Meta-analytical methods to identify who benefits most from treatments: daft, deluded, or deft approach?

Identifying which individuals beneft most from particular treatments or other interventions underpins so-called personalised or stratifed medicine. However, single trials are typically underpowered for exploring whether participant characteristics, such as age or disease severity, determine an individual's response to treatment. A meta-analysis of multiple trials, particularly one where individual participant data (IPD) are available, provides greater power to investigate interactions between participant characteristics (covariates) and treatment e?ects. We use a published IPD meta-analysis to illustrate three broad approaches used for testing such interactions. Based on another systematic review of recently published IPD meta-analyses, we also show that all three approaches can be applied to aggregate data as well as IPD. We also summarise which methods of analysing and presenting interactions are in current use, and describe their advantages and disadvantages. We recommend that testing for interactions using within-trials information alone (the def approach) becomes standard practice, alongside graphical presentation that directly visualises this

Association of acquired and heritable factors with intergenerational differences in age at symptomatic onset of Alzheimer disease between offspring and parents with dementia

Importance: Acquired and heritable traits are associated with dementia risk; however, how these traits are associated with age at symptomatic onset (AAO) of Alzheimer disease (AD) is unknown. Identifying the associations of acquired and heritable factors with variability in intergenerational AAO of AD could facilitate diagnosis, assessment, and counseling of the offspring of parents with AD. Objective: To quantify the associations of acquired and heritable factors with intergenerational differences in AAO of AD. Design, Setting, and Participants: This nested cohort study used data from the Knight Alzheimer Disease Research Center that included community-dwelling participants with symptomatic AD, parental history of dementia, and available DNA data who were enrolled in prospective studies of memory and aging from September 1, 2005, to August 31, 2016. Clinical, biomarker, and genetic data were extracted on January 17, 2017, and data analyses were conducted from July 1, 2017, to August 20, 2019. Main Outcomes and Measures: The associations of acquired (ie, years of education; body mass index; history of cardiovascular disease, hypertension, hypercholesterolemia, diabetes, active depression within 2 years, traumatic brain injury, tobacco use, and unhealthy alcohol use; and retrospective determination of AAO) and heritable factors (ie, ethnicity/race, paternal or maternal inheritance, parental history of early-onset dementia, APOE ε4 allele status, and AD polygenic risk scores) to intergenerational difference in AAO of AD were quantified using stepwise forward multivariable regression. Missense or frameshift variants within genes associated with AD pathogenesis were screened using whole-exome sequencing. Results: There were 164 participants with symptomatic AD, known parental history of dementia, and available DNA data (mean [SD] age, 70.9 [8.3] years; 90 [54.9%] women) included in this study. Offspring were diagnosed with symptomatic AD a mean (SD) 6.1 (10.7) years earlier than their parents (P \u3c .001). The adjusted R2 for measured acquired and heritable factors for intergenerational difference in AAO of AD was 0.29 (F8,155 = 9.13; P \u3c .001). Paternal (β = -9.52 [95% CI, -13.79 to -5.25]) and maternal (β = -6.68 [95% CI, -11.61 to -1.75]) history of dementia, more years of education (β = -0.58 [95% CI -1.08 to -0.09]), and retrospective determination of AAO (β = -3.46 [95% CI, -6.40 to -0.52]) were associated with earlier-than-expected intergenerational difference in AAO of AD. Parental history of early-onset dementia (β = 21.30 [95% CI, 15.01 to 27.59]), presence of 1 APOE ε4 allele (β = 5.00 [95% CI, 2.11 to 7.88]), and history of hypertension (β = 3.81 [95% CI, 0.88 to 6.74]) were associated with later-than-expected intergenerational difference in AAO of AD. Missense or frameshift variants within genes associated with AD pathogenesis were more common in participants with the greatest unexplained variability in intergenerational AAO of AD (19 of 48 participants [39.6%] vs 26 of 116 participants [22.4%]; P = .03). Conclusions and Relevance: Acquired and heritable factors were associated with a substantial proportion of variability in intergenerational AAO of AD. Variants in genes associated with AD pathogenesis may contribute to unexplained variability, justifying further study

