doi.org/10.1016/j.bone.2021.115946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108562PMC
July 2021

Whitney Comorbidity Index to monitor health status for adults with cerebral palsy: validation and thresholds to assist clinical decision making.

Dev Med Child Neurol 2021 Jul 7;63(7):853-859. Epub 2021 Apr 7.

Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.

Aim: To validate the Whitney Comorbidity Index (WCI), which was recently developed to monitor disease status for adults with cerebral palsy (CP), and to identify WCI scores associated with an increased mortality risk using a representative sample of adults with CP.

Method: Data from 2016 to 2018 were used from a random 20% sample from the fee-for-service Medicare database for this retrospective cohort study. The WCI was examined as unweighted (WCI ) and weighted (WCI ) among adults at least 18 years old with CP. Cox regression models were developed with mortality as the outcome after adjusting for demographics. A concordance statistic (C-statistic) of at least 0.70 was considered as showing sufficient validity. The hazard ratio of mortality for each WCI score was estimated. Secondary analyses were performed for subgroups with co-occurring epilepsy and/or intellectual disabilities.

Results: For the entire group (n=16 728) and subgroups, the WCI showed sufficient validity (C-statistic 0.73-0.81). For the entire group, the mortality rate was elevated for a score of 1 compared with 0 from the WCI (hazard ratio 3.06; 95% confidence interval [CI] 1.52-6.17) and WCI (hazard ratio 4.08; 95% CI 1.69-9.85), and became larger with each WCI score. Results were similar for the subgroups.

Interpretation: The WCI is a valid marker for health/disease status for adults with CP. Several WCI score thresholds were identified to assist in clinical decision making for preventive medicine and intervention implementation. What this paper adds The Whitney Comorbidity Index (WCI) is valid among 16 728 adults with CP. The WCI is valid for those with co-occurring epilepsy and/or intellectual disabilities. Thresholds of the WCI score were identified to assist clinical decision making.
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http://dx.doi.org/10.1111/dmcn.14879DOI Listing
July 2021

Timecourse of Morbidity Onset Among Adults Living With Cerebral Palsy.

Am J Prev Med 2021 07 13;61(1):37-43. Epub 2021 Mar 13.

Department of Physical Medicine and Rehabilitation, Michigan Medicine, University of Michigan, Ann Arbor, Michigan; Institute for Healthcare Policy & Innovation, University of Michigan, Ann Arbor, Michigan.

Introduction: Despite the greater risk of an array of morbidities, little is known about when morbidities occur for adults with cerebral palsy. The objective of this study is to determine the timecourse of morbidity risk/development for adults with cerebral palsy and the effect by patient-level factors.

Methods: Cross-sectional data from 2016 were used from a random 20% sample from the fee-for-service Medicare database. Diagnosis codes identified adults aged ≥18 years with cerebral palsy and 16 clinically relevant morbidities. Qualitative and quantitative approaches identified the age where each morbidity became exceedingly prevalent. The effect of the timecourse by sex, race, and co-occurring intellectual disabilities and epilepsy was examined. Data were sequestered and analyzed in 2020.

Results: Among 16,818 adults with cerebral palsy, the prevalence of most morbidities was already high among those aged 18-30 years, and all morbidities increased with age except liver disease and anxiety. Hypertension and diabetes exhibited a positive linear trend with age. Of the morbidities that did not exhibit a linear trend, the qualitative and quantitative approaches were consistent considering that the cardiorespiratory diseases, osteoarthritis, renal disease, and dementia became exceedingly more prevalent at age >50 years, whereas the threshold was >60 years for depression, cancer, and metastatic cancer. There were interactions with sex, race, and co-occurring intellectual disabilities and epilepsy for some of the morbidities.

Conclusions: Morbidity prevalence is already elevated early in adulthood among individuals living with cerebral palsy, with an abrupt increase by age 50 years. Preventive efforts should be adopted early in the lifespan and not later than age 50 years for adults with cerebral palsy.
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http://dx.doi.org/10.1016/j.amepre.2021.01.020DOI Listing
July 2021

The paradoxical relationship between severity of cerebral palsy and renal function in middle-aged adults: better renal function or inappropriate clinical assessment?

Disabil Rehabil 2021 Feb 26:1-7. Epub 2021 Feb 26.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA.

Purpose: To determine the association between severity of cerebral palsy with serum creatinine (sCr) and sCr-based equations to estimate glomerular filtration rate (eGFR), a marker of renal function.

Methods: A clinic-based sample of 30-64 year-olds with cerebral palsy was examined and stratified by motor impairment: gross motor function classification system (GMFCS) I/II ( = 79), GMFCS III ( = 78), and GMFCS IV/V ( = 137). sCr, which is influenced by muscle mass, was obtained and sCr-based eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations.

Results: sCr was lower with increasing GMFCS. The opposite pattern was observed for eGFR: GMFCS IV/V had significantly higher eGFR derived from MDRD compared to other GMFCS groups; GMFCS III had significantly higher eGFR compared to GMFCS I/II. The pattern was similar for CKD-EPI derived eGFR.

Conclusions: According to widely used clinical assessment methods for renal function, higher severity of cerebral palsy among adults is associated with better renal function, which is incongruent with their other biological systems. This paradoxical relationship is likely driven by lower muscle rather than true renal function, and thus, sCr-based eGFR may overestimate renal function, especially for GMFCS IV/V. Further prospective studies are needed.Implications for rehabilitationCommon methods of clinical assessment may over-estimate renal function for adults with cerebral palsy (CP), potentially giving a false positive for normal renal health due to their reliance on muscle mass.This study of a clinic-based sample of middle-aged adults with CP highlights the paradoxical relationship between severity of CP and renal function, which is likely driven by methodological limitations in the presence of low muscle mass rather than actual better renal function.It is recommended that clinicians have a high suspicion of abnormal renal function and the need for a nephrology consultation, especially with changes in creatinine levels, even within the normal range.Rehabilitation for adults with CP must have a strong focus on muscle and kidney health, especially for patients with more severe forms of CP.
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http://dx.doi.org/10.1080/09638288.2021.1890841DOI Listing
February 2021

The Effect of Osteoporosis Medication on Risk Attenuation of Non-Trauma Fracture Among Adults with Cerebral Palsy: A Propensity Score-Matched Observational Study.

Clin Epidemiol 2021 12;13:91-102. Epub 2021 Feb 12.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.

Purpose: The efficacy of osteoporosis medication on reducing the risk of non-trauma fracture (NTFx) among adults with cerebral palsy (CP) has not been comprehensively investigated. There are many logistical and biological factors that may reduce this efficacy, and therefore requires attention. The purpose of this propensity score-matched, observational cohort study was to determine if osteoporosis medication was associated with NTFx risk attenuation among adults with CP and compared to adults without CP.

