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Cohort profile: design and first results of the Dutch IBD Biobank: a prospective, nationwide biobank of patients with inflammatory bowel disease.

Sat, 11/11/2017 - 12:00

Cohort profile: design and first results of the Dutch IBD Biobank: a prospective, nationwide biobank of patients with inflammatory bowel disease.

BMJ Open. 2017 Nov 08;7(11):e016695

Authors: Spekhorst LM, Imhann F, Festen EA, Bodegraven AAV, Boer NK, Bouma G, Fidder HH, D'Haens G, Hoentjen F, Hommes DW, Jong DJ, Löwenberg M, Maljaars PJ, Meulen-de Jong AEV, Oldenburg B, Pierik MJ, Ponsioen CY, Stokkers PC, Verspaget HW, Visschedijk MC, van der Woude CJ, Dijkstra G, Weersma RK, Parelsnoer Institute (PSI) and the Dutch Initiative on Crohn and Colitis (ICC)

Abstract
PURPOSE: The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank.
PARTICIPANTS: Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected.
FINDINGS TO DATE: As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn's disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBD-unclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies.
FUTURE PLANS: The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app.

PMID: 29122790 [PubMed - in process]

Effect of total, domain-specific, and intensity-specific physical activity on all-cause and cardiovascular mortality among hypertensive adults in China.

Fri, 11/10/2017 - 13:50

Effect of total, domain-specific, and intensity-specific physical activity on all-cause and cardiovascular mortality among hypertensive adults in China.

J Hypertens. 2017 Nov 08;:

Authors: Fan M, Yu C, Guo Y, Bian Z, Li X, Yang L, Chen Y, Li M, Li X, Chen J, Chen Z, Lv J, Li L, China Kadoorie Biobank Collaborative Group

Abstract
OBJECTIVES: We aimed to prospectively examine the associations of total, domain-specific, and intensity-specific physical activity with all-cause and cardiovascular mortality among Chinese hypertensive adults.
METHODS: We performed a prospective cohort study in 150 391 hypertensive participants aged 30-79 years from the China Kadoorie Biobank study of 512 891 participants recruited from 10 diverse areas across China during 2004-2008. Participants with heart disease, stroke, chronic obstructive pulmonary disease, and cancer at baseline were excluded.
RESULTS: During 1069 863 person-years of follow-up (median 7.1 years), a total of 5332 men and 4384 women died. Compared with hypertensive participants in the lowest level of total physical activity, the hazard ratios for all-cause mortality were 0.80 (0.76-0.84), 0.69 (0.65-0.73), and 0.67 (0.62-0.72) for those in quartiles 2-4 (Ptrend < 0.001), respectively. Inverse associations were also observed for cardiovascular mortality. Being active in occupational, domestic, and leisure time were associated with lower risk of all-cause and cardiovascular mortality. However, the adjusted ratio for active commuting was 1.08 (1.02-1.15) for all-cause mortality. High levels of low-intensity, moderate-intensity, and vigorous-intensity physical activity were consistently associated with lower risks of all-cause and cardiovascular mortality.
CONCLUSION: Among Chinese hypertensive adults, a higher level of physical activity reduces all-cause and cardiovascular mortality, independent of intensities of physical activity. Not only leisure-time but also occupational and domestic physical activities were benefited.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0.

PMID: 29120959 [PubMed - as supplied by publisher]

Ethics and Epistemology of Big Data.

Fri, 11/10/2017 - 13:50
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Ethics and Epistemology of Big Data.

J Bioeth Inq. 2017 Nov 08;:

Authors: Lipworth W, Mason PH, Kerridge I

Abstract
In this Symposium on the Ethics and Epistemology of Big Data, we present four perspectives on the ways in which the rapid growth in size of research databanks-i.e. their shift into the realm of "big data"-has changed their moral, socio-political, and epistemic status. While there is clearly something different about "big data" databanks, we encourage readers to place the arguments presented in this Symposium in the context of longstanding debates about the ethics, politics, and epistemology of biobank, database, genetic, and epidemiological research.

PMID: 29119459 [PubMed - as supplied by publisher]

Menopause Characteristics, Total Reproductive Years, and Risk of Cardiovascular Disease Among Chinese Women.

