We aimed to compare empirically the treatment effects measured by the hazard ratio (HR) and by the difference (and ratio) of restricted mean survival times (RMST) in oncology randomized trials.
We ...selected oncology randomized controlled trials from five leading journals during the last 6 months of 2014. We reconstructed individual patient data for one time-to-event outcome from each trial, preferably the primary outcome. We reanalyzed each trial and compared the treatment effect estimated by the HR with that by the difference (and ratio) of RMST. We estimated an average ratio of the HR to the ratio of RMST; an average ratio less than one indicates more optimistic assessments with HRs.
We analyzed 54 randomized controlled trials totaling 33,212 patients. The selected outcome was overall survival in 21 (39%) trials. There was evidence of nonproportionality of hazards in 13 (24%) trials. The HR and RMST-based measures were in agreement regarding the statistical significance of the effect, except in one case. The median HR was 0.84 (Q1 to Q3 range, 0.67 to 0.97) and the median difference in RMST was 1.12 months (range, 0.22 to 2.75 months). The average ratio of the HR to the ratio of RMST was 1.11 (95% CI, 1.07 to 1.15), with substantial between-trial variability (I(2) = 86%). Results were consistent by outcome type (overall survival v other outcomes) and whether the proportional hazard assumption held or not.
On average, the HR provided significantly larger treatment effect estimates than the ratio of RMST. The HR may seem large when the absolute effect is small. RMST-based measures should be routinely reported in randomized trials with time-to-event outcomes.
Survival data with competing or semi‐competing risks are common in observational studies. As an alternative to cause‐specific and subdistribution hazard ratios, the between‐group difference in ...cause‐specific restricted mean times lost (RMTL) gives the mean difference in life expectancy lost to a specific cause of death or in disease‐free time lost, in the case of a nonfatal outcome, over a prespecified period. To adjust for covariates, we introduce an inverse probability weighted estimator and its variance for the marginal difference in RMTL. We also introduce an inverse probability of censoring weighted regression model for the RMTL. In simulation studies, we examined the finite sample performance of the proposed methods under proportional and nonproportional subdistribution hazards scenarios. We illustrated both methods with competing risks data from the Framingham Heart Study. We estimated sex differences in atrial fibrillation (AF)‐free times lost over 40 years. We also estimated sex differences in mean lifetime lost to cardiovascular disease (CVD) and non‐CVD death over 10 years among individuals with AF.
STUDY QUESTION
Is there an association between high levels of sperm DNA damage and miscarriage?
SUMMARY ANSWER
Miscarriage rates are positively correlated with sperm DNA damage levels.
WHAT IS KNOWN ...ALREADY
Most ejaculates contain a subpopulation of sperm with DNA damage, also referred to as DNA fragmentation, in the form of double or single-strand breaks which have been induced in the DNA prior to or following ejaculation. This DNA damage may be particularly elevated in some subfertile men, hence several studies have examined the link between sperm DNA damage levels and conception and miscarriage rates.
STUDY DESIGN, SIZE, DURATION
A systematic review and meta-analysis of studies which examined the effect of sperm DNA damage on miscarriage rates was performed. Searches were conducted on MEDLINE, EMBASE and the Cochrane Library without any language restrictions from database inception to January 2012.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We used the terms ‘DNA damage’ or ‘DNA fragmentation’ combined with ‘miscarriage’, ‘abortion’ or ‘pregnancy’ to generate a set of relevant citations. Data extraction was performed by two reviewers. Study quality was assessed using the Newcastle–Ottawa Scale. Meta-analysis of relative risks of miscarriage was performed with a random effects model. Subgroup analyses were performed by the type of DNA damage test, whether the sperm examined were prepared or from raw semen and for pregnancies resulting from IVF or ICSI treatment.