Materials And Methods: Data from 07/01/2011 to 09/30/2015 were extracted from Optum Clinformatics Data Mart. Claims identified adults (≥18 years), CP, osteoporosis medication, pre-index NTFx (6-months), and post-index NTFx (12-months). CP without osteoporosis medication (CP) and without CP with Meds (non-CP; reflects "background" population) served as controls and were matched (6:1 ratio) to adults with CP with Meds (CP; n=306). The Meds groups were further stratified by the initiation of their medication as new users or consistent users. Changes in the prevalence of NTFx from pre- to post-index periods were examined with risk ratios (RR) and the change was compared among groups using the ratio of the RR (RRR) via difference-in-difference analysis.

Results: New users with CP had: a larger risk attenuation of any NTFx compared to CP (RRR=0.39; 95% CI=0.22-0.71), which was consistent for vertebral column/hip and lower extremities; a larger risk attenuation for NTFx of the lower extremities compared to consistent users with CP (RRR=0.22; 95% CI=0.05-0.93); and a similar risk attenuation of any NTFx compared to new users without CP (RRR=0.81; 95% CI=0.45-1.43), which was consistent for vertebral column/hip and lower extremities.

Conclusion: The findings suggest that osteoporosis medication is associated with clinically meaningful risk attenuation of NTFx, especially for new users with CP.
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http://dx.doi.org/10.2147/CLEP.S294202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886102PMC
February 2021

Polypharmacy is a risk factor for mortality, severe chronic kidney disease, and liver disease among privately insured adults with cerebral palsy.

J Manag Care Spec Pharm 2021 Jan;27(1):51-63

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor.

Adults with cerebral palsy (CP) have an increased risk for polypharmacy, premature mortality, and early development of several morbidities, including conditions associated with excess medication exposure, such as chronic kidney disease (CKD) and liver disease. To date, very little is known about the consequence of polypharmacy for adults with CP. To determine if polypharmacy is associated with an increased risk for mortality, severe CKD, and liver disease among adults with CP, before and after adjusting for comorbid neurodevelopmental disabilities (NDDs) and multimorbidity. This is an exploratory treatment effectiveness study. Data from the Optum Clinformatics Data Mart were used for this retrospective cohort study. Adults aged 18 years or older with a diagnosis of CP and without severe CKD (stages IV+) and liver disease were identified from the calendar year 2013 and were subsequently followed from January 1, 2014, to death, severe CKD, liver disease, loss to follow-up, or end of study period (December 31, 2017). Diagnosis codes were used to identify NDDs (intellectual disabilities, epilepsy, autism spectrum disorders, spina bifida) and 24 relevant morbidities at baseline (i.e., calendar year 2013). Polypharmacy was defined as ≥ 5 medications and hyperpolypharmacy was defined as ≥ 10 medications at baseline. Cox regression models were developed to examine the association (as HR and 95% CI) between polypharmacy and hyperpolypharmacy with mortality, severe CKD, and liver disease separately, before and after adjusting for covariates (demographics, NDDs, multimorbidity). Exploratory analyses examined the mediating effect of incident severe CKD or liver disease on the association between the exposure (polypharmacy or hyperpolypharmacy) on outcomes. Of the 9,238 adults with CP, 58.5% had polypharmacy and 29.5% had hyperpolypharmacy. The fully adjusted HR for mortality was 2.14 (95% CI = 1.59-2.89) for polypharmacy and 1.65 (95% CI = 1.31-2.09) for hyperpolypharmacy. The fully adjusted HR for severe CKD was 1.66 (95% CI = 1.17-2.36) for polypharmacy and 1.67 (95% CI = 1.27-2.19) for hyperpolypharmacy. The fully adjusted HR for liver disease was 1.57 (95% CI = 1.27-1.94) for polypharmacy and 1.72 (95% CI = 1.42-2.08) for hyperpolypharmacy. Incident liver disease mediated 5.37% (polypharmacy) and 7.54% (hyperpolypharmacy) of the association between the exposure with incident severe CKD for nonelderly (aged < 65 years), while incident severe CKD mediated 7.05% (polypharmacy) and 6.64% (hyperpolypharmacy) of the association between the exposure with incident liver disease for elderly (aged ≥ 65 years). Polypharmacy and hyperpolypharmacy are robust risk factors for risk of mortality, severe CKD, and liver disease among privately insured adults with CP. While incidence of severe CKD and liver disease had negligible effects on the association between polypharmacy with mortality, there is evidence that they mediate a considerable portion of one another and require further examination. During the work for this study, Whitney was supported by the University of Michigan Office of Health Equity and Inclusion Diversity Fund and American Academy for Cerebral Palsy and Developmental Medicine. The funding sources had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The authors have no conflicts of interest to report.
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http://dx.doi.org/10.18553/jmcp.2021.27.1.051DOI Listing
January 2021

Development of a new comorbidity index for adults with cerebral palsy and comparative assessment with common comorbidity indices.

Dev Med Child Neurol 2021 Mar 2;63(3):313-319. Epub 2020 Dec 2.

Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.

Aim: To develop a new comorbidity index for adults with cerebral palsy (CP), the Whitney Comorbidity Index (WCI), which includes relevant comorbidities for this population and better predicts mortality than the Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI).

Method: Data from the Optum Clinformatics Data Mart was used for this retrospective cohort study. Diagnosis codes were used to identify adults aged 18 years or older with CP (n=1511 females, n=1511 males; mean [SD; range] age=48y [19y 2mo; 18-89y]) and all comorbidities in the year 2014. The WCI was developed based on the comorbidities of the CCI and ECI and other relevant comorbidities associated with 2-year mortality using Cox regression and competing risk analysis. The WCI was examined as unweighted (WCI ) and weighted (WCI ). The model fit and discrimination (C-statistic) of each index was assessed using Cox regression.

Results: Twenty-seven comorbidities were included in the WCI; seven new comorbidities that were not part of the CCI or ECI were added. The WCI and WCI showed a better model fit and discrimination for 1- and 2-year mortality compared to the CCI and ECI. The WCI and WCI were strong predictors for 1- and 2-year mortality (C-statistic [95% confidence interval] ranging from 0.81 [0.76-0.85] to 0.88 [0.82-0.94]).

Interpretation: The new WCI, designed to include clinically relevant comorbidities, provides a better model fit and discrimination of mortality for adults with CP.

What This Paper Adds: Common comorbidity indices exclude relevant comorbidities for adults with cerebral palsy (CP). A new comorbidity index for adults with CP was created by harmonizing clinical theory and data-driven methods. The Whitney Comorbidity Index better predicted 1- and 2-year mortality than other commonly used comorbidity indices.
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http://dx.doi.org/10.1111/dmcn.14759DOI Listing
March 2021

The respiratory disease burden of non-traumatic fractures for adults with cerebral palsy.

Bone Rep 2020 Dec 27;13:100730. Epub 2020 Oct 27.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA.

Background: Individuals with cerebral palsy (CP) are vulnerable to non-trauma fracture (NTFx) and premature mortality due to respiratory disease (RD); however, very little is known about the contribution of NTFx to RD risk among adults with CP. The purpose of this study was to determine if NTFx is a risk factor for incident RD and if NTFx exacerbates RD risk in the adult CP population.

