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Cornelia M. Van Duijn - One of the best experts on this subject based on the ideXlab platform.

  • Genetic Risk of Parkinson's disease in the general population.
    Parkinsonism & related disorders, 2016
    Co-Authors: Sirwan K.l. Darweesh, Cornelia M. Van Duijn, Vincentius J.a. Verlinden, Hieab H.h. Adams, André G. Uitterlinden, Albert Hofman, Bruno H. Stricker, Peter J. Koudstaal, M. Arfan Ikram
    Abstract:

    Abstract Introduction We investigated whether a Risk score based on Genetic Risk variants for Parkinson’s disease (PD) is associated with the Risk and improves prediction of incident PD, and whether the Risk score is associated with basic activities of daily living (BADL) in healthy individuals. Methods Within the population-based Rotterdam Study, we genotyped 26 independent Risk variants for PD and constructed a Genetic Risk score in 7167 participants who were free of parkinsonism and dementia at baseline (1990 or 2000). Participants were followed for a maximum of twenty years for the onset of parkinsonism, dementia or death until January 1, 2011 (median follow-up 12.1 years). We studied the relationship between the Genetic Risk score and incident PD with adjustment for age, sex, smoking and parental history. In an independent sample of 2997 persons free of parkinsonism and dementia, we studied whether the PD Risk score was associated with impaired BADL. Results During follow-up (median 12.1 years), 99 persons were diagnosed with incident PD. The Genetic Risk score was associated with incident PD (hazard ratio per standard deviation Risk 1.25 [95% confidence interval = 1.02; 1.55]), but did not substantially improve prediction (change in C-statistic 0.687 [0.628; 0.745] to 0.698 [0.635; 0.760], ΔC = 0.011 [−0.011; 0.033]). The Genetic Risk score was associated with a higher probability of any impairment in BADL (odds ratio = 1.11 [1.00; 1.23]). Conclusion Genetic variants for PD are associated with the Risk of incident PD in the general population and with impairment in daily functioning in individuals without clinical parkinsonism, but do not improve the clinical prediction of PD. However, we were probably underpowered to detect a small improvement in PD prediction.

  • Genetic Risk of Parkinson Disease in the General Population (P6.373)
    Neurology, 2016
    Co-Authors: Sirwan K.l. Darweesh, Cornelia M. Van Duijn, Vincentius J.a. Verlinden, Hieab H.h. Adams, André G. Uitterlinden, Albert Hofman, Bruno H. Stricker, Peter J. Koudstaal, Mohammad Arfan Ikram
    Abstract:

    Background: Recent genome-wide association studies have identified 28 independent Risk variants for Parkinson Disease (PD), but their clinical relevance remains unknown. We investigated whether a Genetic Risk score based on these variants is associated with the Risk of incident PD, and whether the Risk score improves prediction of PD. We also studied whether the Risk score is associated with basic activities of daily living (BADL) in healthy individuals. Methods: Within the population-based Rotterdam Study, we genotyped 26 independent Genetic Risk variants for PD and constructed a Genetic Risk score in 7167 participants who were free of parkinsonism and dementia at baseline (1990 or 2000). Participants were followed for a maximum of twenty years for the onset of parkinsonism, dementia or death until January 1, 2011 (median follow-up 12.1 years). We used cox proportional hazard models and C-statistics to study the relationship between the Genetic Risk score and incident PD, adding the Risk score to age, sex, smoking and parental history. In an independent sample of 2997 persons free of parkinsonism and dementia, we studied whether the PD Risk genes were associated with impaired BADL. Results: The Genetic Risk score was associated with incident PD (hazard ratio per standard deviation Risk 1.25 [95[percnt] confidence interval=1.02;1.55]), but did not substantially improve prediction (change in C=0.011 [-0.011;0.033]). The Genetic Risk score was associated with a higher probability of any impairment in BADL (odds ratio=1.11 [1.00;1.23]). Conclusions: Genetic variants for PD are associated with the Risk of incident PD in the general population and with impairment in daily functioning in individuals without clinical parkinsonism, but do not improve the clinical prediction of PD. Disclosure: Dr. Darweesh has nothing to disclose. Dr. Verlinden has nothing to disclose. Dr. Adams has nothing to disclose. Dr. Uitterlinden has nothing to disclose. Dr. Hofman has nothing to disclose. Dr. Stricker has nothing to disclose. Dr. Van Duijn has nothing to disclose. Dr. Koudstaal has nothing to disclose. Dr. Ikram has nothing to disclose.

