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An application of the Causal Roadmap in two safety monitoring case studies: Causal inference and outcome prediction using electronic health record data
- Brian D. Williamson, Richard Wyss, Elizabeth A. Stuart, Lauren E. Dang, Andrew N. Mertens, Romain S. Neugebauer, Andrew Wilson, Susan Gruber
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- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue 1 / 2023
- Published online by Cambridge University Press:
- 21 September 2023, e208
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Background:
Real-world data, such as administrative claims and electronic health records, are increasingly used for safety monitoring and to help guide regulatory decision-making. In these settings, it is important to document analytic decisions transparently and objectively to assess and ensure that analyses meet their intended goals.
Methods:The Causal Roadmap is an established framework that can guide and document analytic decisions through each step of the analytic pipeline, which will help investigators generate high-quality real-world evidence.
Results:In this paper, we illustrate the utility of the Causal Roadmap using two case studies previously led by workgroups sponsored by the Sentinel Initiative – a program for actively monitoring the safety of regulated medical products. Each case example focuses on different aspects of the analytic pipeline for drug safety monitoring. The first case study shows how the Causal Roadmap encourages transparency, reproducibility, and objective decision-making for causal analyses. The second case study highlights how this framework can guide analytic decisions beyond inference on causal parameters, improving outcome ascertainment in clinical phenotyping.
Conclusion:These examples provide a structured framework for implementing the Causal Roadmap in safety surveillance and guide transparent, reproducible, and objective analysis.
Quality of life, Illness Perception, Self-perceived success, estimation of Depression/Anxiety symptoms and Disability Assessment, in adult with cerebral palsy
- E. N. Gruber, S. M. Biocina
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S755-S756
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Introduction
Recent studies is showed that adults with Cerebral Palsy (CP) have an elevated prevalence of mental health disorders, especially increased risk of depression or anxiety. Perceptions of the CP condition, and coping behaviors often affect the impact of the condition on the child with CP and his/her family.
Several studies have affirmed that some factors such as interpersonal relationships, sexuality, and physical conditions are also crucial to a higher QoL in the persons with CP.
A Danish study showed that 55% of Danish adults with CP (aged 29–35 years) were unemployed, did not cohabit with a partner and did not have children, compared with only 4% of the control population.
Objectivesto show a case of a 50-year-old male person with cerebral palsy
Methodscase study
The three functional classifications (GMFCS-E&R, CFCS and MACS) is used to provide functional description together with The Quality-of-Life Scale (QOLS), World Health Organization Disability Assessment Schedule 2.0 – (WHODAS-interview), Flourishing Scale Self-perceived success (FS), Depression Anxiety Stress Scales - 10 (DASS-10), the Brief Illness Perception Questionnaire (Brief IPQ)
Resultsmale, 50 år
Quality of Life score: 90
Flourishing scale (FS): 47
Depression Anxiety Stress Scales: 9
the Brief Illness Perception Questionnaire (Brief IPQ):45
Communication issues: CFCS (Communication Function Classification System): Level I
Having a Partner: Domestic partner- reside together with partner, don’t have children. having af parents and brothers that are a great support
Type of Housing: Independent living (own housing, 1 hour of assistance per week)
Mobility issues: GMFCS (Gross Motor Function Classification System): Level II, MACS (Manual Ability Classification System): Level I
ConclusionsCase is showing 50 years old male with cerebral palsy who has not an intellectual disability and who has a high life quality, high self-perceived success, moderate anxiety and high perception of illness. Social, family and romantic relationships together with leisure time and sustainable physical activity and exercise was emphasized.