Methods: Data from 2011 to 2016 Optum Clinformatics® Data Mart and a random 20% sample Medicare fee-for-service were used for this retrospective cohort study. Diagnosis codes were used to identify adults (18+ years) with and without CP, NTFx, incident RD at 3-, 6-, 12-, and 24-month time points (pneumonia, chronic obstructive pulmonary disease, interstitial/pleura disease), and comorbidities. Crude incidence rates per 100 person years of RD were estimated. Cox regression estimated hazard ratios (HR and 95% confidence interval [CI]) for RD measures, comparing: (1) CP and NTFx (CP + NTFx); (2) CP without NTFx (CP w/o NTFx); (3) without CP and with NTFx (w/o CP + NTFx); and (4) without CP and without NTFx (w/o CP w/o NTFx) after adjusting for demographics and comorbidities.

Results: The crude incidence rate was elevated for CP + NTFx vs. CP w/o NTFx and w/o CP + NTFx for each RD measure. After adjustments, the HR was elevated for CP + NTFx vs. CP w/o NTFx for pneumonia and interstitial/pleura disease at all time points (all  < 0.05), but not chronic obstructive pulmonary disease (e.g., 24-month HR = 1.07; 95%CI = 0.88-1.31). The adjusted HR was elevated for CP + NTFx vs. w/o CP + NTFx for pneumonia at all time points, interstitial/pleura disease at 12- and 24-month time points, and chronic obstructive pulmonary disease at 24-months (all  < 0.05). There is evidence of a time-dependent effect of NTFx on pneumonia and interstitial/pleura disease for CP + NTFx as compared to CP w/o NTFx.

Conclusions: Study findings suggest that NTFx is a risk factor for incident RD, including pneumonia and interstitial/pleura disease, among adults with CP and that NTFx exacerbates RD risk for adults with vs. without CP.
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http://dx.doi.org/10.1016/j.bonr.2020.100730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645631PMC
December 2020

Test-Retest Reliability and Correlates of Vertebral Bone Marrow Lipid Composition by Lipidomics Among Children With Varying Degrees of Bone Fragility.

JBMR Plus 2020 Oct 8;4(10):e10400. Epub 2020 Sep 8.

Department of Orthopaedic Surgery University of Michigan Ann Arbor MI USA.

The reliability of lipidomics, an approach to identify the presence and interactions of lipids, to analyze the bone marrow lipid composition among pediatric populations with bone fragility is unknown. The objective of this study was to assess the test-retest reliability, standard error of measurement (SEM), and the minimal detectable change (MDC) of vertebral bone marrow lipid composition determined by targeted lipidomics among children with varying degrees of bone fragility undergoing routine orthopedic surgery. Children aged 10 to 19 years, with a confirmed diagnosis of adolescent idiopathic scoliosis ( = 13) or neuromuscular scoliosis and cerebral palsy ( = 3), undergoing posterior spinal fusion surgery at our institution were included in this study. Transpedicular vertebral body bone marrow samples were taken from thoracic vertebrae (T11, 12) or lumbar vertebrae (L1 to L4). Lipid composition was assessed via targeted lipidomics and all samples were analyzed in the same batch. Lipid composition measures were examined as the saturated, monounsaturated, and polyunsaturated index and as individual fatty acids. Relative and absolute test-retest reliability was assessed using the intraclass correlation coefficient (ICC), SEM, and MDC. Associations between demographics and index measures were explored. The ICC, SEM, and MDC were 0.81 (95% CI, 0.55-0.93), 1.6%, and 4.3%, respectively, for the saturated index, 0.66 (95% CI, 0.25-0.87), 3.5%, and 9.7%, respectively, for the monounsaturated index, and 0.60 (95% CI, 0.17-0.84), 3.6%, and 9.9%, respectively, for the polyunsaturated index. For the individual fatty acids, the ICC showed a considerable range from 0.04 (22:2n-6) to 0.97 (18:3n-3). Age was positively correlated with the saturated index ( = 0.36; = 0.014) and negatively correlated with the polyunsaturated index ( = 0.26; = 0.043); there was no difference in index measures by sex ( > 0.58). The test-retest reliability was moderate-to-good for index measures and poor to excellent for individual fatty acids; this information can be used to power research studies and identify measures for clinical or research monitoring. © 2020 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574707PMC
October 2020

Pattern of bone marrow lipid composition measures along the vertebral column: A descriptive study of adolescents with idiopathic scoliosis.

Bone 2021 01 21;142:115702. Epub 2020 Oct 21.

Department of Orthopaedic Surgery, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 2009, Ann Arbor, MI 48109, United States of America.

Background: There is evidence that the extent of vertebral bone marrow adiposity increases caudally along the vertebral column in children and adolescents. However, no studies have examined the lipid composition of bone marrow along the vertebral column, which may uniquely influence bone acquisition and metabolism during growth independent of the amount of bone marrow adipose tissue. The goal of this study was to characterize the pattern of lipid composition index measures from the thoracic to lumbar spine (T11-L4) among a sample of adolescents with idiopathic scoliosis (AIS) undergoing routine orthopedic surgical care for scoliosis correction.

Methods: Adolescents between 14 and 18 years of age, with a confirmed diagnosis of AIS, and undergoing routine posterior spinal fusion surgery at our institution were initially included for this descriptive study. The surgery yielded transpedicular vertebral body marrow samples from T11 through L4; 11 participants had bone marrow samples from T11 through L2 and 4 of the 11 participants had marrow samples from T11 through L4. Lipid composition index measures, including the saturated, monounsaturated, and polyunsaturated index, were measured using a targeted lipidomics technique. Linear regression equation for the slope (m) and Pearson correlation coefficient (r) was computed to assess the pattern of lipid composition index measures along the vertebral column from T11 to L2 (n = 11) and extended analysis to L4. Exploratory analyses were performed to examine the association between the pattern of lipid composition measures (individual slopes) and physical characteristics for T11-L2.

Results: For T11-L2, the slope of the saturated index was near 0 (r = 0.08; P = 0.92), whereas the slopes of the unsaturated indices were approximately opposite of one another: the monounsaturated index exhibited a -0.55 change (r = 0.58; P = 0.42) per vertebra and the polyunsaturated index exhibited a 0.52 change (r = 0.72; P = 0.28) per vertebra in the caudal direction from T11-L2. For T11-L4, there were modest changes in slope for the saturated (m = 0.12; r = 0.30; P = 0.57) and monounsaturated (m = -0.68; r = 0.74; P = 0.09) indices, while the polyunsaturated index slope remained similar (m = 0.56; r = 0.89; P = 0.02). Age, sex, height, body mass, and BMI were not associated with the pattern of any of the lipid composition index measures.

Conclusions: Study findings in this small sample of individuals with AIS suggest that the bone marrow saturated index may be relatively stable across T11-L4, while the monounsaturated index may decrease by 0.55-0.68% per vertebra and the polyunsaturated index may increase by 0.52-0.56% per vertebra in the caudal direction.
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http://dx.doi.org/10.1016/j.bone.2020.115702DOI Listing
January 2021

Advanced CKD Among Adults With Cerebral Palsy: Incidence and Risk Factors.

Kidney Med 2020 Sep-Oct;2(5):569-577.e1. Epub 2020 Aug 6.