GPS driving: A digital biomarker for preclinical Alzheimer disease

BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia. Preclinical AD is the period during which early AD brain changes are present but cognitive symptoms have not yet manifest. The presence of AD brain changes can be ascertained by molecular biomarkers obtained via imaging and lumbar puncture. However, the use of these methods is limited by cost, acceptability, and availability. The preclinical stage of AD may have a subtle functional signature, which can impact complex behaviours such as driving. The objective of the present study was to evaluate the ability of in-vehicle GPS data loggers to distinguish cognitively normal older drivers with preclinical AD from those without preclinical AD using machine learning methods. METHODS: We followed naturalistic driving in cognitively normal older drivers for 1 year with a commercial in-vehicle GPS data logger. The cohort included n = 64 individuals with and n = 75 without preclinical AD, as determined by cerebrospinal fluid biomarkers. Four Random Forest (RF) models were trained to detect preclinical AD. RF Gini index was used to identify the strongest predictors of preclinical AD. RESULTS: The F1 score of the RF models for identifying preclinical AD was 0.85 using APOE ε4 status and age only, 0.82 using GPS-based driving indicators only, 0.88 using age and driving indicators, and 0.91 using age, APOE ε4 status, and driving. The area under the receiver operating curve for the final model was 0.96. CONCLUSION: The findings suggest that GPS driving may serve as an effective and accurate digital biomarker for identifying preclinical AD among older adults

Autoantibodies in chronic graft versus host result from cognate T-B interactions

A chronic graft-versus-host reaction (GVH) induced in nonautoimmune mice causes a syndrome that closely resembles SLE. In this model, donor T cells react against incompatible host Ia structures and generate excessive help, which activates a subpopulation of self-reactive B cells. We have studied whether these self-reactive B cells are activated by direct interaction with alloreactive T cells or by nonspecific bystander effects. Two types of chimeras were made: double- parental chimeras, differing at both Ia and Igh allotype [B6.C20 + bm12- ---(B6.C20 x bm12)F1]; and control chimeras [(B6.C20 x bm12)F1---- (B6.C20 x bm12)F1]. A chronic GVH syndrome was induced in the chimeras by infusion of B6 or bm12 spleen cells. Coombs and antichromatin autoantibodies were measured using Igh allotype-specific immunoassays. The double-parental chimeras that received bm12 cells made autoantibodies principally of the Igha allotype, indicating that the bm12 T cells interacted only with the Iab-bearing host B cells. Conversely, double-parental chimeras that received B6 cells made mostly Ighb autoantibodies, indicating direct cognate interaction with the Iabm12-bearing host B cells. The control chimeras made autoantibodies of both allotypes. These results indicate that autoantibodies in chronic GVH result from direct T-B interactions and not from nonspecific T cell-derived factors

The Solar Benchmark: Rotational Modulation of the Sun Reconstructed from Archival Sunspot Records

We use archival daily spot coverage measurements from Howard et al. (1984) to study the rotational modulation of the Sun as though it were a distant star. A quasi-periodic Gaussian process measures the solar rotation period $P_\mathrm{rot} = 26.3 \pm 0.1$ days, and activity cycle period $P_\mathrm{cyc} = 10.7 \pm 0.3$ years. We attempt to search for evidence of differential rotation in variations of the apparent rotation period throughout the activity cycle and do not detect a clear signal of differential rotation, consistent with the null results of the hare-and-hounds exercise of Aigrain et al. (2015). The full reconstructed solar light curve is available online.Comment: Accepted for publication in MNRA

Cerebrospinal fluid neurofilament light chain is a marker of aging and white matter damage

