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In precision medicine, there is much interest in estimating the expected-to-benefit (EB) subset, i.e. the subset of patients who are expected to benefit from a new treatment based on a collection of baseline characteristics. There are many statistical methods for estimating the EB subset, most of which produce a 'point estimate' without a confidence statement to address uncertainty. Confidence intervals for the EB subset have been defined only recently, and their construction is a new area for methodological research. This article proposes a pseudo-response approach to EB subset estimation and confidence interval construction. Compared to existing methods, the pseudo-response approach allows us to focus on modelling a conditional treatment effect function (as opposed to the conditional mean outcome given treatment and baseline covariates) and is able to incorporate information from baseline covariates that are not involved in defining the EB subset. Simulation results show that incorporating such covariates can improve estimation efficiency and reduce the size of the confidence interval for the EB subset. The methodology is applied to a randomized clinical trial comparing two drugs for treating HIV infection., Competing Interests: Conflict of interest: Zhiwei Zhang and Calvin J. Cohen are employed by Gilead Sciences. Ping Xu is employed by Janssen. This article expresses the authors’ personal opinions and does not represent the official position of Janssen, Gilead or the National Institutes of Health., (© The Royal Statistical Society 2024. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The primary aim of this work was to convert the Information System for Research in Primary Care (SIDIAP) from Catalonia, Spain, to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Our second aim was to provide a descriptive analysis of COVID-19-related outcomes among the general population., Patients and Methods: We mapped patient-level data from SIDIAP to the OMOP CDM and we performed more than 3,400 data quality checks to assess its readiness for research. We established a general population cohort as of the 1st March 2020 and identified outpatient COVID-19 diagnoses or tested positive for, hospitalised with, admitted to intensive care units (ICU) with, died with, or vaccinated against COVID-19 up to 30th June 2022., Results: After verifying the high quality of the transformed dataset, we included 5,870,274 individuals in the general population cohort. Of those, 604,472 had either an outpatient COVID-19 diagnosis or positive test result, 58,991 had a hospitalisation, 5,642 had an ICU admission, and 11,233 died with COVID-19. A total of 4,584,515 received a COVID-19 vaccine. People who were hospitalised or died were more commonly older, male, and with more comorbidities. Those admitted to ICU with COVID-19 were generally younger and more often male than those hospitalised and those who died., Conclusion: We successfully transformed SIDIAP to the OMOP CDM. From this dataset, a general population cohort of 5.9 million individuals was identified and their COVID-19-related outcomes over time were described. The transformed SIDIAP database is a valuable resource that can enable distributed network research in COVID-19 and beyond., Competing Interests: EAV and CB are employees of Janssen Research and Development LLC and shareholders of Johnson & Johnson (J&J) stock. LH reports edenceHealth, as a certified EHDEN SME, received payment for certifying the earlier OMOP CDM transformation work done by SIDIAP in their function as an EHDEN Data Partner, during the conduct of the study. TD-S reports grants from Innovative Medicines Initiative 2, during the conduct of the study. The authors report no other conflicts of interest in this work., (© 2023 Raventós et al.)