Department of Physical Medicine and Rehabilitation, Michigan Medicine, University of Michigan, Ann Arbor, MI.

Rationale & Objective: Recent evidence suggests that adults with cerebral palsy have an elevated risk for developing advanced chronic kidney disease (CKD). To develop effective interventions, the objective was to identify whether demographics and preexisting medical conditions are risk factors for advanced CKD among adults with cerebral palsy.

Study Design: Retrospective cohort study.

Setting & Participants: Data were from the Optum Clinformatics Data Mart. Adults 18 years or older with cerebral palsy and without advanced CKD (CKD stage 4 or later) were identified from 2013 and subsequently followed up from January 1, 2014, to the development of advanced CKD, death, loss to follow-up, or end of the study period (December 31, 2017), whichever came first. Diagnostic, procedure, and diagnosis-related group codes were used to identify cerebral palsy, incident cases of advanced CKD, comorbid intellectual disability, and 10 preexisting medical conditions.

Exposures: Demographic variables and 10 preexisting medical conditions: CKD stages 1-3, hypertension, diabetes, heart and cerebrovascular disease, non-CKD urologic conditions, bowel conditions, respiratory disease, skeletal fragility, arthritis, and dysphagia.

Outcome: Incidence of advanced CKD.

Analytic Approach: Crude incidence rate (IR) of advanced CKD and IR ratios with 95% CIs were estimated. Cox proportional hazards regression models that were adjusted for demographics, intellectual disability, and preexisting medical conditions were used to evaluate the adjusted independent effect of predictor variables.

Results: 237 of the 8,011 adults with cerebral palsy developed advanced CKD during follow-up (IR, 10.16/1,000 person years; 95% CI, 8.87-11.46). In the crude analysis, all preexisting medical conditions were associated with an elevated IR and IR ratio of advanced CKD. In the fully adjusted Cox proportional hazards regression model, the HR was elevated for older age, CKD stages 1-3 (HR, 3.32; 95% CI, 2.39-4.61), diabetes (HR, 2.69; 95% CI, 2.03-3.57), hypertension (HR, 1.54; 95% CI, .10-2.16), heart and cerebrovascular disease (HR, 1.53; 95% CI, 1.12-2.07), and non-CKD urologic conditions (HR, 1.39; 95% CI, 1.05-1.84).

Limitations: Private insurance database, short follow-up period, and lack of laboratory values, such as albuminuria/proteinuria.

Conclusions: Advanced CKD was common among adults with cerebral palsy and its development was associated with both traditional and nontraditional urologic risk factors.
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http://dx.doi.org/10.1016/j.xkme.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568081PMC
August 2020

Effectiveness of osteoporosis medication on site-specific fracture-risk attenuation among adults with epilepsy.

Authors:
Daniel G Whitney

Epilepsia 2020 11 14;61(11):2583-2592. Epub 2020 Oct 14.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA.

Objective: The objective of this propensity score-matched, observational cohort study was to determine the effectiveness of osteoporosis medication on reducing the risk of non-trauma fracture (NTFx) among adults with epilepsy.

Methods: Data from 01/01/2012 to 09/30/2015 was extracted from Optum Clinformatics Data Mart. NTFx risk attenuation from 12 months prior to 12 months after the individual's index date was examined for each group of adults ≥50 years of age as risk ratios (RRs with 95% confidence intervals [CIs]). Groups were stratified based on: (1) epilepsy status, as with vs without epilepsy (EP); and (2) if and when osteoporosis medication was first prescribed, as new users (treatment naive), consistent users (osteoporosis medication prescribed in pre-index period), and no users. Comparison groups were matched 1:1 to EP new users (n = 828/group) for demographics, glucocorticoid and antiseizure medication, and the Elixhauser comorbidity index. Difference-in-difference analysis compared the change in pre- to post-index NTFx risk among groups as the ratio of the RR (RRR).

Results: The pre- to post-index NTFx risk at any site was reduced for EP new users (RR = 0.49; 95% CI = 0.40-0.61) and EP consistent users (RR = 0.70; 95% CI = 0.38-0.98), but nonsignificantly elevated for EP no users (RR = 1.39; 95% CI = 0.93-2.07)-findings were consistent for most sites (eg, vertebral column). EP new users had a larger NTFx risk attenuation at any site compared to EP no users (RRR = 0.35; 95% CI = 0.23-0.54) and EP consistent users (RRR = 0.70; 95% CI = 0.51-0.97). EP consistent users had a larger NTFx risk attenuation at any site compared to EP no users (RRR = 0.50; 95% CI = 0.32-0.79). The extent of NTFx risk attenuation at any site was similar for new users with vs without epilepsy (RRR = 0.99; 95% CI = 0.73-1.34) and consistent users with vs without epilepsy (RRR = 0.81; 95% CI = 0.55-1.17). There was evidence of site-specific effects (eg, hip).

Conclusion: Osteoporosis medication is associated with a clinically meaningful 12-month NTFx risk attenuation for adults with epilepsy, especially for those just starting osteoporosis medication.
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http://dx.doi.org/10.1111/epi.16700DOI Listing
November 2020

The mortality burden of non-trauma fracture for adults with cerebral palsy.

Bone Rep 2020 Dec 7;13:100725. Epub 2020 Oct 7.

Department of Orthopaedic Surgery, University of Michigan, 1540 E Hospital Dr., Ann Arbor, MI 48109, United States of America.

Background: Individuals with cerebral palsy (CP) manifest skeletal fragility problems early in life, are vulnerable to non-trauma fracture (NTFx), and have a high burden of premature mortality. No studies have examined the contribution of NTFx to mortality among adults with CP. The purpose of this study was to determine if NTFx is a risk factor for mortality among adults with CP and if NTFx exacerbates mortality risk compared to adults without CP.

Methods: Data from 2011 to 2016 Optum Clinformatics® Data Mart and a random 20% sample Medicare fee-for-service were used for this retrospective cohort study. Diagnosis codes were used to identify adults (18+ years) with and without CP, NTFx, and pre-NTFx comorbidities. Crude mortality rates per 100 person years were estimated. Cox regression estimated hazard ratios (HR and 95% confidence interval [CI]) for mortality, comparing: (1) CP and NTFx (CP + NTFx;  = 1777); (2) CP without NTFx (CP w/o NTFx;  = 12,933); (3) without CP and with NTFx (w/o CP + NTFx;  = 433,560); and (4) without CP and without NTFx (w/o CP w/o NTFx;  = 6.8 M) after adjusting for demographics and pre-NTFx comorbidities.

Results: The 3-, 6-, and 12-month crude mortality rates were highest among CP + NTFx (12-month mortality rate = 6.80), followed by w/o CP + NTFx (12-month mortality rate = 4.91), CP w/o NTFx (12-month mortality rate = 2.15), and w/o CP w/o NTFx (12-month mortality rate = 0.49). After adjustments, the mortality rate was elevated for CP + NTFx for all time points compared to CP w/o NTFx (e.g., 12-month HR = 1.61; 95%CI = 1.29-2.01), w/o CP + NTFx (e.g., 12-month HR = 1.49; 95%CI = 1.24-1.80), and w/o CP w/o NTFx (e.g., 12-month HR = 5.33; 95%CI = 4.42-6.44). There were site-specific effects (vertebral column, lower extremities) on 12-month mortality.