MAIN RESULTS AND THE ROLE OF CHANCE
We identified 16 cohort studies (2969 couples), 14 of which were prospective. Eight studies used acridine orange-based assays, six the TUNEL assay and two the COMET assay. Meta-analysis showed a significant increase in miscarriage in patients with high DNA damage compared with those with low DNA damage risk ratio (RR) = 2.16 (1.54, 3.03), P < 0.00001). A subgroup analysis showed that the miscarriage association is strongest for the TUNEL assay (RR = 3.94 (2.45, 6.32), P < 0.00001).
LIMITATIONS, REASONS FOR CAUTION
There is some variation in study characteristics, including the use of different assays and different thresholds for DNA damage and the definition of pregnancy loss.
WIDER IMPLICATIONS OF THE FINDINGS
The use of methods which select sperm without DNA damage for use in assisted conception treatment may reduce the risk of miscarriage. This finding indicates that assays detecting DNA damage could be considered in those suffering from recurrent pregnancy loss. Further research is necessary to study the mechanisms of DNA damage and the potential therapeutic effects of antioxidant therapy.
STUDY FUNDING/COMPETING INTEREST(S)
None.
Count and recurrent event endpoints are common key efficacy endpoints in clinical research. For example, in clinical research of pulmonary diseases such as chronic obstructive pulmonary disease ...(COPD) or asthma, the reduction of the occurrence of a recurrent event, pulmonary exacerbation (PEx) caused by acute respiratory symptoms, is often used to measure the treatment effect. The occurrence of PEx is often analyzed with nonlinear models, such as Poisson regression or Negative Binomial regression. It is observed that model-estimated within-group PEx rates are often lower than the descriptive statistics of within-group PEx rates. Motivated by this observation, we explore their relationship mathematically and demonstrate that it is due to the difference between conditional PEx rates and population-level PEx rates (marginal rates). Our findings corroborate the recent FDA guidance (2023) 1, which discusses considerations for covariate adjustment in nonlinear models, and that conditional or subgroup treatment effects with covariate adjustment may differ from marginal treatment effects. In this article, we demonstrate how covariate adjustment impacts the estimation of event rates and rate ratios with both closed form and simulation studies. Additionally, following the ICH E9 addendum on the estimand framework 2, we discuss the estimand framework for count and recurrent event data.
Fibroblast growth factor 23 is an emerging vascular biomarker, recently associated with cerebral small vessel disease and poor cognition in patients on dialysis. It also interacts with klotho, an ...anti-aging and cognition enhancing protein.
To determine if circulating Fibroblast growth factor 23 (FGF23) is associated with new-onset cognitive outcomes in a community-based cohort of cognitively healthy adults with long-term follow-up.
We measured serum FGF23 levels in 1537 53% women, mean age 68.7 (SD 5.7) dementia-free Framingham Offspring participants at their 7th quadrennial examination (1998-2001), and followed these participants for the development of clinical all-cause dementia and Alzheimer's disease (AD). Secondary outcomes included MRI-based structural brain measures, and neurocognitive test performance at exam 7.
During a median (Q1, Q3) 12-year (7.0, 13.3) follow up, 122 (7.9%) participants developed dementia, of whom 91 (5.9%) had AD. Proportional-hazards regression analysis, adjusted for age, sex, education, systolic blood pressure, antihypertensive medication, prevalent cardiovascular disease, diabetes mellitus, smoking status and apoE ε4 carrier status, revealed that higher serum FGF23 levels were associated with an increased risk of incident dementia and AD (Hazard ratio HR per 1 standard deviation increment in inverse transformed FGF23 level 1.25, 95% CI 1.02-1.53, and 1.32, 95% CI 1.04-1.69, respectively). There was no significant interaction according to presence/absence of significant renal impairment (eGFR <30 versus ≥30ml/min) and risk of dementia (based on 1537; p = 0.97).
