ABSTRACT
Due to a combination of asymptomatic or undiagnosed infections, the proportion of the United States population infected with SARS-CoV-2 was unclear from the beginning of the pandemic. We previously established a platform to screen for SARS-CoV-2 positivity across a representative proportion of the US population, from which we reported that almost 17 million Americans were estimated to have had undocumented infections in the Spring of 2020. Since then, vaccine rollout and prevalence of different SARS-CoV-2 variants have further altered seropositivity trends within the United States population. To explore the longitudinal impacts of the pandemic and vaccine responses on seropositivity, we re-enrolled participants from our baseline study in a 6- and 12- month follow-up study to develop a longitudinal antibody profile capable of representing seropositivity within the United States during a critical period just prior to and during the initiation of vaccine rollout. Initial measurements showed that, since July 2020, seropositivity elevated within this population from 4.8% at baseline to 36.2% and 89.3% at 6 and 12 months, respectively. We also evaluated nucleocapsid seropositivity and compared to spike seropositivity to identify trends in infection versus vaccination relative to baseline. These data serve as a window into a critical timeframe within the COVID-19 pandemic response and serve as a resource that could be used in subsequent respiratory illness outbreaks.
ABSTRACT
Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective.
Subject(s)
Neoplasms, Second Primary , Neoplasms , Humans , Precision Medicine/methods , Neoplasms/drug therapy , Neoplasms/genetics , Medical Oncology/methodsABSTRACT
Multi-attribute method (MAM) using peptide map analysis with high resolution mass spectrometry is increasingly common in product characterization and the identification of critical quality attributes (CQAs) of biotherapeutic proteins. Capable of providing structural information specific to amino acid residues, quantifying relative abundance of product variants or degradants, and detecting profile changes between product lots, a robust MAM can replace multiple traditional methods that generate profile-based information for product release and stability testing. In an effort to provide informative and efficient analytical monitoring for monoclonal antibody (mAb) products, from early development to manufacturing quality control, we describe the desired MAM performance profile and address the major scientific challenges in MAM method validation. Furthermore, to support fast speed investigational product development, we describe a platform method validation strategy and results of an optimized MAM workflow. This strategy is applied to support the use of MAM for multiple mAb products with similar structures and physicochemical properties, requiring minimal product-specific method validation activities. Three mAb products were used to demonstrate MAM performance for common and representative product quality attributes. Method validation design and acceptance criteria were guided by the Analytical Target Profile concept, as well as relevant regulatory guidelines to ensure the method is fit-for-purpose. A comprehensive system suitability control strategy was developed, and reported here, to ensure adequate performance of the method including sample preparation, instrument operation, and data analysis. Our results demonstrated sufficient method performance for the characteristics required for quantitative measurement of product variants and degradants.
Subject(s)
Antibodies, Monoclonal , Antineoplastic Agents, Immunological , Amino Acids , Quality Control , Research DesignABSTRACT
TP53 is one of the most frequently altered genes in cancer; it can be inactivated by a number of different mechanisms. NM_000546.6 (ENST00000269305.9) is by far the predominant TP53 isoform, however a few other alternative isoforms have been described to be expressed at much lower levels. To better understand patterns of TP53 alternative isoforms expression in cancer and normal samples we performed exon-exon junction reads based analysis of TP53 isoforms using RNA-seq data from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx) project. TP53 C-terminal alternative isoforms have abolished or severely decreased tumor suppressor activity, and therefore, an increase in fraction of TP53 C-terminal alternative isoforms may be expected in tumors with wild type TP53. Despite our expectation that there would be increase of fraction of TP53 C-terminal alternative isoforms, we observed no substantial increase in fraction of TP53 C-terminal alternative isoforms in TCGA tumors and CCLE cancer cell lines with wild type TP53, likely indicating that TP53 C-terminal alternative isoforms expression cannot be reliably selected for during tumor progression.