Disclosure of InterestNone Declared
Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium
- E. Walton, D. P. Hibar, T. G. M. van Erp, S. G. Potkin, R. Roiz-Santiañez, B. Crespo-Facorro, P. Suarez-Pinilla, N. E. M. van Haren, S. M. C. de Zwarte, R. S. Kahn, W. Cahn, N. T. Doan, K. N. Jørgensen, T. P. Gurholt, I. Agartz, O. A. Andreassen, L. T. Westlye, I. Melle, A. O. Berg, L. Morch-Johnsen, A. Færden, L. Flyckt, H. Fatouros-Bergman, Karolinska Schizophrenia Project Consortium (KaSP), E. G. Jönsson, R. Hashimoto, H. Yamamori, M. Fukunaga, N. Jahanshad, P. De Rossi, F. Piras, N. Banaj, G. Spalletta, R. E. Gur, R. C. Gur, D. H. Wolf, T. D. Satterthwaite, L. M. Beard, I. E. Sommer, S. Koops, O. Gruber, A. Richter, B. Krämer, S. Kelly, G. Donohoe, C. McDonald, D. M. Cannon, A. Corvin, M. Gill, A. Di Giorgio, A. Bertolino, S. Lawrie, T. Nickson, H. C. Whalley, E. Neilson, V. D. Calhoun, P. M. Thompson, J. A. Turner, S. Ehrlich
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- Journal:
- Psychological Medicine / Volume 48 / Issue 1 / January 2018
- Published online by Cambridge University Press:
- 26 May 2017, pp. 82-94
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Background
Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity.
MethodsThis study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores).
ResultsMeta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (βstd = −0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged.
ConclusionsUsing an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.
Occupational differences in US Army suicide rates
- R. C. Kessler, M. B. Stein, P. D. Bliese, E. J. Bromet, W. T. Chiu, K. L. Cox, L. J. Colpe, C. S. Fullerton, S. E. Gilman, M. J. Gruber, S. G. Heeringa, L. Lewandowski-Romps, A. Millikan-Bell, J. A. Naifeh, M. K. Nock, M. V. Petukhova, A. J. Rosellini, N. A. Sampson, M. Schoenbaum, A. M. Zaslavsky, R. J. Ursano
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- Journal:
- Psychological Medicine / Volume 45 / Issue 15 / November 2015
- Published online by Cambridge University Press:
- 20 July 2015, pp. 3293-3304
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Background
Civilian suicide rates vary by occupation in ways related to occupational stress exposure. Comparable military research finds suicide rates elevated in combat arms occupations. However, no research has evaluated variation in this pattern by deployment history, the indicator of occupation stress widely considered responsible for the recent rise in the military suicide rate.
MethodThe joint associations of Army occupation and deployment history in predicting suicides were analysed in an administrative dataset for the 729 337 male enlisted Regular Army soldiers in the US Army between 2004 and 2009.
ResultsThere were 496 suicides over the study period (22.4/100 000 person-years). Only two occupational categories, both in combat arms, had significantly elevated suicide rates: infantrymen (37.2/100 000 person-years) and combat engineers (38.2/100 000 person-years). However, the suicide rates in these two categories were significantly lower when currently deployed (30.6/100 000 person-years) than never deployed or previously deployed (41.2–39.1/100 000 person-years), whereas the suicide rate of other soldiers was significantly higher when currently deployed and previously deployed (20.2–22.4/100 000 person-years) than never deployed (14.5/100 000 person-years), resulting in the adjusted suicide rate of infantrymen and combat engineers being most elevated when never deployed [odds ratio (OR) 2.9, 95% confidence interval (CI) 2.1–4.1], less so when previously deployed (OR 1.6, 95% CI 1.1–2.1), and not at all when currently deployed (OR 1.2, 95% CI 0.8–1.8). Adjustment for a differential ‘healthy warrior effect’ cannot explain this variation in the relative suicide rates of never-deployed infantrymen and combat engineers by deployment status.
ConclusionsEfforts are needed to elucidate the causal mechanisms underlying this interaction to guide preventive interventions for soldiers at high suicide risk.
Anxious and non-anxious major depressive disorder in the World Health Organization World Mental Health Surveys
- R. C. Kessler, N. A. Sampson, P. Berglund, M. J. Gruber, A. Al-Hamzawi, L. Andrade, B. Bunting, K. Demyttenaere, S. Florescu, G. de Girolamo, O. Gureje, Y. He, C. Hu, Y. Huang, E. Karam, V. Kovess-Masfety, S Lee, D. Levinson, M. E. Medina Mora, J. Moskalewicz, Y. Nakamura, F. Navarro-Mateu, M. A. Oakley Browne, M. Piazza, J. Posada-Villa, T. Slade, M. ten Have, Y. Torres, G. Vilagut, M. Xavier, Z. Zarkov, V. Shahly, M. A. Wilcox
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- Journal:
- Epidemiology and Psychiatric Sciences / Volume 24 / Issue 3 / June 2015
- Published online by Cambridge University Press:
- 27 February 2015, pp. 210-226
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Background.