Objectives: Determinants of cognitive functioning in individuals aged 90 years and older, the oldest-old, remain poorly understood. We aimed to establish the association of risk factors, white matter hyperintensities (WMHs), hippocampal atrophy, and amyloid aggregation with cognition in the oldest-old., Method: We included 84 individuals without cognitive impairment and 38 individuals with cognitive impairment from the EMIF-AD 90+ Study (mean age 92.4 years) and tested cross-sectional associations between risk factors (cognitive activity, physical parameters, nutritional status, inflammatory markers, and cardiovascular risk factors), brain pathology biomarkers (WMH and hippocampal volume on magnetic resonance imaging, and amyloid binding measured with positron emission tomography), and cognition. Additionally, we tested whether the brain pathology biomarkers were independently associated with cognition. When applicable, we tested whether the effect of risk factors on cognition was mediated by brain pathology., Results: Lower values for handgrip strength, Short Physical Performance Battery (SPPB), nutritional status, HbA1c, and hippocampal volume, and higher values for WMH volume and amyloid binding were associated with worse cognition. Higher past cognitive activity and lower body mass index were associated with increased amyloid binding, lower muscle mass with more WMH, and lower SPPB scores with more WMH and hippocampal atrophy. The brain pathology markers were independently associated with cognition. The association of SPPB with cognition was partially mediated by hippocampal volume., Discussion: In the oldest-old, physical parameters, nutritional status, HbA1c, WMH, hippocampal atrophy, and amyloid binding are associated with cognitive impairment. Physical performance may affect cognition through hippocampal atrophy. This study highlights the importance to consider multiple factors when assessing cognition in the oldest-old., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Experimental human immunodeficiency virus (HIV)-1 vaccines frequently elicit antibodies against HIV-1 that may react with commonly used HIV diagnostic tests, a phenomenon known as vaccine-induced seropositivity/seroreactivity (VISP/VISR). We sought to determine, under clinic conditions, whether a patient-controlled HIV test, OraQuick ADVANCE Rapid HIV-1/2 Antibody Test, detected HIV-1 vaccine-induced antibodies., Methods: Plasma assessment of HIV-1 cross-reactivity was examined in end-of-study samples from 57 healthy, HIV-uninfected participants who received a candidate vaccine that has entered Phase 2B and 3 testing. We also screened 120 healthy, HIV-uninfected, unblinded HIV-1 vaccine participants with VISP/VISR for an assessment using saliva. These participants came from 21 different parent vaccine protocols representing 17 different vaccine regimens, all of which contained an HIV-1 envelope immunogen. OraQuick ADVANCE was compared with results from concurrent blood samples using a series of commercial HIV screening immunoassays., Results: Fifty-seven unique participant plasma samples were assayed in vitro, and only 1 (1.8%) was reactive by OraQuick ADVANCE. None of the 120 clinic participants (0%; 95% confidence interval, 0% to 3.7%) tested positive by OraQuick ADVANCE, and all were confirmed to be uninfected by HIV-1 viral ribonucleic acid testing. One hundred eighteen of the 120 (98.3%) participants had a reactive HIV test for VISP/VISR: 77 (64%) had at least 1 reactive fourth-generation HIV-1 diagnostic test ( P  < .0001 vs no reactive OraQuick ADVANCE results), and 41 (34%) only had a reactive test by the less specific third-generation Abbott Prism assay., Conclusions: These data suggest that this widely available patient-controlled test has limited reactivity to HIV-1 antibodies elicited by these candidate HIV-1 vaccines., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Hippocampal atrophy (HA) is one of the biomarkers for Alzheimer's disease (AD)., Objective: To identify the best biomarkers and develop models for prediction of HA over 24 months using baseline data., Methods: The study included healthy elderly controls, subjects with mild cognitive impairment, and subjects with AD, obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI 1) and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) databases. Predictor variables included cognitive and neuropsychological tests, amyloid-β, tau, and p-tau from cerebrospinal fluid samples, apolipoprotein E, and features extracted from magnetic resonance images (MRI). Least-mean-squares regression with elastic net regularization and least absolute deviation regression models were tested using cross-validation in ADNI 1. The generalizability of the models including only MRI features was evaluated by training the models with ADNI 1 and testing them with AIBL. The models including the full set of variables were not evaluated with AIBL because not all needed variables were available in it., Results: The models including the full set of variables performed better than the models including only MRI features (root-mean-square error (RMSE) 1.76-1.82 versus 1.93-2.08). The MRI-only models performed well when applied to the independent validation cohort (RMSE 1.66-1.71). In the prediction of dichotomized HA (fast versus slow), the models achieved a reasonable prediction accuracy (0.79-0.87)., Conclusions: These models can potentially help identifying subjects predicted to have a faster HA rate. This can help in selection of suitable patients into clinical trials testing disease-modifying drugs for AD.

