Financial Distress and Medical Financial Hardship among Young Adult Survivors of Blood Cancer.

BACKGROUND: The long-term financial impact of cancer care has not been adequately addressed in young adults (YAs). As part of a remote intervention study, we describe medical financial distress and hardship of YA survivors of blood cancer at study entry. METHODS: YAs were recruited from six United States hospitals. Via a REDCap™ link, YAs confirmed eligibility: currently 18-39, blood cancer diagnosis ≥3 years ago, off active treatment, and not on parent's insurance. Following consent, the baseline assessment was sent. The primary outcome measure, the Personal Financial Wellness (PFW) Scale, measured financial distress (scored: 1-2 severe, 3-4 high, 5-6 average, 7-10 low-to-no). Medical financial hardship encompassed material hardship, psychological impact, and coping behaviors. Descriptive summary statistics and linear regression were used. RESULTS: The 126 participants consisted of 54.5% minority racial/ethnic representation. Median time since diagnosis was 10 years (IQR, 6-16), with 56% diagnosed between the ages of 18-39. Overall mean PFW score was 5.1 (SD = 2.4), however 49% reported severe or high distress. In multivariable analysis, female sex, Hispanic ethnicity, and lower income were significantly associated with worse PFW scores. Among participants with severe financial distress (n = 26), 72% reported ≥2 household material hardships, had worse scores across all psychological domains, and altered survivorship care due to cost (68%). DISCUSSION: Nearly half of long-term YA survivors reported severe or high levels of financial distress. YAs in severe or high distress also reported more medical financial hardship than other participants. This highlights the need for ongoing financial intervention in this vulnerable population. CLINICALTRIALS.GOV: NCT05620979.

The survival-incorporated median vs the median in the survivors or in the always-survivors: What are we measuring? and Why?

Many clinical studies evaluate the benefit of a treatment based on both survival and other continuous/ordinal clinical outcomes, such as quality of life scores. In these studies, when subjects die before the follow-up assessment, the clinical outcomes become undefined and are truncated by death. Treating outcomes as "missing" or "censored" due to death can be misleading for treatment effect evaluation. We show that if we use the median in the survivors or in the always-survivors as estimands to summarize clinical outcomes, we may conclude that a trade-off exists between the probability of survival and good clinical outcomes, even in settings where both the probability of survival and the probability of any good clinical outcome are better for one treatment. Therefore, we advocate not always treating death as a mechanism through which clinical outcomes are missing, but rather as part of the outcome measure. To account for the survival status, we describe the survival-incorporated median as an alternative summary measure for outcomes in the presence of death. The survival-incorporated median is the threshold such that 50% of the population is alive with an outcome above that threshold. Through conceptual examples and an application to a prostate cancer treatment study, we show that the survival-incorporated median provides a simple and useful summary measure to inform clinical practice.

Signatures of Neuropsychological Test Results in the Long Life Family Study: A Cluster Analysis.

BACKGROUND: Discovering patterns of cognitive domains and characterizing how these patterns associate with other risk factors and biomarkers can improve our understanding of the determinants of cognitive aging. OBJECTIVE: To discover patterns of cognitive domains using neuropsychological test results in Long Life Family Study (LLFS) and characterize how these patterns associate with aging markers. METHODS: 5,086 LLFS participants were administered neuropsychological tests at enrollment. We performed a cluster analysis of six baseline neuropsychological test scores and tested the association between the identified clusters and various clinical variables, biomarkers, and polygenic risk scores using generalized estimating equations and the Chi-square test. We used Cox regression to correlate the clusters with the hazard of various medical events. We investigated whether the cluster information could enhance the prediction of cognitive decline using Bayesian beta regression. RESULTS: We identified 12 clusters with different cognitive signatures that represent profiles of performance across multiple neuropsychological tests. These signatures significantly correlated with 26 variables including polygenic risk scores, physical and pulmonary functions, and blood biomarkers and were associated with the hazard of mortality (p < 0.01), cardiovascular disease (p = 0.03), dementia (p = 0.01), and skin cancer (p = 0.03). CONCLUSION: The identified cognitive signatures capture multiple domains simultaneously and provide a holistic vision of cognitive function, showing that different patterns of cognitive function can coexist in aging individuals. Such patterns can be used for clinical intervention and primary care.