Conclusions: NTFx is associated with an increase of 12-month mortality risk among adults with CP and compared to adults without CP. Findings suggest that NTFx may be a robust risk factor for mortality among adults with CP.
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http://dx.doi.org/10.1016/j.bonr.2020.100725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560646PMC
December 2020

Intersite reliability of vertebral bone marrow lipidomics-derived lipid composition among children with varying degrees of bone fragility undergoing routine orthopedic surgery.

Bone 2021 02 11;143:115633. Epub 2020 Sep 11.

Department of Orthopaedic Surgery, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 2009, Ann Arbor, MI 48109, United States of America.

Background: Lipidomics, a branch of metabolomics, is an attractive technique to characterize bone marrow lipid composition, which may be associated with skeletal acquisition and homeostasis. However, the reliability of lipidomics-derived lipid composition of the bone marrow is unknown, especially for pediatric populations with bone fragility. The purpose of this study was to evaluate the intersite reliability and standard error of measurement (SEM) of vertebral bone marrow lipid composition at the thoracic (T11/T12) and lumbar (L1/L2) spine determined by targeted lipidomics among children with varying degrees of bone fragility undergoing routine orthopedic surgery.

Methods: Children aged between 12 and 19 years of age, with a confirmed diagnosis of adolescent idiopathic scoliosis or neuromuscular scoliosis and cerebral palsy, and undergoing routine posterior spinal fusion surgery at our institution were initially included in this study. Transpedicular vertebral body bone marrow samples were taken from thoracic (T) or lumbar (L) vertebrae. Further inclusion criteria involved having bone marrow extracted from both T11 and T12 (n = 24) or L1 and L2 (n = 19). Lipid composition was measured using a targeted lipidomics technique and examined as the saturated, monounsaturated, and polyunsaturated index and as individual fatty acids. Relative and absolute test-retest reliability was assessed using the intraclass correlation coefficient (ICC) and SEM.

Results: For the T11/T12 analysis: the ICC and SEM were 0.59 and 1.7% for the saturated index, 0.31 and 6.2% for the monounsaturated index, and 0.44 and 6.1% for the polyunsaturated index; the ICC showed a considerable range for individual fatty acids from 0.07 (fatty acid 20:2) to 0.82 (15:0) with 62.1% of the fatty acids having poor reliability (i.e., ICC < 0.50). For the L1/L2 analysis: the ICC and SEM were 0.50 and 2.4% for the saturated index, -0.12 and 6.0% for the monounsaturated index, and 0.00 and 4.9% for the polyunsaturated index; the ICC showed a considerable range for individual fatty acids from -0.34 (18:1_n-9) to 0.88 (15:0 and 18:3_n-3) with 79.3% of the fatty acids having poor reliability.

Conclusions: The intersite test-retest reliability was poor-to-moderate for index measures and generally poor for individual fatty acids for the thoracic and lumbar spine. At this time, it is not recommended to pool bone marrow adipose tissue across vertebral sites for bone marrow adiposity research or clinical monitoring for pediatric populations with bone fragility.
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http://dx.doi.org/10.1016/j.bone.2020.115633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770023PMC
February 2021

Polypharmacy Among Privately Insured Adults with Cerebral Palsy: A Retrospective Cohort Study.

J Manag Care Spec Pharm 2020 Sep;26(9):1153-1161

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor.

Background: Adults with cerebral palsy (CP) have increased risk for developing various secondary chronic diseases, especially when they have other neurodevelopmental disabilities (NDDs). Multiple medications are likely prescribed to manage the greater morbidity-related burden for adults with CP; however, because health care delivery and care coordination is suboptimal for this population, adults with CP may have an increased risk for polypharmacy. To date, very little is known about the prescribing practices and extent of polypharmacy for adults with CP.

Objective: To determine the prevalence and adjusted odds of polypharmacy among adults with CP only and those with CP+NDDs, compared with adults without CP.

Methods: Data from 2017 Optum Clinformatics Data Mart, a U.S. private administrative database, was used for this retrospective cohort study. Diagnosis codes were used to identify adults (aged ≥ 18 years) with CP, NDDs (e.g., intellectual disabilities, epilepsy, and autism spectrum disorders), and 24 relevant morbidities. Polypharmacy was examined as 0-4 versus ≥ 5, 0-9 versus ≥ 10, and 0-14 versus ≥ 15 medications. Logistic regression estimated the OR and 95% CI of polypharmacy before and after adjusting for age, sex, region of residence, and multimorbidity (as 0, 1, 2, 3, 4-5, and ≥ 6 morbidities). Exploratory analyses were conducted to compare polypharmacy among young (18-40 years) and middle-aged (41-64 years) adults with CP only and CP + NDDs with elderly (≥ 65 years) adults without CP.

Results: Adults with CP only (n = 5,603) and CP + NDDs (n = 2,474) had higher unadjusted prevalence and adjusted OR for each polypharmacy definition compared with adults without CP (n = 9.0 million; e.g., ≥ 5 medications: adjusted OR for CP only = 1.38, 95% CI = 1.30-1.47; CP + NDDs: OR = 2.42, 95% CI = 2.20-2.67). Adults with CP+NDDs had higher unadjusted prevalence and adjusted OR of each polypharmacy definition compared with CP only. Compared with elderly without CP, the unadjusted prevalence of polypharmacy was lower for young adults with CP only (e.g., ≥ 5 medications: 60.2%, 43.8%), similar for young adults with CP+NDDs (e.g., ≥ 15 medications: 10.9%, 12.5%), and elevated for middle-aged CP only and CP + NDDs (e.g., ≥ 10 medications: 28.7%, 34.3%, 41.7%).

Conclusions: Privately insured adults with CP only and CP + NDDs have an elevated prevalence of polypharmacy compared with adults without CP, even after accounting for multimorbidity. Importantly, adults aged 18-40 years with CP have a similar (CP + NDDs) prevalence of polypharmacy compared with the general geriatric population, with the prevalence increasing further for CP by middle age.

Disclosures: Whitney was supported by the University of Michigan Office of Health Equity and Inclusion Diversity Fund and the American Academy of Cerebral Palsy and Developmental Medicine. These funding sources had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The other authors have no conflicts of interest to disclose.
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http://dx.doi.org/10.18553/jmcp.2020.26.9.1153DOI Listing
September 2020

Risk for respiratory and cardiovascular disease and mortality after non-trauma fracture and the mediating effects of respiratory and cardiovascular disease on mortality risk among adults with epilepsy.

Epilepsy Res 2020 10 29;166:106411. Epub 2020 Jun 29.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA; Epidemiology Group, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Scotland, UK.

Background: Non-trauma fracture (NTFx), an indicator of skeletal fragility, is a risk factor for mortality among adults with epilepsy. NTFx may elicit its effect on mortality through development of respiratory disease (RD) and cardiovascular disease (CVD). Therefore, the objective was to determine if NTFx increases risk for RD and CVD, and if incident RD and CVD mediates the association between NTFx and mortality for adults with epilepsy.