Fri, 11/10/2017 - 13:50
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Menopause Characteristics, Total Reproductive Years, and Risk of Cardiovascular Disease Among Chinese Women.

Circ Cardiovasc Qual Outcomes. 2017 Nov;10(11):

Authors: Yang L, Lin L, Kartsonaki C, Guo Y, Chen Y, Bian Z, Xie K, Jin D, Li L, Lv J, Chen Z, China Kadoorie Biobank Study Collaborative Group

Abstract
BACKGROUND: Previous studies, mostly of Western women, have reported inconsistent findings on the association of menopause characteristics (status, age, and time since menopause) and total reproductive years with risk of cardiovascular disease (CVD).
METHODS AND RESULTS: The China Kadoorie Biobank recruited 302 632 women in 2004 to 2008 from 10 regions across China. During 9-year follow-up, 19 393 incident cases of stroke, 18 611 of ischemic heart disease, and 4978 CVD deaths occurred. Cox regression yielded adjusted hazard ratios relating each menopause characteristic and total reproductive years to CVD risk. Among 274 233 women with no prior CVD at baseline, 134 010 were naturally postmenopausal women (mean [SD] age at menopause of 48.6 [4.0] years and total reproductive years 32.7 [4.4]). Compared with premenopausal women, naturally peri- or postmenopausal women were at a higher risk of either fatal or nonfatal CVD. Among women who had had menopause, inverse associations were observed between age at menopause and risks of CVD mortality, incident ischemic heart disease, stroke, and subtypes of stroke, with 1.5% higher risk of CVD death (P<0.001), 0.7% for incident ischemic heart disease (P=0.002), and 0.5% for incident stroke (P=0.02) for every 1 year lower age at menopause. Compared with women who had menopause at age 48 to 50 years, lower age at menopause (ie, <43 years) was associated with 14% higher risk of CVD death and 6% higher risks of both incident ischemic heart disease and stroke. Higher risks of both fatal and nonfatal CVD were also found in women with 5 to 10, 10 to 15, 15 to 20, or >20 years since menopause compared with <5 years since menopause. Total reproductive years were inversely associated with risks of both fatal and nonfatal CVD, with 1.4% lower risk of CVD death per additional reproductive year (P<0.001).
CONCLUSIONS: Women with younger age at menopause, longer time since menopause, or fewer total reproductive years had a higher risk of CVD.

PMID: 29117982 [PubMed - in process]

Association of Physical Activity With Risk of Major Cardiovascular Diseases in Chinese Men and Women.

Thu, 11/09/2017 - 12:34

Association of Physical Activity With Risk of Major Cardiovascular Diseases in Chinese Men and Women.

JAMA Cardiol. 2017 Nov 08;:

Authors: Bennett DA, Du H, Clarke R, Guo Y, Yang L, Bian Z, Chen Y, Millwood I, Yu C, He P, Zheng X, Collins R, Chen J, Peto R, Li L, Chen Z, China Kadoorie Biobank Study Collaborative Group