Higher circulating FGF23 is associated with an increased risk of dementia, suggesting that FGF23-related biological pathways may play a role in the development of dementia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In observational studies with censored data, exposure‐outcome associations are commonly measured with adjusted hazard ratios from multivariable Cox proportional hazards models. The difference in ...restricted mean survival times (RMSTs) up to a pre‐specified time point is an alternative measure that offers a clinically meaningful interpretation. Several regression‐based methods exist to estimate an adjusted difference in RMSTs, but they digress from the model‐free method of taking the area under the survival function. We derive the adjusted RMST by integrating an adjusted Kaplan‐Meier estimator with inverse probability weighting (IPW). The adjusted difference in RMSTs is the area between the two IPW‐adjusted survival functions. In a Monte Carlo‐type simulation study, we demonstrate that the proposed estimator performs as well as two regression‐based approaches: the ANCOVA‐type method of Tian et al and the pseudo‐observation method of Andersen et al. We illustrate the methods by reexamining the association between total cholesterol and the 10‐year risk of coronary heart disease in the Framingham Heart Study.
OBJECTIVETo assess the association of early morning serum cortisol with cognitive performance and brain structural integrity in community-dwelling young and middle-aged adults without dementia.
...METHODSWe evaluated dementia-free Framingham Heart Study (generation 3) participants (mean age 48.5 years, 46.8% men) who underwent cognitive testing for memory, abstract reasoning, visual perception, attention, and executive function (n = 2,231) and brain MRI (n = 2018) to assess total white matter, lobar gray matter, and white matter hyperintensity volumes and fractional anisotropy (FA) measures. We used linear and logistic regression to assess the relations of cortisol (categorized in tertiles, with the middle tertile as referent) to measures of cognition, MRI volumes, presence of covert brain infarcts and cerebral microbleeds, and voxel-based microstructural white matter integrity and gray matter density, adjusting for age, sex, APOE, and vascular risk factors.
RESULTSHigher cortisol (highest tertile vs middle tertile) was associated with worse memory and visual perception, as well as lower total cerebral brain and occipital and frontal lobar gray matter volumes. Higher cortisol was associated with multiple areas of microstructural changes (decreased regional FA), especially in the splenium of corpus callosum and the posterior corona radiata. The association of cortisol with total cerebral brain volume varied by sex (p for interaction = 0.048); higher cortisol was inversely associated with cerebral brain volume in women (p = 0.001) but not in men (p = 0.717). There was no effect modification by the APOE4 genotype of the relations of cortisol and cognition or imaging traits.
CONCLUSIONHigher serum cortisol was associated with lower brain volumes and impaired memory in asymptomatic younger to middle-aged adults, with the association being evident particularly in women.
To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties.
Findings were pooled from 5 ...population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis.
After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity.
Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND AND PURPOSE—Little is known about associations between vascular growth factors and magnetic resonance imaging (MRI) markers in midlife. We investigated the association of serum VEGF ...(vascular endothelial growth factor), Ang2 (angiopoietin 2), sTie2 (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2), and HGF (hepatocyte growth factor) concentrations with MRI markers of brain aging in middle-aged adults.
METHODS—We evaluated 1853 participants (mean age, 46±9 years; 46% men) from the Framingham Heart Study. Serum growth factor concentrations were measured using standardized immunoassays. Outcomes included total brain, cortical and subcortical gray matter, white matter, cerebrospinal fluid, and white matter hyperintensity volumes derived from MRI; as well as fractional anisotropy in white matter tracts from diffusion tensor imaging. We related VEGF, Ang2, sTie2, and HGF to MRI measures using multivariable regression models adjusting for vascular risk factors. We tested for interactions with APOE (apolipoprotein E) genotype and CRP (C-reactive protein). Results were corrected for multiple comparisons.
RESULTS—Higher sTie2 was associated with smaller total brain (estimate by SD unit±SE=−0.08±0.02, P=0.002) and larger white matter hyperintensity (0.08±0.02, P=0.002) volumes. Furthermore, higher Ang2 (0.06±0.02, P=0.049) and HGF (0.09±0.02, P=0.001) were associated with larger cerebrospinal fluid volumes. Finally, higher Ang2 was associated with decreased fractional anisotropy, in APOE-ε4 carriers only.
CONCLUSIONS—Vascular growth factors are associated with early MRI markers of small vessel disease and neurodegeneration in middle-aged adults.
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