Methods: Data were gathered from Optum Clinformatics® Data Mart years 2011-2016 for this retrospective cohort study. Diagnosis codes identified adults (≥18 years) with epilepsy, NTFx, RD (pneumonia, chronic obstructive pulmonary disease, interstitial/pleura disease), CVD (ischemic heart disease, heart failure, cerebrovascular disease), and baseline comorbidities. Crude incidence rate (IR) and crude IR ratio (IRR and 95 % confidence intervals [CI]) was estimated for mortality and incidence of RD and CVD for up to 2 years of follow up. Cox regression estimated hazard ratios (HR and 95 % CI) for each outcome, comparing adults with vs. without NTFx after adjusting for sociodemographics and baseline comorbidities. Separate mediation analyses estimated the extent that incident RD and CVD mediated the association between NTFx and mortality.

Results: Adults with epilepsy with vs. without NTFx had a higher crude incidence of mortality (IRR = 2.42; 95 %CI = 2.24-2.60) and each RD and CVD measure (IRR = 1.60-2.02). After adjustments, the HR remained elevated for mortality (HR = 1.66; 95 %CI = 1.54-1.79) and each RD and CVD measure (HR = 1.18-1.61). Incident pneumonia and interstitial/pleura disease mediated 9.82 % and 7.51 %, respectively, of the association between NTFx and mortality.

Conclusions: In a relatively short follow up of 2 years, NTFx was a robust risk factor for mortality, RD, and CVD among adults with epilepsy, and post-NTFx incidence of RD mediated a portion of the association between NTFx and mortality.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106411DOI Listing
October 2020

Clinical factors associated with mood affective disorders among adults with cerebral palsy.

Neurol Clin Pract 2020 Jun;10(3):206-213

Department of Physical Medicine and Rehabilitation (DGW, SAW, DW, AK, SLM, EAH, MDP), University of Michigan; University of Michigan (DGW, MDP), Institute for Healthcare Policy and Innovation; University of Michigan (DGW), University of Michigan Depression Center, Ann Arbor, MI; and Epidemiology Group (DW), University of Aberdeen, School of Medicine, Medical Sciences and Nutrition, Scotland, UK.

Objective: To determine individual and aggregated associations of cerebral palsy (CP)-related symptoms and the effect of comorbid neurodevelopmental conditions on mood (affective) disorders among adults with CP.

Methods: Cross-sectional data from 2016 were extracted from a random 20% sample of the Medicare fee-for-service database. diagnosis codes were used to identify 18- to -64-year-old beneficiaries with CP, as well as mood (affective) disorders, pain, sleep disorders, fatigue, and comorbid neurodevelopmental conditions (intellectual disabilities [ID], autism spectrum disorders [ASD], and epilepsy).

Results: Four thousand eight hundred twenty-three of the 17,212 adults with CP had mood (affective) disorders (28.0%). After adjusting for age, sex, and race, pain (odds ratio [OR] = 2.15; 99.5% confidence interval [CI] = 1.94-2.39), sleep disorders (OR = 2.43; 99.5% CI = 2.13-2.77), fatigue (OR = 1.38; 99.5% CI = 1.18-1.60), ID (OR = 1.47; 99.5% CI = 1.31-1.63), ASD (OR = 1.44; 99.5% CI = 1.16-1.80), and epilepsy (OR = 0.81; 99.5% CI = 0.73-0.91) were each associated with mood (affective) disorders. When pain, sleep disorders, and fatigue were presented as a count variable, the adjusted odds of mood (affective) disorders increased with the number of factors: 1 factor (OR = 1.99; 99.5% CI = 1.79-2.22), 2 factors (OR = 4.18; 99.5% CI = 3.58-4.89), and all 3 factors (OR = 7.38; 99.5% CI = 5.17-10.53).

Conclusions: Among young and middle-aged adults with CP, mood (affective) disorders were associated with pain, sleep disorders, and fatigue, and increasing co-occurrence of these factors further increased the likelihood of mood (affective) disorders. Further, comorbid neurodevelopmental conditions were also associated with mood (affective) disorders among adults with CP. Study findings could be used to improve screening strategies for mood (affective) disorders among adults with CP in the clinical setting.
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http://dx.doi.org/10.1212/CPJ.0000000000000721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292558PMC
June 2020

Effect of pain on mood affective disorders in adults with cerebral palsy.

Dev Med Child Neurol 2020 08 10;62(8):926-932. Epub 2020 May 10.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA.

Aim: To determine if pain is associated with 12-month incidence of mood affective disorders (MAD) in adults with cerebral palsy (CP).

Method: Data from Optum Clinformatics Data Mart (2013-2016) were used for this retrospective cohort study. Diagnostic codes were used to identify adults (≥18y) with CP, incident cases of MAD, and covariates (other neurodevelopmental conditions, sleep disorders, arthritis). Pain (any type, location) was identified between 1st October 2014 and 30th September 2015. The pain group was divided into new or consistent pain if they had a history of pain (i.e. consistent) in the 12 months before their first pain claim date. Crude incidence rates of MAD (expressed per 100 person-years) were estimated. Cox regression was used to estimate hazard ratio (95% confidence interval [CI]) of MAD after adjusting for covariates.

Results: Adults that had new pain (n=859; incidence rate=15.5) or consistent pain (n=1303; incidence rate=17.9) had greater crude incidence rate of MAD compared to adults without pain (n=3726; incidence rate=5.9). The elevated rate of MAD remained after adjusting for covariates, for new pain (hazard ratio=2.4; 95% CI=1.9-3.0) and consistent pain (hazard ratio=2.1; 95% CI=1.7-2.7).

Interpretation: Pain is associated with greater incidence of MAD in adults with CP. This association remained after accounting for potential confounding factors.

What This Paper Adds: What this paper adds Pain was associated with higher 12-month incidence of mood affective disorders (MAD). The 12-month MAD incidence was similar between new and consistent pain groups. The MAD incidence remained higher adjusting for neurodevelopmental comorbidities, sleep disorders, and arthritis.
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http://dx.doi.org/10.1111/dmcn.14559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955588PMC
August 2020

The cardiovascular disease burden of non-traumatic fractures for adults with and without cerebral palsy.

Bone 2020 07 23;136:115376. Epub 2020 Apr 23.

Department of Kinesiology, University of Texas at Arlington, Arlington, TX, USA.

Background: Individuals with cerebral palsy (CP) are vulnerable to non-trauma fracture (NTFx) and have an elevated burden of cardiovascular disease (CVD) related morbidity and mortality. However, very little is known about the contribution of NTFx to CVD risk among adults with CP. The purpose of this study was to determine if NTFx is a risk factor for CVD among adults with CP and if NTFx exacerbates CVD risk compared to adults without CP.