Background: The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest-old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study., Methods: The EMIF-AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer's Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid β and tau in cerebrospinal fluid/blood and neurophysiological measures., Discussion: The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration., Trial Registration: Nederlands Trial Register NTR5867 . Registered 20 May 2016.

Background: With the shift of research focus towards the pre-dementia stage of Alzheimer's disease (AD), there is an urgent need for reliable, non-invasive biomarkers to predict amyloid pathology. The aim of this study was to assess whether easily obtainable measures from structural MRI, combined with demographic data, cognitive data and apolipoprotein E (APOE) ε4 genotype, can be used to predict amyloid pathology using machine-learning classification., Methods: We examined 810 subjects with structural MRI data and amyloid markers from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, including subjects with normal cognition (CN, n = 337, age 66.5 ± 7.2, 50% female, 27% amyloid positive), mild cognitive impairment (MCI, n = 375, age 69.1 ± 7.5, 53% female, 63% amyloid positive) and AD dementia (n = 98, age 67.0 ± 7.7, 48% female, 97% amyloid positive). Structural MRI scans were visually assessed and Freesurfer was used to obtain subcortical volumes, cortical thickness and surface area measures. We first assessed univariate associations between MRI measures and amyloid pathology using mixed models. Next, we developed and tested an automated classifier using demographic, cognitive, MRI and APOE ε4 information to predict amyloid pathology. A support vector machine (SVM) with nested 10-fold cross-validation was applied to identify a set of markers best discriminating between amyloid positive and amyloid negative subjects., Results: In univariate associations, amyloid pathology was associated with lower subcortical volumes and thinner cortex in AD-signature regions in CN and MCI. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.81 ± 0.07 in MCI and an AUC of 0.74 ± 0.08 in CN. In CN, selected features for the classifier included APOE ε4, age, memory scores and several MRI measures such as hippocampus, amygdala and accumbens volumes and cortical thickness in temporal and parahippocampal regions. In MCI, the classifier including demographic and APOE ε4 information did not improve after additionally adding imaging measures., Conclusions: Amyloid pathology is associated with changes in structural MRI measures in CN and MCI. An automated classifier based on clinical, imaging and APOE ε4 data can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in clinical trials to pre-screen subjects for anti-amyloid therapies.

Background: Mosaic immunogens are bioinformatically engineered human immunodeficiency virus type 1 (HIV-1) sequences designed to elicit clade-independent coverage against globally circulating HIV-1 strains., Methods: This phase 1, double-blinded, randomized, placebo-controlled trial enrolled healthy HIV-uninfected adults who received 2 doses of a modified vaccinia Ankara (MVA)-vectored HIV-1 bivalent mosaic immunogen vaccine or placebo on days 0 and 84. Two groups were enrolled: those who were HIV-1 vaccine naive (n = 15) and those who had received an HIV-1 vaccine (Ad26.ENVA.01) 4-6 years earlier (n = 10). We performed prespecified blinded cellular and humoral immunogenicity analyses at days 0, 14, 28, 84, 98, 112, 168, 270, and 365., Results: All 50 planned vaccinations were administered. Vaccination was safe and generally well tolerated. No vaccine-related serious adverse events occurred. Both cellular and humoral cross-clade immune responses were elicited after 1 or 2 vaccinations in all participants in the HIV-1 vaccine-naive group. Env-specific responses were induced after a single immunization in nearly all subjects who had previously received the prototype Ad26.ENVA.01 vaccine., Conclusions: No safety concerns were identified, and multiclade HIV-1-specific immune responses were elicited., Clinical Trials Registration: NCT02218125.