Abstract
Importance: In China, the patterns and levels of physical activity differed from those in high-income countries. Substantial uncertainty remains about the relevance, both qualitatively and quantitatively, of domain-specific physical activity for cardiovascular disease (CVD) subtypes in Chinese adults.
Objective: To assess the shape and strength of the associations of total, occupational, and nonoccupational physical activity with CVD subtypes in Chinese men and women.
Design, Setting, and Participants: This population-based prospective cohort study in 10 (5 urban, 5 rural) areas across China included 487 334 adults who were aged 30 to 79 (mean 51) years with no prior CVD history when enrolled from June 2004 to July 2008.
Exposures: Self-reported total, occupational, and nonoccupational physical activity, quantified as metabolic equivalent of task hours per day (MET-h/d) based on the type, frequency, and duration of specific activities.
Main Outcomes and Measures: Major vascular events (n = 36 184) and their components, including major coronary events (n = 5082), ischemic stroke (n = 25 647), intracerebral hemorrhage (n = 5252), and CVD death (n = 8437). Cox regression yielded adjusted hazard ratios for each disease that was associated with physical activity.
Results: Of the 487 334 study participants, 287 527 (59%) were women and the mean (SD) age was 51 (10.5) years. The overall mean (SD) total physical activity was 21.5 (12.8) MET-h/d, mainly from occupational activity, especially among men (75% vs 50% in women). Total physical activity was inversely associated with the risk of major vascular events, with the adjusted hazard ratio that compared the top vs bottom quintiles of physical activity being 0.77 (95% CI, 0.74-0.80). Throughout the range of total physical activity studied, the association with CVD with each 4 MET-h/d higher usual total physical activity (approximately 1 hour of brisk walking per day) associated with a 6% (95% CI, 5%-7%) lower risk of major vascular events, and a 9%, 5%, 6%, and 12% lower risk of major coronary events, ischemic stroke, intracerebral hemorrhage, and CVD death, respectively. The strength of the associations was similar and independent of each other for occupational and nonoccupational physical activity. However, for occupational physical activity, the associations with CVD subtypes were greatly attenuated above 20 MET-h/d, especially for intracerebral hemorrhage. The associations of total physical activity with major vascular events were similar among men and women and across different levels of sedentary leisure time but were much weaker among individuals with high blood pressure.
Conclusions and Relevance: Among Chinese adults, higher occupational or nonoccupational physical activity was associated with significantly lower risks of major CVD.

PMID: 29117341 [PubMed - as supplied by publisher]

Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Thu, 11/09/2017 - 12:34

Erratum: Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Nat Commun. 2017 Nov 07;8(1):1414

Authors: Zillikens MC, Demissie S, Hsu YH, Yerges-Armstrong LM, Chou WC, Stolk L, Livshits G, Broer L, Johnson T, Koller DL, Kutalik Z, Luan J, Malkin I, Ried JS, Smith AV, Thorleifsson G, Vandenput L, Hua Zhao J, Zhang W, Aghdassi A, Åkesson K, Amin N, Baier LJ, Barroso I, Bennett DA, Bertram L, Biffar R, Bochud M, Boehnke M, Borecki IB, Buchman AS, Byberg L, Campbell H, Campos Obanda N, Cauley JA, Cawthon PM, Cederberg H, Chen Z, Cho NH, Jin Choi H, Claussnitzer M, Collins F, Cummings SR, De Jager PL, Demuth I, Dhonukshe-Rutten RAM, Diatchenko L, Eiriksdottir G, Enneman AW, Erdos M, Eriksson JG, Eriksson J, Estrada K, Evans DS, Feitosa MF, Fu M, Garcia M, Gieger C, Girke T, Glazer NL, Grallert H, Grewal J, Han BG, Hanson RL, Hayward C, Hofman A, Hoffman EP, Homuth G, Hsueh WC, Hubal MJ, Hubbard A, Huffman KM, Husted LB, Illig T, Ingelsson E, Ittermann T, Jansson JO, Jordan JM, Jula A, Karlsson M, Khaw KT, Kilpeläinen TO, Klopp N, Kloth JSL, Koistinen HA, Kraus WE, Kritchevsky S, Kuulasmaa T, Kuusisto J, Laakso M, Lahti J, Lang T, Langdahl BL, Launer LJ, Lee JY, Lerch MM, Lewis JR, Lind L, Lindgren C, Liu Y, Liu T, Liu Y, Ljunggren Ö, Lorentzon M, Luben RN, Maixner W, McGuigan FE, Medina-Gomez C, Meitinger T, Melhus H, Mellström D, Melov S, Michaëlsson K, Mitchell BD, Morris AP, Mosekilde L, Newman A, Nielson CM, O'Connell JR, Oostra BA, Orwoll ES, Palotie A, Parker SCJ, Peacock M, Perola M, Peters A, Polasek O, Prince RL, Räikkönen K, Ralston SH, Ripatti S, Robbins JA, Rotter JI, Rudan I, Salomaa V, Satterfield S, Schadt EE, Schipf S, Scott L, Sehmi J, Shen J, Soo Shin C, Sigurdsson G, Smith S, Soranzo N, Stančáková A, Steinhagen-Thiessen E, Streeten EA, Styrkarsdottir U, Swart KMA, Tan ST, Tarnopolsky MA, Thompson P, Thomson CA, Thorsteinsdottir U, Tikkanen E, Tranah GJ, Tuomilehto J, van Schoor NM, Verma A, Vollenweider P, Völzke H, Wactawski-Wende J, Walker M, Weedon MN, Welch R, Wichmann HE, Widen E, Williams FMK, Wilson JF, Wright NC, Xie W, Yu L, Zhou Y, Chambers JC, Döring A, van Duijn CM, Econs MJ, Gudnason V, Kooner JS, Psaty BM, Spector TD, Stefansson K, Rivadeneira F, Uitterlinden AG, Wareham NJ, Ossowski V, Waterworth D, Loos RJF, Karasik D, Harris TB, Ohlsson C, Kiel DP