Subject(s)
Alternative Splicing , Exons/genetics , Gene Expression Regulation, Neoplastic , Mutation , Neoplasms/genetics , Tumor Suppressor Protein p53/genetics , Cell Line, Tumor , Disease Progression , Genes, Tumor Suppressor , Humans , Neoplasms/metabolism , Neoplasms/pathology , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA-Seq/methods , Tumor Suppressor Protein p53/metabolismABSTRACT
We report the results from a Foundation for the National Institutes of Health Biomarkers Consortium project to address the absence of well-validated quality control materials (QCMs) for circulating tumor DNA (ctDNA) testing. This absence is considered a cause of variance and inconsistencies in translating ctDNA results into clinical actions. METHODS: In this phase I study, QCMs with 14 clinically relevant mutations representing single nucleotide variants, insertions or deletions (indels), translocations, and copy number variants were sourced from three commercial manufacturers with variant allele frequencies (VAFs) of 5%, 2.5%, 1%, 0.1%, and 0%. Four laboratories tested samples in quadruplicate using two allele-specific droplet digital polymerase chain reaction and three (amplicon and hybrid capture) next-generation sequencing (NGS) panels. RESULTS: The two droplet digital polymerase chain reaction assays reported VAF values very close to the manufacturers' claimed concentrations for all QCMs. NGS assays reported most single nucleotide variants and indels, but not translocations, close to the expected VAF values. Notably, two NGS assays reported lower VAF than expected for all translocations in all QCM mixtures, possibly related to technical challenges detecting these variants. The ability to call ERBB2 copy number amplifications varied across assays. All three QCMs provided valuable insight into assay precision. Each assay across all variant types demonstrated dropouts at 0.1%, suggesting that the QCM can serve for testing of an assay's limit of detection with confidence claims for specific variants. CONCLUSION: These results support the utility of the QCM in testing ctDNA assay analytical performance. However, unique designs and manufacturing methods for the QCM, and variations in a laboratory's testing configuration, may require testing of multiple QCMs to find the best reagents for accurate result interpretation.
Subject(s)
Circulating Tumor DNA/genetics , High-Throughput Nucleotide Sequencing , Neoplasms/genetics , Polymerase Chain Reaction , Quality Control , Biomarkers, Tumor/genetics , Circulating Tumor DNA/blood , DNA Copy Number Variations , Gene Frequency , Humans , Mutation/genetics , National Institutes of Health (U.S.) , Neoplasms/blood , United StatesABSTRACT
Natural products remain a significant source of anticancer chemotherapeutics. The search for targeted drugs for cancer treatment includes consideration of natural products, which may provide new opportunities for antitumor cytotoxicity as single agents or in combination therapy. We examined the association of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 1302 small molecules which included natural products, semisynthetic natural product derivatives, and synthetic compounds based on a natural product pharmacophore from the Developmental Therapeutics Program of the US National Cancer Institute's database. These compounds were obtained from a variety of plant, marine, and microbial species. Molecular information utilized for the analysis included expression measures for 23059 annotated transcripts, lncRNAs, and miRNAs, and data on protein-changing single nucleotide variants in 211 cancer-related genes. We found associations of expression of multiple genes including SLFN11, CYP2J2, EPHX1, GPC1, ELF3, and MGMT involved in DNA damage repair, NOTCH family members, ABC and SLC transporters, and both mutations in tyrosine kinases and BRAF V600E with NCI-60 responses to specific categories of natural products. Hierarchical clustering identified groups of natural products, which correlated with a specific mechanism of action. Specifically, several natural product clusters were associated with SLFN11 gene expression, suggesting that potential action of these compounds may involve DNA damage. The associations between gene expression or genome alterations of functionally relevant genes with the response of cancer cells to natural products provide new information about potential mechanisms of action of these identified clusters of compounds with potentially similar biological effects. This information will assist in future drug discovery and in design of new targeted cancer chemotherapy agents.