To examine cross-national patterns and correlates of lifetime and 12-month comorbid DSM-IV anxiety disorders among people with lifetime and 12-month DSM-IV major depressive disorder (MDD).
Method.Nationally or regionally representative epidemiological interviews were administered to 74 045 adults in 27 surveys across 24 countries in the WHO World Mental Health (WMH) Surveys. DSM-IV MDD, a wide range of comorbid DSM-IV anxiety disorders, and a number of correlates were assessed with the WHO Composite International Diagnostic Interview (CIDI).
Results.45.7% of respondents with lifetime MDD (32.0–46.5% inter-quartile range (IQR) across surveys) had one of more lifetime anxiety disorders. A slightly higher proportion of respondents with 12-month MDD had lifetime anxiety disorders (51.7%, 37.8–54.0% IQR) and only slightly lower proportions of respondents with 12-month MDD had 12-month anxiety disorders (41.6%, 29.9–47.2% IQR). Two-thirds (68%) of respondents with lifetime comorbid anxiety disorders and MDD reported an earlier age-of-onset (AOO) of their first anxiety disorder than their MDD, while 13.5% reported an earlier AOO of MDD and the remaining 18.5% reported the same AOO of both disorders. Women and previously married people had consistently elevated rates of lifetime and 12-month MDD as well as comorbid anxiety disorders. Consistently higher proportions of respondents with 12-month anxious than non-anxious MDD reported severe role impairment (64.4 v. 46.0%; χ21 = 187.0, p < 0.001) and suicide ideation (19.5 v. 8.9%; χ21 = 71.6, p < 0.001). Significantly more respondents with 12-month anxious than non-anxious MDD received treatment for their depression in the 12 months before interview, but this difference was more pronounced in high-income countries (68.8 v. 45.4%; χ21 = 108.8, p < 0.001) than low/middle-income countries (30.3 v. 20.6%; χ21 = 11.7, p < 0.001).
Conclusions.Patterns and correlates of comorbid DSM-IV anxiety disorders among people with DSM-IV MDD are similar across WMH countries. The narrow IQR of the proportion of respondents with temporally prior AOO of anxiety disorders than comorbid MDD (69.6–74.7%) is especially noteworthy. However, the fact that these proportions are not higher among respondents with 12-month than lifetime comorbidity means that temporal priority between lifetime anxiety disorders and MDD is not related to MDD persistence among people with anxious MDD. This, in turn, raises complex questions about the relative importance of temporally primary anxiety disorders as risk markers v. causal risk factors for subsequent MDD onset and persistence, including the possibility that anxiety disorders might primarily be risk markers for MDD onset and causal risk factors for MDD persistence.
Understanding the elevated suicide risk of female soldiers during deployments
- A. E. Street, S. E. Gilman, A. J. Rosellini, M. B. Stein, E. J. Bromet, K. L. Cox, L. J. Colpe, C. S. Fullerton, M. J. Gruber, S. G. Heeringa, L. Lewandowski-Romps, R. J. A. Little, J. A. Naifeh, M. K. Nock, N. A. Sampson, M. Schoenbaum, R. J. Ursano, A. M. Zaslavsky, R. C. Kessler
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- Journal:
- Psychological Medicine / Volume 45 / Issue 4 / March 2015
- Published online by Cambridge University Press:
- 31 October 2014, pp. 717-726
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Background
The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) has found that the proportional elevation in the US Army enlisted soldier suicide rate during deployment (compared with the never-deployed or previously deployed) is significantly higher among women than men, raising the possibility of gender differences in the adverse psychological effects of deployment.
MethodPerson-month survival models based on a consolidated administrative database for active duty enlisted Regular Army soldiers in 2004–2009 (n = 975 057) were used to characterize the gender × deployment interaction predicting suicide. Four explanatory hypotheses were explored involving the proportion of females in each soldier's occupation, the proportion of same-gender soldiers in each soldier's unit, whether the soldier reported sexual assault victimization in the previous 12 months, and the soldier's pre-deployment history of treated mental/behavioral disorders.