Methods: Data from 2011 to 2016 Optum Clinformatics® Data Mart and a random 20% sample Medicare fee-for-service were used for this retrospective cohort study. Diagnosis codes were used to identify adults (18+ years) with and without CP, NTFx, incident CVD up to 2 years (i.e., ischemic heart disease, heart failure, cerebrovascular disease), and pre-NTFx comorbidities. Crude incidence rates per 100 person years of CVD measures were estimated. Cox regression estimated hazard ratios (HR and 95% confidence interval [CI]) for CVD measures, comparing: (1) CP and NTFx (CP + NTFx; n = 1012); (2) CP without NTFx (CP w/o NTFx; n = 8345); (3) without CP and with NTFx (w/o CP + NTFx; n = 257,355); and (4) without CP and without NTFx (w/o CP w/o NTFx; n = 4.8 M) after adjusting for demographics and pre-NTFx comorbidities.

Results: The crude incidence rate was elevated for CP + NTFx vs. CP w/o NTFx and w/o CP + NTFx for any CVD and for each CVD subtype. After adjustments, the HR was elevated for CP + NTFx vs. CP w/o NTFx for any CVD (HR = 1.16; 95%CI = 0.98-1.38), heart failure (HR = 1.31; 95%CI = 1.01-1.70), and cerebrovascular disease (HR = 1.23; 95%CI = 0.98-1.55); although, only heart failure was statistically significant. The adjusted HR was elevated for CP + NTFx vs. w/o CP + NTFx for any CVD and for each CVD subtype (all P < .05). Stratified analyses showed a higher CVD risk by NTFx location, <65 year olds, and men when comparing CP + NTFx vs. CP w/o NTFx and w/o CP + NTFx.

Conclusions: NTFx increases 2-year CVD risk among adults with CP and compared to adults without CP. Findings suggest that NTFx is a risk factor for CVD among adults with CP.
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http://dx.doi.org/10.1016/j.bone.2020.115376DOI Listing
July 2020

Nontrauma fracture increases risk for respiratory disease among adults with cerebral palsy.

Authors:
Daniel G Whitney

J Orthop Res 2020 12 6;38(12):2551-2558. Epub 2020 Apr 6.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan.

Individuals with cerebral palsy (CP) manifest skeletal fragility problems early in life and are vulnerable to nontrauma fracture (NTFx), which may exacerbate the risk of respiratory disease (RD)- the main cause of premature mortality for this population. The purpose of this study was to determine if adults with CP had a greater 12-month risk of RD post-NTFx compared to adults without CP. Data from 2011 to 2017 were leveraged from Optum Clinformatics Data Mart; a claims database from a single private payer in the United States diagnostic codes were used to identify adults (≥18 years) with and without CP, NTFx, incident RD, and pre-NTFx cardiometabolic diseases. Cox proportional hazards regression models were used to compare 12-month RD incidence following NTFx with adjustment for sociodemographics and cardiometabolic diseases. Mean age (SD) at baseline was 57.5 (18.4) for adults with CP (n = 646) and 61.8 (19.7) for adults without CP (n = 321,482). During the follow-up, 172 adults with CP (26.6%) and 73 937 adults without CP (23.0%) developed RD. Adults with CP had higher 12-month post-NTFx RD incidence compared to adults without CP (hazard ratio [HR] = 1.20; 95% confidence interval [CI] = 1.03-1.37). When stratified by the RD subtype, adults with CP had a higher incidence of pneumonia (HR = 2.15; 95% CI = 1.56-2.95), interstitial/pleura disease (HR = 2.13; 95% CI = 1.53-2.96), and other RD (eg, respiratory failure; HR = 2.33; 95% CI = 1.82-2.98), but not acute respiratory infection (HR = 0.93; 95% CI = 0.75-1.15) or chronic obstructive pulmonary disease (HR = 1.15; 95% CI = 0.86-1.53). Among privately insured adults with CP, NTFx is associated with greater risk of RD among adults with vs without CP.
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http://dx.doi.org/10.1002/jor.24675DOI Listing
December 2020

Incidence Rate of Advanced Chronic Kidney Disease Among Privately Insured Adults with Neurodevelopmental Disabilities.

Clin Epidemiol 2020 27;12:235-243. Epub 2020 Feb 27.

Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.

Purpose: Due to complex medical profiles, adults with neurodevelopmental disabilities (NDDs) may have a heightened risk for early development of chronic kidney disease (CKD) and accelerated CKD progression to advanced stages and kidney failure. The purpose of this study was to estimate the incidence rate of advanced CKD for adults with NDDs and compare the incidence rate to adults without NDDs.

Patients And Methods: Data were used from the Optum Clinformatics Data Mart to conduct this retrospective cohort study. The calendar year 2013 was used to identify eligible participants: individuals ≥18 years of age and without advanced CKD. Participants were followed from 01/01/2014 to advanced CKD, loss to follow-up, death, or end of the study period (12/31/2017), whichever came first. Diagnostic, procedure, and diagnosis-related group codes identified NDDs (intellectual disabilities, cerebral palsy, autism spectrum disorders), incident cases of advanced CKD (CKD stages 4+), diabetes, cardiovascular diseases, and hypertension present in the year 2013. Crude incidence rates (IR) of advanced CKD and IR ratios (IRR), comparing adults with vs without NDDs (with 95% CI) were estimated. Then, Cox regression estimated the hazard ratio (HR and 95% CI) for advanced CKD, comparing adults with NDDs to adults without NDDs while adjusting for covariates.

Results: Adults with NDDs (n=33,561) had greater crude IR of advanced CKD (IRR=1.32; 95% CI=1.24-1.42) compared to adults without NDDs (n=6.5M). The elevated rate of advanced CKD among adults with NDDs increased after adjusting for demographics (HR=2.19; 95% CI=2.04-2.34) and remained elevated with further adjustment for hypertension and diabetes (HR=2.01; 95% CI=1.87-2.15) plus cardiovascular disease (HR=1.84; 95% CI=1.72-1.97). Stratified analyses showed that the risk of advanced CKD was greater for all NDD subgroups.

Conclusion: Study findings suggest that adults with NDDs have a greater risk of advanced CKD than do adults without NDDs, and that difference is not explained by covariates used in our analysis.
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http://dx.doi.org/10.2147/CLEP.S242264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051893PMC
February 2020

The mortality burden attributable to nontrauma fracture for privately insured adults with epilepsy.

Epilepsia 2020 04 27;61(4):714-724. Epub 2020 Feb 27.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan.

Objective: Individuals with epilepsy have poor bone development and preservation throughout the lifespan and are vulnerable to nontrauma fracture (NTFx) and post-NTFx complications. However, no studies have examined the contribution of NTFx to mortality among adults with epilepsy. The objective was to determine whether NTFx is a risk factor for mortality among adults with epilepsy.

Methods: Data from 2011 to 2016 were obtained from Optum Clinformatics Data Mart, a nationwide claims database from a single private payer in the United States. Diagnosis codes were used to identify adults (≥18 years old) with epilepsy, NTFx, and covariates (demographics and pre-NTFx cardiovascular disease, respiratory disease, diabetes, chronic kidney disease, cancer). Crude mortality rate per 100 person-years was estimated. Cox regression estimated hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for mortality, comparing epilepsy and NTFx (EP + NTFx; n = 11 471), epilepsy without NTFx (EP without NTFx; n = 50 384), without epilepsy and with NTFx (without EP + NTFx; n = 423 041), and without epilepsy and without NTFx (without EP without NTFx; n = 6.8 million) after adjusting for covariates.