Subject(s)
Antineoplastic Agents/pharmacology , Biological Products/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Neoplasm Proteins , Neoplasms , RNA, Neoplasm , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , RNA, Neoplasm/biosynthesis , RNA, Neoplasm/geneticsABSTRACT
Liquid biopsy, particularly the analysis of circulating tumor DNA (ctDNA), has demonstrated considerable promise for numerous clinical intended uses. Successful validation and commercialization of novel ctDNA tests have the potential to improve the outcomes of patients with cancer. The goal of the Blood Profiling Atlas Consortium (BloodPAC) is to accelerate the development and validation of liquid biopsy assays that will be introduced into the clinic. To accomplish this goal, the BloodPAC conducts research in the following areas: Data Collection and Analysis within the BloodPAC Data Commons; Preanalytical Variables; Analytical Variables; Patient Context Variables; and Reimbursement. In this document, the BloodPAC's Analytical Variables Working Group (AV WG) attempts to define a set of generic analytical validation protocols tailored for ctDNA-based Next-Generation Sequencing (NGS) assays. Analytical validation of ctDNA assays poses several unique challenges that primarily arise from the fact that very few tumor-derived DNA molecules may be present in circulation relative to the amount of nontumor-derived cell-free DNA (cfDNA). These challenges include the exquisite level of sensitivity and specificity needed to detect ctDNA, the potential for false negatives in detecting these rare molecules, and the increased reliance on contrived samples to attain sufficient ctDNA for analytical validation. By addressing these unique challenges, the BloodPAC hopes to expedite sponsors' presubmission discussions with the Food and Drug Administration (FDA) with the protocols presented herein. By sharing best practices with the broader community, this work may also save the time and capacity of FDA reviewers through increased efficiency.
Subject(s)
Biomarkers, Tumor/blood , Circulating Tumor DNA/blood , Guidelines as Topic , High-Throughput Nucleotide Sequencing/standards , Humans , Liquid Biopsy , Neoplasms/blood , Neoplasms/pathology , Reference Standards , Validation Studies as TopicABSTRACT
In recent years, cancer immunotherapy has emerged as a highly promising approach to treat patients with cancer, as the patient's own immune system is harnessed to attack cancer cells. However, the application of these approaches is still limited to a minority of patients with cancer and it is difficult to predict which patients will derive the greatest clinical benefit.One of the challenges faced by the biomedical community in the search of more effective biomarkers is the fact that translational research efforts involve collecting and accessing data at many different levels: from the type of material examined (e.g., cell line, animal models, clinical samples) to multiple data type (e.g., pharmacodynamic markers, genetic sequencing data) to the scale of a study (e.g., small preclinical study, moderate retrospective study on stored specimen sets, clinical trials with large cohorts).This chapter reviews several publicly available bioinformatics tools and data resources for high throughput molecular analyses applied to a range of data types, including those generated from microarray, whole-exome sequencing (WES), RNA-seq, DNA copy number, and DNA methylation assays, that are extensively used for integrative multidimensional data analysis and visualization.
Subject(s)
Biomarkers, Tumor/genetics , Computational Biology/methods , Neoplasms/genetics , DNA Copy Number Variations , DNA Mutational Analysis , Gene Expression Regulation, Neoplastic , High-Throughput Nucleotide Sequencing , Humans , Retrospective Studies , Software , Exome SequencingABSTRACT
Oncology clinical trials are undergoing transformation to evaluate targeted therapies addressing a wider variety of biologically defined cancer subgroups. Multiarm basket and umbrella trials conducted under master protocols have become more prominent mechanisms for the clinical evaluation of promising new biologically driven anticancer therapies that are integral to precision oncology medicine. These new trial designs permit efficient clinical evaluation of multiple therapies in a variety of histologically and biologically defined cancers. These complex trials require extensive planning and attention to many factors, including choice of biomarker assay platform, mechanism for processing clinicopathologic and biomarker data to assign patients to substudies, and statistical design, monitoring, and analysis of substudies. Trial teams have expanded to include expertise in the interface between biology, clinical oncology, bioinformatics, and statistics. Strategies for the design, conduct, and analysis of these complex trials will continue to evolve to meet new challenges and opportunities in precision oncology medicine.