  • Scientific reporting is suboptimal for aspects that characterize Genetic Risk prediction studies: a review of published articles based on the Genetic Risk Prediction Studies statement
    Journal of clinical epidemiology, 2014
    Co-Authors: Adriana I. Iglesias, John P. A. Ioannidis, Raluca Mihaescu, Muin J. Khoury, Julian Little, Cornelia M. Van Duijn, A. Cecile J.w. Janssens
    Abstract:

    Abstract Objectives Our main objective was to raise awareness of the areas that need improvements in the reporting of Genetic Risk prediction articles for future publications, based on the Genetic Risk Prediction Studies (GRIPS) statement. Study Design and Setting We evaluated studies that developed or validated a prediction model based on multiple DNA variants, using empirical data, and were published in 2010. A data extraction form based on the 25 items of the GRIPS statement was created and piloted. Results Forty-two studies met our inclusion criteria. Overall, more than half of the evaluated items (34 of 62) were reported in at least 85% of included articles. Seventy-seven percentage of the articles were identified as Genetic Risk prediction studies through title assessment, but only 31% used the keywords recommended by GRIPS in the title or abstract. Seventy-four percentage mentioned which allele was the Risk variant. Overall, only 10% of the articles reported all essential items needed to perform external validation of the Risk model. Conclusion Completeness of reporting in Genetic Risk prediction studies is adequate for general elements of study design but is suboptimal for several aspects that characterize Genetic Risk prediction studies such as description of the model construction. Improvements in the transparency of reporting of these aspects would facilitate the identification, replication, and application of Genetic Risk prediction models.

  • Strengthening the Reporting of Genetic Risk Prediction Studies: The GRIPS Statement
    Circulation. Cardiovascular genetics, 2011
    Co-Authors: A. Cecile J.w. Janssens, John P. A. Ioannidis, Julian Little, Cornelia M. Van Duijn, Muin J. Khoury
    Abstract:

    The recent successes of genome-wide association studies and the promises of whole genome sequencing fuel interest in the translation of this new wave of basic Genetic knowledge to health care practice. Knowledge about Genetic Risk factors may be used to target diagnostic, preventive, and therapeutic interventions for complex disorders based on a person's Genetic Risk, or to complement existing Risk models based on classical nonGenetic factors, such as the Framingham Risk score for cardiovascular disease. Implementation of Genetic Risk prediction in health care requires a series of studies that encompass all phases of translational research,1,2 starting with a comprehensive evaluation of Genetic Risk prediction. With increasing numbers of discovered Genetic markers that can be used in future Genetic Risk prediction studies, it is crucial to enhance the quality of the reporting of these studies, since valid interpretation could be compromised by the lack of reporting of key information. Information that is often missing includes details in the description of how the study was designed and conducted (eg, how Genetic variants were selected and coded, how Risk models or Genetic Risk scores were constructed, and how Risk categories were chosen), or how the results should be interpreted. An appropriate assessment of the study's strengths and weaknesses is not possible without this information. There is ample evidence that prediction research often suffers from poor design and bias, and these may also have an impact on the results of the studies and on models of disease outcomes based on these studies.3–5 Although most prognostic studies published to date claim significant results,6,7 very few translate to clinically useful applications. Just as for observational epidemiological studies,8 poor reporting complicates the use of the specific study for research, clinical, or public health purposes and hampers the …

  • strengthening the reporting of Genetic Risk prediction studies the grips statement
    Annals of Internal Medicine, 2011
    Co-Authors: Cecile A J W Janssens, John P. A. Ioannidis, Julian Little, Cornelia M. Van Duijn, Muin J. Khoury
    Abstract:

    Guidelines for reporting various research designs have been published, but none is fully suited to Genetic Risk prediction studies, an emerging field of investigation with specific methodological c...

Cristina Hotoleanu - One of the best experts on this subject based on the ideXlab platform.

Johan Elf - One of the best experts on this subject based on the ideXlab platform.

Anders M. Dale - One of the best experts on this subject based on the ideXlab platform.

  • Genetic Risk for coronary heart disease alters the influence of Alzheimer's Genetic Risk on mild cognitive impairment.
    Neurobiology of aging, 2019
    Co-Authors: Jeremy A. Elman, Matthew S. Panizzon, Mark W. Logue, Nathan A. Gillespie, Michael C. Neale, Chandra A. Reynolds, Daniel E. Gustavson, Brinda K. Rana, Ole A. Andreassen, Anders M. Dale
    Abstract:

    Abstract Understanding Genetic influences on Alzheimer's disease (AD) may improve early identification. AD polygenic Risk scores (AD-PRSs) are associated with increased odds of AD and mild cognitive impairment (MCI). Additional sources of Genetic Risk may also contribute to disease outcomes. Coronary artery disease (CAD) is a Risk factor for AD, interacts with AD pathology, and is also heritable. We showed that incidence-based and prevalence-based CAD-PRSs moderate the association between the AD-PRS and MCI, but in opposing directions. Higher incidence-based CAD-PRSs interacted with the AD-PRS to further increase MCI Risk. Conversely, the AD-PRS was predictive of MCI when prevalence-based CAD-PRSs were low. The latter finding is likely due to prevalent CAD cases being biased toward longer postevent survival times, perhaps selecting for protective loci that offset AD Risk. These results demonstrate (1) the importance of examining multiple PRSs and their interactions; (2) how Genetic Risk for one disease can modify the impact of Genetic Risk for another; and (3) the importance of considering ascertainment procedures of GWAS used for Genetic Risk prediction.