Abstract
A correction to this article has been published and is linked from the HTML version of this article.

PMID: 29116125 [PubMed - in process]

[Biobanks as the basis for developing biomedicine: Problems and prospects].

Thu, 11/09/2017 - 12:34

[Biobanks as the basis for developing biomedicine: Problems and prospects].

Mol Biol (Mosk). 2017 Sep-Oct;51(5):761-771

Authors: Reznik ON, Kuzmin DO, Reznik AO

Abstract
Biobanking is crucial for the development of life sciences in general and biomedical science in particular. A systematic study of stored biomaterials enables the discovery of new biomarkers for various physiological and pathophysiological states, identification of the drug targets, and validation of these findings in human population studies. During the last decades, the importance of biobanking has increased in parallel with the growth in their size from relatively small collections to very large national and international biorepositories. Here, we have systematically reviewed modern approaches to biobanking, a variety of biobank definitions and types, and the current states of biobanking art in Russia and in the world and have discussed the obstacles to the global development of biobanking, along with possible solutions.

PMID: 29116062 [PubMed - in process]

Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study.

Thu, 11/09/2017 - 12:34

Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study.

Breast Cancer Res. 2017 Nov 07;19(1):119

Authors: Brouckaert O, Rudolph A, Laenen A, Keeman R, Bolla MK, Wang Q, Soubry A, Wildiers H, Andrulis IL, Arndt V, Beckmann MW, Benitez J, Blomqvist C, Bojesen SE, Brauch H, Brennan P, Brenner H, Chenevix-Trench G, Choi JY, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Eriksson M, Fasching PA, Figueroa J, Flyger H, Giles GG, González-Neira A, Guénel P, Hall P, Hollestelle A, Hopper JL, Ito H, Jones M, Kang D, kConFab, Knight JA, Kosma VM, Li J, Lindblom A, Lilyquist J, Lophatananon A, Mannermaa A, Manoukian S, Margolin S, Matsuo K, Muir K, Nevanlinna H, Peterlongo P, Pylkäs K, Saajrang S, Seynaeve C, Shen CY, Shu XO, Southey MC, Swerdlow A, Teo SH, Tollenaar RAEM, Truong T, Tseng CC, van den Broek AJ, van Deurzen CHM, Winqvist R, Wu AH, Yip CH, Yu JC, Zheng W, Milne RL, Pharoah PDP, Easton DF, Schmidt MK, Garcia-Closas M, Chang-Claude J, Lambrechts D, Neven P

Abstract
BACKGROUND: Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis.
METHODS: We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years.
RESULTS: Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16-1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01-2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45-1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70-0.88, p < 0.0001), but this effect was not apparent at a later FFTP.
CONCLUSIONS: Our main findings suggest that parity is associated with TNBC across all ages at BC diagnosis, whereas the association with luminal HER2-like BC was present only for early onset BC.

PMID: 29116004 [PubMed - in process]

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations.

Thu, 11/09/2017 - 12:34
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Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations.