Subject(s)
Biostatistics , Clinical Trials as Topic , Medical Oncology , Precision Medicine , Research Design , Biomarkers, Tumor , Biostatistics/methods , Data Interpretation, Statistical , Humans , Medical Oncology/methods , Medical Oncology/standards , Precision Medicine/methods , Precision Medicine/standardsABSTRACT
Biomarkers are frequently being included in early-phase clinical trials. This article is meant to introduce clinical investigators to the fundamentals of choosing a biomarker test for use in an early phase trial. Steps to consider are briefly outlined including defining the role of the biomarker in the early phase trial; selecting a fit-for-purpose biomarker test and laboratory; describing the test procedures; carrying out analytical validation testing appropriate for the research objectives and the risk involved in the trial; implementing the test in the trial; and planning for the future. Examples illustrate analytical validation approaches in the context of typical biomarker roles. The importance of collaboration between clinical investigators and laboratory researchers is emphasized.
Subject(s)
Biological Assay/standards , Clinical Trials as Topic , Research Design , Validation Studies as Topic , Biomarkers/analysis , Guidelines as Topic , Humans , Patient Safety , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Time between recurrent medical events may be correlated with the cost incurred at each event. As a result, it may be of interest to describe the relationship between recurrent events and recurrent medical costs by estimating a joint distribution. In this paper, we propose a nonparametric estimator for the joint distribution of recurrent events and recurrent medical costs in right-censored data. We also derive the asymptotic variance of our estimator, a test for equality of recurrent marker distributions, and present simulation studies to demonstrate the performance of our point and variance estimators. Our estimator is shown to perform well for a wide range of levels of correlation, demonstrating that our estimators can be employed in a variety of situations when the correlation structure may be unknown in advance. We apply our methods to hospitalization events and their corresponding costs in the second Multicenter Automatic Defibrillator Implantation Trial (MADIT-II), which was a randomized clinical trial studying the effect of implantable cardioverter-defibrillators in preventing ventricular arrhythmia.
Subject(s)
Defibrillators, Implantable , Randomized Controlled Trials as Topic , Survival Analysis , Humans , Research DesignABSTRACT
OBJECTIVES: To determine whether lifestyle factors, measured late in life, could compress the disabled period toward the end of life. DESIGN: Community-based cohort study of older adults followed from 1989 to 2015. SETTING: Four U.S. communities. PARTICIPANTS: Community-living men and women aged 65 and older (N = 5,248, mean age 72.7 ± 5.5, 57% female, 15.2% minority) who were not wheelchair dependent and were able to give informed consent at baseline. MEASUREMENTS: Multiple lifestyle factors, including smoking, alcohol consumption, physical activity, diet, body mass index (BMI), social networks, and social support, were measured at baseline. Activities of daily living (ADLs) were assessed at baseline and throughout follow-up. Years of life (YoL) was defined as years until death. Years of able life (YAL) was defined as years without any ADL difficulty. YAL/YoL%, the proportion of life lived able, was used to indicate the relative compression or expansion of the disabled period. RESULTS: The average duration of disabled years was 4.5 (out of 15.4 mean YoL) for women and 2.9 (out of 12.4 mean YoL) for men. In a multivariable model, obesity was associated with 7.3 percentage points (95% confidence interval (CI) = 5.4-9.2) lower YAL/YoL% than normal weight. Scores in the lowest quintile of the Alternate Healthy Eating Index were associated with a 3.7% (95% CI = 1.6-5.9) lower YAL/YoL% than scores in the highest quintile. Every 25 blocks walked in a week was associated with 0.5 percentage points (95% CI = 0.3-0.8) higher YAL/YoL%. CONCLUSION: The effects of healthy lifestyle factors on the proportion of future life lived free of disability indicate that the disabled period can be compressed, given the right combination of these factors.