  • Genetic Risk for coronary heart disease alters the influence of Alzheimer's Genetic Risk on mild cognitive impairment
    2018
    Co-Authors: Jeremy A. Elman, Matthew S. Panizzon, Mark W. Logue, Nathan A. Gillespie, Michael C. Neale, Chandra A. Reynolds, Daniel E. Gustavson, Ole A. Andreassen, Anders M. Dale, Carol E. Franz
    Abstract:

    Alzheimer's disease (AD) is under considerable Genetic influence. We previously found that an AD polygenic Risk score (PRS) was significantly associated with mild cognitive impairment (MCI), an early stage of AD. However, known susceptibility loci only explain a modest proportion of variance in MCI and AD outcomes. This small proportion could occur if the etiology of AD is heterogeneous. Poor cardiovascular health is also associated with increased Risk for AD and has been found to interact with AD pathology. Conditions such as coronary artery disease (CAD) are also heritable, therefore we were interested in whether there are interactions between Genetic Risk for CAD and AD as there is phenotypically. A potential problem with this approach is that case-control designs based on prevalent cases of a disease with relatively high case-fatality rate (such as CAD) may be biased toward individuals who have long post-event survival times. Genome-wide association studies (GWAS) of prevalent cases may potentially identify protective Risk loci. Therefore, we tested two CAD-PRSs: one based on a GWAS of incident cases and one on prevalent cases. As expected, the incidence-based CAD-PRS interacts with the AD-PRS to further increase MCI Risk. Conversely, higher prevalence-based CAD-PRSs reduced the effect of AD Genetic Risk on MCI status. These results demonstrate: i) the utility of including multiple PRSs and their interaction effects; ii) how Genetic Risk for one disease may modify the impact of Genetic Risk for another; and iii) the importance of considering ascertainment procedures of GWAS being used for Genetic Risk prediction.

Robert Roberts - One of the best experts on this subject based on the ideXlab platform.

  • Genetic Risk Stratification: Tipping Point for Global Primary Prevention of Coronary Artery Disease.
    Circulation, 2018
    Co-Authors: Robert Roberts
    Abstract:

    In 2003, Wald and Law1 predicted that coronary artery disease (CAD) would be markedly attenuated if not eliminated. CAD is a preventable disease based on randomized, placebo-controlled clinical trials that consistently showed 30% to 40% reduction in cardiac events with decreased plasma cholesterol.1 Epidemiologists claimed for decades that 40% to 50% of predisposition for CAD is Genetic. Discovery of the first Genetic Risk variant in 2007 has led to an avalanche of >90 Genetic Risk variants predisposing to CAD, each of genome-wide significance and replicated in independent populations,2 but each with relatively low individual effect sizes. The total individual Genetic Risk burden for CAD is proportional to the number of Genetic Risk variants inherited. These variants account for ≈25% of Genetic predisposition to CAD, which is less than the predicted 40%, signaling that more Genetic Risk variants are yet to be discovered. It is interesting to note that only one third of the Genetic Risk variants for CAD mediate their Risk through known conventional Risk factors. Exploration of the unknown pathways mediating the Risk conferred by these Genetic variants is already enabling new insights into the pathogenesis of coronary atherosclerosis (eg, inflammation, lack of protection of high-density lipoprotein cholesterol) and novel targets for the development of specific drugs. A major impetus for our pursuit of Genetic Risk variants was to better predict those at higher Risk for CAD who would benefit most from preventive measures, particularly primary prevention. The Genetic …

  • The Role of Genetic Risk Factors in Coronary Artery Disease
    Current Cardiology Reports, 2014
    Co-Authors: Sonny Dandona, Robert Roberts
    Abstract:

    Genome-wide association studies for coronary artery disease utilizing the case control association study approach has identified 50 Genetic Risk variants associated with coronary artery disease or myocardial infarction. All of these Genetic variants are of genome wide significance and replicated in an independent population. It is of note that 35 of these 50 Genetic Risk variants act through mechanisms as yet unknown. These findings have great implications for the pathogenesis of atherosclerosis, as well as new targets for the development of novel therapies for the prevention and treatment of CAD. The Genetic variant PCSK9 has already led to the development of a monoclonal anti-body which is undergoing assessment in phases I, II, and III clinical trials. This therapy shows very promising results and since it increases removal of LDL-C, it is complementary to current statin therapy. Assessing the beneficial or deleterious effects of a lifelong exposure to a Genetic Risk variant (Mendelian randomization) will be an important adjunct to clinical trials.