ResultsThe suicide rate of currently deployed women (14.0/100 000 person-years) was 3.1–3.5 times the rates of other (i.e. never-deployed/previously deployed) women. The suicide rate of currently deployed men (22.6/100 000 person-years) was 0.9–1.2 times the rates of other men. The adjusted (for time trends, sociodemographics, and Army career variables) female:male odds ratio comparing the suicide rates of currently deployed v. other women v. men was 2.8 (95% confidence interval 1.1–6.8), became 2.4 after excluding soldiers with Direct Combat Arms occupations, and remained elevated (in the range 1.9–2.8) after adjusting for the hypothesized explanatory variables.
ConclusionsThese results are valuable in excluding otherwise plausible hypotheses for the elevated suicide rate of deployed women and point to the importance of expanding future research on the psychological challenges of deployment for women.
The effects of co-morbidity in defining major depression subtypes associated with long-term course and severity
- K. J. Wardenaar, H. M. van Loo, T. Cai, M. Fava, M. J. Gruber, J. Li, P. de Jonge, A. A. Nierenberg, M. V. Petukhova, S. Rose, N. A. Sampson, R. A. Schoevers, M. A. Wilcox, J. Alonso, E. J. Bromet, B. Bunting, S. E. Florescu, A. Fukao, O. Gureje, C. Hu, Y. Q. Huang, A. N. Karam, D. Levinson, M. E. Medina Mora, J. Posada-Villa, K. M. Scott, N. I. Taib, M. C. Viana, M. Xavier, Z. Zarkov, R. C. Kessler
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- Journal:
- Psychological Medicine / Volume 44 / Issue 15 / November 2014
- Published online by Cambridge University Press:
- 17 July 2014, pp. 3289-3302
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Background.
Although variation in the long-term course of major depressive disorder (MDD) is not strongly predicted by existing symptom subtype distinctions, recent research suggests that prediction can be improved by using machine learning methods. However, it is not known whether these distinctions can be refined by added information about co-morbid conditions. The current report presents results on this question.
Method.Data came from 8261 respondents with lifetime DSM-IV MDD in the World Health Organization (WHO) World Mental Health (WMH) Surveys. Outcomes included four retrospectively reported measures of persistence/severity of course (years in episode; years in chronic episodes; hospitalization for MDD; disability due to MDD). Machine learning methods (regression tree analysis; lasso, ridge and elastic net penalized regression) followed by k-means cluster analysis were used to augment previously detected subtypes with information about prior co-morbidity to predict these outcomes.
Results.Predicted values were strongly correlated across outcomes. Cluster analysis of predicted values found three clusters with consistently high, intermediate or low values. The high-risk cluster (32.4% of cases) accounted for 56.6–72.9% of high persistence, high chronicity, hospitalization and disability. This high-risk cluster had both higher sensitivity and likelihood ratio positive (LR+; relative proportions of cases in the high-risk cluster versus other clusters having the adverse outcomes) than in a parallel analysis that excluded measures of co-morbidity as predictors.
Conclusions.Although the results using the retrospective data reported here suggest that useful MDD subtyping distinctions can be made with machine learning and clustering across multiple indicators of illness persistence/severity, replication with prospective data is needed to confirm this preliminary conclusion.
Sociodemographic and career history predictors of suicide mortality in the United States Army 2004–2009
- S. E. Gilman, E. J. Bromet, K. L. Cox, L. J. Colpe, C. S. Fullerton, M. J. Gruber, S. G. Heeringa, L. Lewandowski-Romps, A. M. Millikan-Bell, J. A. Naifeh, M. K. Nock, M. V. Petukhova, N. A. Sampson, M. Schoenbaum, M. B. Stein, R. J. Ursano, S. Wessely, A. M. Zaslavsky, R. C. Kessler,
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- Journal:
- Psychological Medicine / Volume 44 / Issue 12 / September 2014
- Published online by Cambridge University Press:
- 19 February 2014, pp. 2579-2592
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Background
The US Army suicide rate has increased sharply in recent years. Identifying significant predictors of Army suicides in Army and Department of Defense (DoD) administrative records might help focus prevention efforts and guide intervention content. Previous studies of administrative data, although documenting significant predictors, were based on limited samples and models. A career history perspective is used here to develop more textured models.