Clinical trial data are the gold standard for evaluating pharmaceutical safety and efficacy. There is an ethical and scientific imperative for transparency and data sharing to confirm published results and generate new knowledge. The Open Translational Science in Schizophrenia (OPTICS) Project was an open-science initiative aggregating Janssen clinical trial and NIH/NIMH data from real-world studies and trials in schizophrenia. The project aims were to show the value of using shared data to examine: therapeutic safety and efficacy; disease etiologies and course; and methods development. The success of project investigators was due to collaboration from project applications through analyses, with support from the Harvard Catalyst. Project work was independent of Janssen; all intellectual property was dedicated to the public. Efforts such as this are necessary to gain deeper insights into the biology of disease, foster collaboration, and to achieve the goal of developing better treatments, reducing the overall public health burden of devastating brain diseases.

We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.

Introduction: The European Medical Information Framework consortium has assembled electronic health record (EHR) databases for dementia research. We calculated dementia prevalence and incidence in 25 million persons from 2004 to 2012., Methods: Six EHR databases (three primary care and three secondary care) from five countries were interrogated. Dementia was ascertained by consensus harmonization of clinical/diagnostic codes. Annual period prevalences and incidences by age and gender were calculated and meta-analyzed., Results: The six databases contained 138,625 dementia cases. Age-specific prevalences were around 30% of published estimates from community samples and incidences were around 50%. Pooled prevalences had increased from 2004 to 2012 in all age groups but pooled incidences only after age 75 years. Associations with age and gender were stable over time., Discussion: The European Medical Information Framework initiative supports EHR data on unprecedented number of people with dementia. Age-specific prevalences and incidences mirror estimates from community samples in pattern at levels that are lower but increasing over time., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Bapineuzumab, a humanized monoclonal antibody, targets amyloid-β (Aβ1-40/1 -42) that is believed to play a key role in the pathogenesis of Alzheimer disease (AD)., Objectives: To assess the effects of monthly subcutaneous (SC) bapineuzumab versus placebo on cerebral amyloid signal in amyloid-positive patients with mild to moderate AD. The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), pharmacokinetics, pharmacodynamics, immunogenicity, and other safety aspects of bapineuzumab were also evaluated., Methods: In this multicenter, double-blind study, 146 patients were randomized (1 : 1:1 : 1) to SC bapineuzumab 2, 7, or 20 mg/month or placebo. Lack of efficacy of intravenous (IV) bapineuzumab in Phase III studies led to truncation of the treatment duration from 24 months to 12 months. Primary endpoint: change from baseline to month 12 in brain amyloid signal as measured by standardized uptake value ratio (SUVR) using florbetapir positron emission tomography (PET)., Results: Florbetapir PET SUVR decreased significantly (p = 0.038) from baseline to month 12 for the bapineuzumab 7 mg/month group only; reductions versus placebo were not significant for any dosage. One patient each in bapineuzumab 2 mg/month and 20 mg/month groups had ARIA-E. The percentages of patients with treatment-emergent adverse events were similar in placebo (77.8%) and bapineuzumab 2 mg/month (78.4%) group, but higher in 7 mg/month (94.4%) and 20 mg/month (89.2%) groups., Conclusion: Bapineuzumab SC once-monthly did not demonstrate significant treatment difference over placebo on cerebral amyloid signal at one year but was well-tolerated. There was less ARIA-E than had been expected based on prior experience with comparable exposure on IV bapineuzumab.

Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

The prevalence of mild cognitive impairment (MCI) and dementia according to age remain uncertain. We systematically extracted age-stratified estimates of MCI and dementia prevalence reported in European studies published since 1995, and performed meta-analyses for dementia. We identified 10 relevant studies on MCI and 26 studies on dementia. Studies on MCI presented substantial heterogeneity preventing a meta-analysis, with a majority reporting an increase in prevalence at ≥75 years old. Pooled prevalence of dementia rose continuously from 55 years of age, reaching 44.7% (39.8; 49.6) in those ≥95 years of age. Homogenization of MCI criteria, and additional studies in Northern European population would be warranted.

Background: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development., Methods: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data., Results: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011., Conclusions: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency., (Copyright © 2014 The Alzheimer's Association. All rights reserved.)