| 1. |
- Thompson, Paul M., et al.
(author)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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In: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Journal article (peer-reviewed)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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| 2. |
- Scholl, Ute I, et al.
(author)
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Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:9, s. 1050-1054
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Journal article (peer-reviewed)abstract
- Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca2+ influx cause ~40% of these tumors1. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca2+ influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa2. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca2+ channel mutations in APAs and primary aldosteronism.
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| 3. |
- Auerswald, Guenter, et al.
(author)
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Beyond patient benefit: clinical development in hemophilia
- 2012
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In: Hematology. - 1607-8454. ; 17:1, s. 1-8
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Research review (peer-reviewed)abstract
- Historically in hemophilia, outcome measures have not been collected systematically. Hence, there are insufficient clearly defined, evidence-based measures that can be applied consistently across hemophilia trials. This review focuses on some key challenges to evaluating patient outcomes and performing trials identified by experts at the Fourth and Fifth Zurich Haemophilia Forums. As procedures appear inconsistent across Europe, guidelines require modification to be more appropriate and/or realistically achievable. The outcome measures utilized, and the timing of their collection, should also be standardized, and more objective measures used where feasible. Implementation of outcome measures could be refined through greater understanding of patient heterogeneity, and tailored to differentiate between hemophilia- and aging-related disease effects. Furthermore, robust outcome measures that can also inform health-economic decisions are increasingly needed. Lastly, as patient recruitment poses a challenge, the panel proposed a call for action to motivate physicians and patients to participate in clinical trials.
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| 4. |
- Benson, Barbara J., et al.
(author)
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Extreme events, trends, and variability in Northern Hemisphere lake-ice phenology (1855-2005)
- 2012
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In: Climatic Change. - : Springer Science and Business Media LLC. - 0165-0009 .- 1573-1480. ; 112:2, s. 299-323
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Journal article (peer-reviewed)abstract
- Often extreme events, more than changes in mean conditions, have the greatest impact on the environment and human well-being. Here we examine changes in the occurrence of extremes in the timing of the annual formation and disappearance of lake ice in the Northern Hemisphere. Both changes in the mean condition and in variability around the mean condition can alter the probability of extreme events. Using long-term ice phenology data covering two periods 1855-6 to 2004-5 and 1905-6 to 2004-5 for a total of 75 lakes, we examined patterns in long-term trends and variability in the context of understanding the occurrence of extreme events. We also examined patterns in trends for a 30-year subset (1975-6 to 2004-5) of the 100-year data set. Trends for ice variables in the recent 30-year period were steeper than those in the 100- and 150-year periods, and trends in the 150-year period were steeper than in the 100-year period. Ranges of rates of change (days per decade) among time periods based on linear regression were 0.3-1.6 later for freeze, 0.5-1.9 earlier for breakup, and 0.7-4.3 shorter for duration. Mostly, standard deviation did not change, or it decreased in the 150-year and 100-year periods. During the recent 50-year period, standard deviation calculated in 10-year windows increased for all ice measures. For the 150-year and 100-year periods changes in the mean ice dates rather than changes in variability most strongly influenced the significant increases in the frequency of extreme lake ice events associated with warmer conditions and decreases in the frequency of extreme events associated with cooler conditions.
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| 5. |
- Jay, Jeremy J., et al.
(author)
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A systematic comparison of genome-scale clustering algorithms
- 2012
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In: BMC Bioinformatics. - : BioMed Central. - 1471-2105. ; 13
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Journal article (peer-reviewed)abstract
- Background: A wealth of clustering algorithms has been applied to gene co-expression experiments. These algorithms cover a broad range of approaches, from conventional techniques such as k-means and hierarchical clustering, to graphical approaches such as k-clique communities, weighted gene co-expression networks (WGCNA) and paraclique. Comparison of these methods to evaluate their relative effectiveness provides guidance to algorithm selection, development and implementation. Most prior work on comparative clustering evaluation has focused on parametric methods. Graph theoretical methods are recent additions to the tool set for the global analysis and decomposition of microarray co-expression matrices that have not generally been included in earlier methodological comparisons. In the present study, a variety of parametric and graph theoretical clustering algorithms are compared using well-characterized transcriptomic data at a genome scale from Saccharomyces cerevisiae. Methods: For each clustering method under study, a variety of parameters were tested. Jaccard similarity was used to measure each clusters agreement with every GO and KEGG annotation set, and the highest Jaccard score was assigned to the cluster. Clusters were grouped into small, medium, and large bins, and the Jaccard score of the top five scoring clusters in each bin were averaged and reported as the best average top 5 (BAT5) score for the particular method. Results: Clusters produced by each method were evaluated based upon the positive match to known pathways. This produces a readily interpretable ranking of the relative effectiveness of clustering on the genes. Methods were also tested to determine whether they were able to identify clusters consistent with those identified by other clustering methods. Conclusions: Validation of clusters against known gene classifications demonstrate that for this data, graph-based techniques outperform conventional clustering approaches, suggesting that further development and application of combinatorial strategies is warranted.
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| 6. |
- Stangou, Arie J, et al.
(author)
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Solid organ transplantation for non-TTR hereditary amyloidosis : report from the 1st International Workshop on the Hereditary Renal Amyloidoses
- 2012
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In: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 19:S1, s. 81-84
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Journal article (peer-reviewed)abstract
- Fibrinogen A alpha-chain (AFib) and apolipoprotein AI (AApoAI) amyloidosis due to variants in the AFib and ApoAI genes are the most common types of hereditary amyloidosis in Europe and the United States. Liver is the exclusive source of the aberrant amyloidogenic protein in AFib and responsible for supplying approximately half of the circulating variant ApoAI. Nephrotic syndrome and renal impairment due to renal amyloidosis are common disease manifestations; however, recent research provides evidence to support a more diverse and systemic disease phenotype, which in turn has implications in the management of the hereditary amyloidoses with solid organ transplantation and, in particular, liver transplantation.
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| 7. |
- Weyhenmeyer, Gesa, et al.
(author)
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Large geographical differences in the sensitivity of ice-covered lakes and rivers in the Northern Hemisphere to temperature changes
- 2011
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 17:1, s. 268-275
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Journal article (peer-reviewed)abstract
- Based on a unique dataset of more than 50 000 observations of ice phenology from 1213 lakes and 236 rivers in 12 different countries, we show that interannual variations in the timing of ice-on and ice-off on lakes and rivers are not equally pronounced over the entire Northern Hemisphere, but increase strongly towards geographical regions that experience only short periods during which the air temperature falls below 0 degrees C. We explain our observations by interannual fluctuation patterns of air temperature and suggest that lake and river ecosystems in such geographical regions are particularly vulnerable to global warming, as high interannual variability is known to have important ramifications for ecosystem structure and functioning. We estimate that the standard deviation of the duration of ice cover, viewed as a measure of interannual variability, exceeds 25 days for lakes and rivers located on 7% of the land area of the Northern Hemisphere. Such high variability might be an early warning signal for a critical transition from strictly dimictic, ice-covered systems to monomictic, open-water systems. Using the Global Lake and Wetland Database, we suggest that 3.7% of the world's lakes larger than 0.1 km2 are at high risk of becoming open-water systems in the near future, which will have immediate consequences for global biogeochemical cycles.
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