MethodThe analysis was carried out as part of the Historical Administrative Data Study (HADS) of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). De-identified data were combined across numerous Army and DoD administrative data systems for all Regular Army soldiers on active duty in 2004–2009. Multivariate associations of sociodemographics and Army career variables with suicide were examined in subgroups defined by time in service, rank and deployment history.
ResultsSeveral novel results were found that could have intervention implications. The most notable of these were significantly elevated suicide rates (69.6–80.0 suicides per 100 000 person-years compared with 18.5 suicides per 100 000 person-years in the total Army) among enlisted soldiers deployed either during their first year of service or with less than expected (based on time in service) junior enlisted rank; a substantially greater rise in suicide among women than men during deployment; and a protective effect of marriage against suicide only during deployment.
ConclusionsA career history approach produces several actionable insights missed in less textured analyses of administrative data predictors. Expansion of analyses to a richer set of predictors might help refine understanding of intervention implications.
Composite International Diagnostic Interview screening scales for DSM-IV anxiety and mood disorders
- R. C. Kessler, J. R. Calabrese, P. A. Farley, M. J. Gruber, M. A. Jewell, W. Katon, P. E. Keck, Jr., A. A. Nierenberg, N. A. Sampson, M. K. Shear, A. C. Shillington, M. B. Stein, M. E. Thase, H.-U. Wittchen
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- Psychological Medicine / Volume 43 / Issue 8 / August 2013
- Published online by Cambridge University Press:
- 18 October 2012, pp. 1625-1637
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Background
Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem.
MethodExpert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives.
ResultsStepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance [area under the receiver operating characteristic curve (AUC)] was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9–38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ21 = 0.0–2.9, p = 0.09–0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81–0.86, sensitivity 68.0–80.2%, specificity 90.1–98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR− is 0.1 or less at informative thresholds for all diagnoses.
ConclusionsCIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.
Cross-national differences in the prevalence and correlates of burden among older family caregivers in the World Health Organization World Mental Health (WMH) Surveys
- V. Shahly, S. Chatterji, M. J. Gruber, A. Al-Hamzawi, J. Alonso, L. H. Andrade, M. C. Angermeyer, R. Bruffaerts, B. Bunting, J. M. Caldas-de-Almeida, G. de Girolamo, P. de Jonge, S. Florescu, O. Gureje, J. M. Haro, H. R. Hinkov, C. Hu, E. G. Karam, J.-P. Lépine, D. Levinson, M. E. Medina-Mora, J. Posada-Villa, N. A. Sampson, J. K. Trivedi, M. C. Viana, R. C. Kessler
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- Journal:
- Psychological Medicine / Volume 43 / Issue 4 / April 2013
- Published online by Cambridge University Press:
- 09 August 2012, pp. 865-879
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Background
Current trends in population aging affect both recipients and providers of informal family caregiving, as the pool of family caregivers is shrinking while demand is increasing. Epidemiological research has not yet examined the implications of these trends for burdens experienced by aging family caregivers.
MethodCross-sectional community surveys in 20 countries asked 13 892 respondents aged 50+ years about the objective (time, financial) and subjective (distress, embarrassment) burdens they experience in providing care to first-degree relatives with 12 broadly defined serious physical and mental conditions. Differential burden was examined by country income category, kinship status and type of condition.
ResultsAmong the 26.9–42.5% respondents in high-, upper-middle-, and low-/lower-middle-income countries reporting serious relative health conditions, 35.7–42.5% reported burden. Of those, 25.2–29.0% spent time and 13.5–19.4% money, while 24.4–30.6% felt distress and 6.4–21.7% embarrassment. Mean caregiving hours per week in those giving any time were 16.6–23.6 (169.9–205.8 h/week per 100 people aged 50+ years). Burden in low-/lower-middle-income countries was 2- to 3-fold higher than in higher-income countries, with any financial burden averaging 14.3% of median family income in high-, 17.7% in upper-middle-, and 39.8% in low-/lower-middle-income countries. Higher burden was reported by women than men and for conditions of spouses and children than parents or siblings.
ConclusionsUncompensated family caregiving is an important societal asset that offsets rising formal healthcare costs. However, the substantial burdens experienced by aging caregivers across multiple family health conditions and geographic regions threaten the continued integrity of their caregiving capacity. Initiatives supporting older family caregivers are consequently needed, especially in low-/lower-middle-income countries.