Subject(s)
Activities of Daily Living , Aging , Diet, Healthy , Healthy Lifestyle/physiology , Obesity , Smoking/epidemiology , Aged , Aging/physiology , Aging/psychology , Body Mass Index , Diet, Healthy/methods , Diet, Healthy/statistics & numerical data , Disability Evaluation , Exercise , Female , Humans , Life Expectancy , Male , Obesity/diagnosis , Obesity/epidemiology , Quality-Adjusted Life Years , Social Support , United States/epidemiologyABSTRACT
Various anthropometric measures, including height, have been associated with atrial fibrillation (AF). This raises questions about the appropriateness of using ratio measures such as body mass index (BMI), which contains height squared in its denominator, in the evaluation of AF risk. Among older adults, the optimal anthropometric approach to risk stratification of AF remains uncertain. Anthropometric and bioelectrical impedance measures were obtained from 4,276 participants (mean age = 72.4 years) free of cardiovascular disease in the Cardiovascular Health Study. During follow-up (1989-2008), 1,050 cases of AF occurred. BMI showed a U-shaped association, whereas height, weight, waist circumference, hip circumference, fat mass, and fat-free mass were linearly related to incident AF. The strongest adjusted association occurred for height (per each 1-standard-deviation increment, hazard ratio = 1.38, 95% confidence interval: 1.25, 1.51), which exceeded all other measures, including weight (hazard ratio = 1.21, 95% confidence interval: 1.13, 1.29). Combined assessment of log-transformed weight and height showed regression coefficients that departed from the 1 to -2 ratio inherent in BMI, indicating a loss of predictive information. Risk estimates for AF tended to be stronger for hip circumference than for waist circumference and for fat-free mass than for fat mass, which was explained largely by height. These findings highlight the prominent role of body size and the inadequacy of BMI as determinants of AF in older adults.
Subject(s)
Atrial Fibrillation/epidemiology , Body Weights and Measures/statistics & numerical data , Black or African American/statistics & numerical data , Aged , Aged, 80 and over , Atrial Fibrillation/ethnology , Blood Glucose , Blood Pressure , Body Height , Body Mass Index , Electrocardiography , Exercise , Female , Health Behavior , Humans , Lipids/blood , Male , Proportional Hazards Models , Prospective Studies , Risk Factors , Sex FactorsABSTRACT
OBJECTIVE: Longevity fails to account for health and functional status during aging. We sought to quantify differences in years of total life, years of healthy life, and years of able life among groups defined by age, sex, and race. DESIGN: Primary analysis of a cohort study. SETTING: 18 years of annual evaluations in four U.S. communities. PARTICIPANTS: 5888 men and women aged 65 and older. MEASUREMENTS: Years of life were calculated as the time from enrollment to death or 18 years. Years of total, healthy, and able life were determined from self-report during annual or semi-annual contacts. Cumulative years were summed across each of the age and sex groups. RESULTS: White women had the best outcomes for all three measures, followed by white men, non-white women, and non-white men. For example, at the mean age of 73, a white female participant could expect 12.9 years of life, 8.9 of healthy life and 9.5 of able life, while a non-white female could expect 12.6, 7.0, and 8.0 years, respectively. A white male could expect 11.2, 8.1, and 8.9 years of life, healthy life, and able life, and a non-white male 10.3, 6.2, and 7.9 years. Regardless of starting age, individuals of the same race and sex groups spent similar amounts (not proportions) of time in an unhealthy or unable state. CONCLUSION: Gender had a greater effect on longevity than did race, but race had a greater effect on years spent healthy or able. The mean number of years spent in an unable or sick state was surprisingly independent of the lifespan.