Results: The 3-, 6-, and 12-month crude mortality rates were highest among EP + NTFx (12-month mortality rate = 8.79), followed by without EP + NTFx (12-month mortality rate = 4.80), EP without NTFx (12-month mortality rate = 3.06), and without EP without NTFx (12-month mortality rate = 0.47). After adjustments, the mortality rate was elevated for EP + NTFx for all time points compared to EP without NTFx (eg, 12-month HR = 1.70, 95% CI = 1.58-1.85), without EP + NTFx (eg, 12-month HR = 1.41, 95% CI = 1.32-1.51), and without EP without NTFx (eg, 12-month HR = 5.23, 95% CI = 4.88-5.60). Stratified analyses showed higher adjusted HRs of 12-month mortality for EP + NTFx for all NTFx sites (ie, vertebral column, hip, extremities), all age categories (young, middle-aged, older), and for both women and men.

Significance: Among adults with epilepsy and compared to adults without epilepsy, NTFx is associated with a higher 12-month mortality rate. Findings suggest that NTFx may be a robust risk factor for mortality among adults with epilepsy.
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http://dx.doi.org/10.1111/epi.16465DOI Listing
April 2020

Risk of advanced chronic kidney disease among adults with spina bifida.

Ann Epidemiol 2020 03 10;43:71-74.e1. Epub 2020 Jan 10.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI.

Purpose: Adults with spina bifida (SB) may be susceptible to accelerated progression of chronic kidney disease (CKD) to advanced stages. However, little is known regarding risk of advanced CKD for this underserved population. The objective was to estimate the risk of advanced CKD among adults with vs. without SB.

Methods: Data were from Optum Clinformatics Data Mart. Adults (18+ years) without advanced CKD (CKD stages 4+) in 2013 were followed from 01/01/2014 to advanced CKD, death, loss to follow-up, or 12/31/2017. Diagnostic, procedure, and diagnosis-related group codes were used to identify SB, advanced CKD, and baseline cardiovascular diseases, hypertension, and diabetes. Incidence rate (IR) and IR ratio and their 95% confidence intervals (CIs) of advanced CKD were estimated. Cox regression estimated adjusted hazard ratio (HR) for incidence of advanced CKD.

Results: The crude IR of advanced CKD was 7.40 for adults with SB (n = 4295) and 6.25 for adults without SB (n = 6.6 M). After adjusting for demographics, adults with SB had greater risk of advanced CKD compared to adults without SB (HR = 2.12; 95% CI = 1.72-2.60), which remained elevated with further adjustment for cardiovascular diseases, hypertension, and diabetes (HR = 1.91; 95% CI = 1.55-2.35).

Conclusions: Adults with SB may have greater risk of advanced CKD incidence compared to adults without SB.
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http://dx.doi.org/10.1016/j.annepidem.2020.01.003DOI Listing
March 2020

Early-Onset Noncommunicable Disease and Multimorbidity Among Adults With Pediatric-Onset Disabilities.

Mayo Clin Proc 2020 02 3;95(2):274-282. Epub 2019 Dec 3.

Department of Physical Medicine and Rehabilitation, Michigan Medicine, University of Michigan, Ann Arbor; Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor. Electronic address:

Objective: To determine the prevalence of major noncommunicable diseases among young adults with pediatric-onset disabilities (PoDs) compared with young adults without PoDs.

Patients And Methods: Data were obtained from the Optum Clinformatics Data Mart, a de-identified nationwide claims database of beneficiaries from a single private payer in the United States. Beneficiaries were included if they were 18 to 40 years old and had an International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code for a PoD known to originate in childhood. Diagnostic codes were used to identify high-burden noncommunicable diseases: ischemic heart disease, cerebrovascular disease, hypertensive and other cardiovascular disease, type 2 diabetes, malignant cancer, osteoporosis, mood affective disorders, chronic obstructive pulmonary disease, chronic kidney disease, and liver disease. The prevalence of noncommunicable diseases and multimorbidity (≥2 diseases) was compared between adults with (N=47,077) and without (N=2,180,250) PoDs, before and after adjusting for sociodemographic characteristics. This study was conducted between July 1, 2018, and February 1, 2019.

Results: Adults with PoDs had higher prevalences and adjusted odds of all noncommunicable diseases (odds ratio, 2.1-9.0; all P<.05) and multimorbidity (odds ratio, 3.8; 95% CI, 3.7-3.9) compared with adults without PoDs. After stratifying by the type of PoD (eg, musculoskeletal, circulatory), all PoD categories had higher prevalence of all noncommunicable diseases and multimorbidity compared with young adults without PoDs, except for ischemic heart disease and cerebrovascular disease among adults with PoDs of the genital organs.

Conclusion: Young adults with PoDs have an early onset of several noncommunicable diseases that represent major contributors to the global and national burden of disease and mortality.
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http://dx.doi.org/10.1016/j.mayocp.2019.07.010DOI Listing
February 2020

Prevalence of High-Burden Medical Conditions Among Young and Middle-Aged Adults With Pediatric-Onset Medical Conditions: Findings From US Private and Public Administrative Claims Data.

Authors:
Daniel G Whitney

Int J Health Policy Manag 2019 11 1;8(11):629-635. Epub 2019 Nov 1.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA.

Adults with pediatric-onset medical conditions (POMCs) are susceptible to early development of high-burden medical conditions. However, research pertaining to this topic is lacking, which is vital information that could assist in health benefit planning and administration. The purpose of this study was to determine the prevalence of high-burden medical conditions among privately and publicly insured adults with POMCs, as compared to adults without POMCs, from the US. Data from 2016 were extracted from Optum Clinformatics® Data Mart (private insurance) and a random 20% sample from Medicare fee-for-service (public insurance). International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis codes were used to identify 18-64-year-old beneficiaries with POMCs, as well as several high-burden medical conditions, including pain, fracture, mood affective disorders, anxiety disorders, ischemic heart diseases, cerebrovascular diseases, hypertensive and other cardiovascular diseases, type 2 diabetes, osteoporosis, osteoarthritis, chronic obstructive pulmonary diseases, liver diseases, and cancer. Privately and publicly insured adults with POMCs had higher prevalence of all medical conditions compared to adults without POMCs. Publicly insured adults with POMCs had higher prevalence of all medical conditions compared to privately insured adults with POMCs, except for the lower prevalence of pain and cancer. When stratified by the category of POMCs (eg, musculoskeletal, circulatory), privately and publicly insured groups tended to have higher prevalence of most (private) or all (public) medical conditions compared to adults without POMCs. Adults with POMCs have higher prevalence of several high-burden medical conditions compared to adults without POMCs. This health disparity was present regardless of insurance coverage, but was generally more pronounced for public vs. private insured adults with POMCs.
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http://dx.doi.org/10.15171/ijhpm.2019.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885858PMC
November 2019