Mosaic Chromosomal Alterations and Human Longevity.

Mosaic chromosomal alterations (mCAs) are structural alterations associated with aging, cancer, cardiovascular disease, infectious diseases, and mortality. The distribution of mCAs in centenarians and individuals with familial longevity is poorly understood. We used MOsaic CHromosomal Alteration (MoChA) to discover mCAs in 2050 centenarians, offspring, and 248 controls from the New England Centenarian Study (NECS) and in 3 642 subjects with familial longevity and 920 spousal controls from the Long-Life Family Study (LLFS). We analyzed study-specific associations of somatic mCAs with age, familial longevity, the incidence of age-related diseases, and mortality and aggregated the results by meta-analysis. We show that the accumulation of mCAs > 100 KB increased to 102 years and plateaued at older ages. Centenarians and offspring accumulated fewer autosomal mCAs compared with controls (relative risk 0.637, p = .0147). Subjects with the APOE E4 allele had a 35.3% higher risk of accumulating autosomal mCAs (p = .002). Males were at higher risk for mCAs compared to females (male relative risk 1.36, p = 5.15e-05). mCAs were associated with increased hazard for cancer (hazard ratio 1.2) and dementia (hazard ratio 1.259) at a 10% false discovery rate. We observed a borderline significant association between mCAs and risk for mortality (hazard ratio 1.07, p = .0605). Our results show that the prevalence of individuals with mCAs does not continue to increase at ages >102 years and factors promoting familial longevity appear to confer protections from mCAs. These results suggest that limited mCA accumulation could be an important mechanism for extreme human longevity that needs to be investigated.

A metabolomic signature of the APOE2 allele.

With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR < 10%. The group includes 10 glycerolipids and 4 glycerophospholipids that were all higher in E2 carriers compared to E3, with fold change ranging from 1.08 to 1.25. The organic acid 6-hydroxyindole sulfate, previously linked to changes in gut microbiome that were reflective of healthy aging and longevity, was also higher in E2 carriers compared to E3 carriers. Three sterol lipids and one sphingolipid species were significantly lower in carriers of the E2 genotype group. For some of these metabolites, the effect of the E2 genotype opposed the age effect. No metabolites reached a statistically significant association with the E4 group. This work confirms and expands previous results connecting the APOE gene to lipid regulation and suggests new links between the e2 allele, lipid metabolism, aging, and the gut-brain axis.

Studying the Interplay Between Apolipoprotein E and Education on Cognitive Decline in Centenarians Using Bayesian Beta Regression.

Apolipoprotein E (APOE) is an important risk factor for cognitive decline and Alzheimer's disease in aging individuals. Among the 3 known alleles of this gene: e2, e3, and e4, the e4 allele is associated with faster cognitive decline and increased risk for Alzheimer's and dementia, while the e2 allele has a positive effect on longevity, and possibly on preservation of cognitive function. Education also has an important effect on cognition and longevity but the interplay between APOE and education is not well-characterized. Previous studies of the effect of APOE on cognitive decline often used linear regression with the normality assumption, which may not be appropriate for analyzing bounded and skewed neuropsychological test scores. In this paper, we applied Bayesian beta regression to assess the effect of APOE alleles on cognitive decline in a cohort of centenarians with longitudinal assessment of their cognitive function. The analysis confirmed the negative association between older age and cognition and the beneficial effect of education that persists even at the extreme of human lifespan in carriers of the e3 allele. In addition, the analysis showed an association between APOE and cognition that is modified by education. Surprisingly, an antagonistic interaction existed between higher education and APOE alleles, suggesting that education may reduce the positive effect of APOE e2 and increase the negative effect of APOE e4 at extreme old age.