ABSTRACT
Mutations in genes encoding cilia proteins cause human ciliopathies, diverse disorders affecting many tissues. Individual genes can be linked to ciliopathies with dramatically different phenotypes, suggesting that genetic modifiers may participate in their pathogenesis. The ciliary transition zone contains two protein complexes affected in the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP). The BBSome is a third protein complex, affected in the ciliopathy Bardet-Biedl syndrome (BBS). We tested whether mutations in MKS, NPHP and BBS complex genes modify the phenotypic consequences of one another in both C. elegans and mice. To this end, we identified TCTN-1, the C. elegans ortholog of vertebrate MKS complex components called Tectonics, as an evolutionarily conserved transition zone protein. Neither disruption of TCTN-1 alone or together with MKS complex components abrogated ciliary structure in C. elegans. In contrast, disruption of TCTN-1 together with either of two NPHP complex components, NPHP-1 or NPHP-4, compromised ciliary structure. Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did. As in nematodes, disrupting two components of the mouse MKS complex did not cause additive phenotypes compared to single mutants. However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1. Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.
Subject(s)
Cilia/genetics , Signal Transduction , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cilia/metabolism , HumansABSTRACT
As the costs of medical care increase, more studies are evaluating cost in addition to effectiveness of treatments. Cost-effectiveness analyses in randomized clinical trials have typically been conducted only at the end of follow-up. However, cost-effectiveness may change over time. We therefore propose a nonparametric estimator to assess the incremental cost-effectiveness ratio over time. We also derive the asymptotic variance of our estimator and present formulation of Fieller-based simultaneous confidence bands. Simulation studies demonstrate the performance of our point estimators, variance estimators, and confidence bands. We also illustrate our methods using data from a randomized clinical trial, the second Multicenter Automatic Defibrillator Implantation Trial. This trial studied the effects of implantable cardioverter-defibrillators on patients at high risk for cardiac arrhythmia. Results show that our estimator performs well in large samples, indicating promising future directions in the field of cost-effectiveness. Copyright © 2015 John Wiley & Sons, Ltd.
Subject(s)
Cost-Benefit Analysis/statistics & numerical data , Biostatistics , Computer Simulation , Confidence Intervals , Death, Sudden, Cardiac/prevention & control , Defibrillators, Implantable , Humans , Multicenter Studies as Topic/statistics & numerical data , Randomized Controlled Trials as Topic/economics , Randomized Controlled Trials as Topic/statistics & numerical data , Statistics, Nonparametric , Survival AnalysisABSTRACT
BACKGROUND: As the U.S. population grows older, there is greater need to examine physical independence. Previous studies have assessed risk factors in relation to either disability or mortality, but an outcome that combines both is still needed. METHODS AND RESULTS: The Cardiovascular Health Study is a population-based, prospective study where participants underwent baseline echocardiogram, measurement of carotid intima-media thickness (IMT), and various biomarkers, then followed for up to 18 years. Years of able life (YAL) constituted the number of years the participant was able to perform all activities of daily living. Linear regression was used to model the relationship between selected measures and outcomes, adjusted for confounding variables. Among 4902 participants, mean age was 72.6 ± 5.4 years, median YAL for males was 8.8 (interquartile range [IQR], 4.3 to 13.8) and 10.3 (IQR, 5.8 to 15.8) for females. Reductions in YAL in the fully adjusted model for females and males, respectively, were: -1.34 (95% confidence interval [CI], -2.18, -0.49) and -1.41 (95% CI, -2.03, -0.8) for abnormal left ventricular (LV) ejection fraction, -0.5 (95% CI, -0.78, -0.22) and -0.62 (95% CI, -0.87, -0.36) per SD increase in LV mass, -0.5 (95% CI, -0.7, -0.29) and -0.79 (95% CI, -0.99, -0.58) for IMT, -0.5 (95% CI, -0.64, -0.37) and -0.79 (95% CI, -0.94, -0.65) for N-terminal pro-brain natriuretic peptide, -1.08 (95% CI, -1.34, -0.83) and -0.73 (95% CI, -0.97, -0.5) for high-sensitivity troponin-T, and -0.26 (95% CI, -0.42, -0.09) and -0.23 (95% CI, -0.41, -0.05) for procollagen-III N-terminal propeptide. Most tested variables remained significant even after adjusting for incident cardiovascular (CV) disease. CONCLUSIONS: In this population-based cohort, variables obtained by CV imaging and biomarkers of inflammation, coagulation, atherosclerosis, myocardial injury and stress, and cardiac collagen turnover were associated with YAL, an important outcome that integrates physical ability and longevity in older persons.