BACKGROUND: Cerebrospinal fluid (CSF) neurofilament light chain (NfL) reflects neuro-axonal damage and is increasingly used to evaluate disease progression across neurological conditions including Alzheimer disease (AD). However, it is unknown how NfL relates to specific types of brain tissue. We sought to determine whether CSF NfL is more strongly associated with total gray matter, white matter, or white matter hyperintensity (WMH) volume, and to quantify the relative importance of brain tissue volume, age, and AD marker status (i.e., APOE genotype, brain amyloidosis, tauopathy, and cognitive status) in predicting CSF NfL. METHODS: 419 participants (Clinical Dementia Rating [CDR] Scale \u3e 0, N = 71) had CSF, magnetic resonance imaging (MRI), and neuropsychological data. A subset had amyloid positron emission tomography (PET) and tau PET. Pearson correlation analysis was used to determine the association between CSF NfL and age. Multiple regression was used to determine which brain volume (i.e., gray, white, or WMH volume) most strongly associated with CSF NfL. Stepwise regression and dominance analyses were used to determine the individual contributions and relative importance of brain volume, age, and AD marker status in predicting CSF NfL. RESULTS: CSF NfL increased with age (r = 0.59, p \u3c 0.001). Elevated CSF NfL was associated with greater total WMH volume (p \u3c 0.001), but not gray or white matter volume (p\u27s \u3e 0.05) when considered simultaneously. Age and WMH volume were consistently more important (i.e., have greater R CONCLUSIONS: CSF NfL is a non-specific marker of aging and white matter integrity with limited sensitivity to specific markers of AD. CSF NfL likely reflects processes associated with cerebrovascular disease

An intrinsic B cell defect is required for the production of autoantibodies in the lpr model of murine systemic autoimmunity

Mice homozygous for the gene lpr develop marked lymphadenopathy and a spectrum of autoantibodies closely resembling that of human systemic lupus erythematosus. The unusual T cell phenotype of the expanded lymphocyte population and the T-dependence of several antibodies in this strain have suggested that primary T cell abnormalities underlie the autoimmune syndrome. Using double chimeras, we now show that expression of the lpr gene in B cells is absolutely necessary for autoantibody production. Combinations of anti-Thy 1.2 + C' treated bone marrow from congenic strains of C57BL/6 mice, differing only at the immunoglobulin heavy chain (Igh) and lpr loci, were transferred into lethally irradiated B6/lpr mice. Double chimerism was documented by allotype-specific surface IgD and IgM immunofluorescence assay of peripheral blood and by allotype-specific enzyme-linked immunosorbent assay for total IgM in serum. Despite the presence of both +/+ and lpr B cells, IgM and IgG2a anti-chromatin as well as IgM anti-IgG were entirely the products of lpr B cells. Total serum IgG2a and IgG1 were also dominated by the lpr phenotype but not to the same extent. A similar experiment using B6/lpr-Igha recipients confirmed these findings. Additional experiments in which B6/lpr recipients were infused with ratios of donor bone marrow favoring B6.C20 +/+ over B6/lpr showed that even though +/+ B cells were overrepresented, autoantibodies were only of the lpr allotype. In addition, in the presence of lpr B cells, normal B cells showed little response to an exogenous, T cell-dependent antigen. The data thus indicate that lpr B cells manifest an intrinsic abnormality which is essential for autoantibody production in the lpr model

Falls: A marker of preclinical Alzheimer disease: A cohort study protocol

INTRODUCTION: Progression to symptomatic Alzheimer disease (AD) occurs slowly over a series of preclinical stages. Declining functional mobility may be an early indicator of loss of brain network integration and may lead to an increased risk of experiencing falls. It is unknown whether measures of functional mobility and falls are preclinical markers of AD. The purpose of this study is to examine (1) the relationship between falls and functional mobility with AD biomarkers to determine when falls occur within the temporal progression to symptomatic Alzheimer disease, and (2) the attentional compared with perceptual/motor systems that underlie falls and functional mobility changes seen with AD. METHODS AND ANALYSIS: This longitudinal cohort study will be conducted at the Knight Alzheimer Disease Research Center. Approximately 350 cognitively normal participants (with and without preclinical AD) will complete an in-home visit every year for 4 years. During each yearly assessment, functional mobility will be assessed using the Performance Oriented Mobility Assessment, Timed Up and Go, and Timed Up and Go dual task. Data regarding falls (including number and severity) will be collected monthly by self-report and confirmed through interviews. This study will leverage ongoing neuropsychological assessments and neuroimaging (including molecular imaging using positron emission tomography and MRI) performed by the Knight Alzheimer Disease Research Center. Relationships between falls and biomarkers of amyloid, tau and neurodegeneration will be evaluated. ETHICS AND DISSEMINATION: This study was approved by the Washington University in St. Louis Institutional Review Board (reference number 201807135). Written informed consent will be obtained in the home prior to the collection of any study data. Results will be published in peer-reviewed publications and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04949529; Pre-results