Subject(s)
Carotid Intima-Media Thickness/statistics & numerical data , Echocardiography , Independent Living/statistics & numerical data , Activities of Daily Living , Aged , Biomarkers/blood , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Female , Humans , Male , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Procollagen/blood , Prospective Studies , Stroke Volume , Troponin I/bloodABSTRACT
Reporting recently in Nature Cell Biology, Lu et al. (2015) identify two Eps15-homology-domain-containing proteins as critical effectors of ciliary vesicle formation, an early event in ciliogenesis. Functional dissection reveals that one of them works to convert small vesicles associated with mother centriole distal appendages into a larger ciliary vesicle.
Subject(s)
Carrier Proteins/genetics , Cilia/metabolism , Epithelial Cells/metabolism , Gene Expression Regulation, Developmental , Transport Vesicles/metabolism , Vesicular Transport Proteins/genetics , Animals , HumansABSTRACT
Objective: To create personalized estimates of future health and ability status for older adults. Method: Data came from the Cardiovascular Health Study (CHS), a large longitudinal study. Outcomes included years of life, years of healthy life (based on self-rated health), years of able life (based on activities of daily living), and years of healthy and able life. We developed regression estimates using the demographic and health characteristics that best predicted the four outcomes. Internal and external validity were assessed. Results: A prediction equation based on 11 variables accounted for about 40% of the variability for each outcome. Internal validity was excellent, and external validity was satisfactory. The resulting CHS Healthy Life Calculator (CHSHLC) is available at http://healthylifecalculator.org. Conclusion: CHSHLC provides a well-documented estimate of future years of healthy and able life for older adults, who may use it in planning for the future.
ABSTRACT
OBJECTIVES: To determine whether elderly people with different patterns of magnetic resonance imaging (MRI) findings have different long-term outcomes. DESIGN: Longitudinal cohort study. SETTING: Cardiovascular Health Study. PARTICIPANTS: Individuals aged 65 and older were recruited (N = 5,888); 3,660 of these underwent MRI, and 3,230 without a stroke before MRI were included in these analyses. MEASUREMENTS: Cluster analysis of brain MRI findings was previously used to define five clusters: normal, atrophy, simple infarct, leukoaraiosis, and complex infarct. Participants were subsequently classified as healthy if they rated their health as excellent, very good, or good and as able if they did not report any limitations in activities of daily living (ADLs). Mean years of life (YoL), years of healthy life (YHL), and years of able life (YAL) were calculated over 16 years after the MRI and compared between clusters using unadjusted and adjusted regression analyses. RESULTS: Mean age of participants was 75.0. With 16 years of follow-up, mean YoL was 11.3; YHL, 8.0; and YAL, 8.4. Outcomes differed significantly between clusters. With or without adjustments, outcomes were all significantly better in the normal than complex infarct cluster. The three remaining clusters had intermediate results, significantly different from the normal and complex infarct clusters but not usually from one another. Over 16 years of follow-up, participants in the complex infarct cluster (n = 368) spent the largest percentage of their 8.4 years alive being sick (38%) and not able (38%). CONCLUSION: Findings on MRI scans in elderly adults are associated not only with long-term survival, but also with long-term self-rated health and limitation in ADLs. The combination of infarcts and leukoaraiosis carried the worst prognosis, presumably reflecting small vessel disease.