Int J Cancer. 2017 Nov 07;:

Authors: van Duijnhoven FJB, Jenab M, Hveem K, Siersema PD, Fedirko V, Duell EJ, Kampman E, Halfweeg A, van Kranen HJ, van den Ouweland JMW, Weiderpass E, Murphy N, Langhammer A, Ness-Jensen E, Olsen A, Tjønneland A, Overvad K, Cadeau C, Kvaskoff M, Boutron-Ruault MC, Katzke VA, Kühn T, Boeing H, Trichopoulou A, Kotanidou A, Kritikou M, Palli D, Agnoli C, Tumino R, Panico S, Matullo G, Peeters P, Brustad M, Standahl Olsen K, Lasheras C, Obón-Santacana M, Sánchez MJ, Dorronsoro M, Chirlaque MD, Barricarte A, Manjer J, Almquist M, Renström F, Ye W, Wareham N, Khaw KT, Bradbury KE, Freisling H, Aune D, Norat T, Riboli E, Bueno-de-Mesquita HB

Abstract
Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer. However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and pancreatic cancer incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident pancreatic cancer cases (EPIC n=626; HUNT2 n=112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53); and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with pancreatic cancer risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of pancreatic cancer risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant. This article is protected by copyright. All rights reserved.

PMID: 29114875 [PubMed - as supplied by publisher]

Multimorbidity and co-morbidity in atrial fibrillation and effects on survival: findings from UK Biobank cohort.

Wed, 11/08/2017 - 14:02
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Multimorbidity and co-morbidity in atrial fibrillation and effects on survival: findings from UK Biobank cohort.

Europace. 2017 Nov 02;:

Authors: Jani BD, Nicholl BI, McQueenie R, Connelly DT, Hanlon P, Gallacher KI, Lee D, Mair FS

Abstract
Aims: To examine the number and type of co-morbid long-term health conditions (LTCs) and their associations with all-cause mortality in an atrial fibrillation (AF) population.
Methods and results: Community cohort participants (UK Biobank n = 502 637) aged 37-73 years were recruited between 2006 and 2010. Self-reported LTCs (n = 42) identified in people with AF at baseline. All-cause mortality was available for a median follow-up of 7 years (interquartile range 76-93 months). Hazard ratios (HRs) examined associations between number and type of co-morbid LTC and all-cause mortality, adjusting for age, sex, socio-economic status, smoking, and anticoagulation status. Three thousand six hundred fifty-one participants (0.7% of the study population) reported AF; mean age was 61.9 years. The all-cause mortality rate was 6.7% (248 participants) at 7 years. Atrial fibrillation participants with ≥4 co-morbidities had a six-fold higher risk of mortality compared to participants without any LTC. Co-morbid heart failure was associated with higher risk of mortality [HR 2.96, 95% confidence interval (CI) 1.83-4.80], whereas the presence of co-morbid stroke did not have a significant association. Among non-cardiometabolic conditions, presence of chronic obstructive pulmonary disease (HR 3.31, 95% CI 2.14-5.11) and osteoporosis (HR 3.13, 95% CI 1.63-6.01) was associated with a higher risk of mortality.
Conclusion: Survival in middle-aged to older individuals with self-reported AF is strongly correlated with level of multimorbidity. This group should be targeted for interventions to optimize their management, which in turn may potentially reduce the impact of their co-morbidities on survival. Future AF clinical guidelines need to place greater emphasis on the issue of co-morbidity.

PMID: 29112751 [PubMed - as supplied by publisher]

Gray matter network measures are associated with cognitive decline in mild cognitive impairment.

Wed, 11/08/2017 - 14:02
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Gray matter network measures are associated with cognitive decline in mild cognitive impairment.

Neurobiol Aging. 2017 Oct 06;61:198-206

Authors: Dicks E, Tijms BM, Ten Kate M, Gouw AA, Benedictus MR, Teunissen CE, Barkhof F, Scheltens P, van der Flier WM

Abstract
Gray matter networks are disrupted in Alzheimer's disease and related to cognitive impairment. However, it is still unclear whether these disruptions are associated with cognitive decline over time. Here, we studied this question in a large sample of patients with mild cognitive impairment with extensive longitudinal neuropsychological assessments. Gray matter networks were extracted from baseline structural magnetic resonance imaging, and we tested associations of network measures and cognitive decline in Mini-Mental State Examination and 5 cognitive domains (i.e., memory, attention, executive function, visuospatial, and language). Disrupted network properties were cross-sectionally related to worse cognitive impairment. Longitudinally, lower small-world coefficient values were associated with a steeper decline in almost all domains. Lower betweenness centrality values correlated with a faster decline in Mini-Mental State Examination and memory, and at a regional level, these associations were specific for the precuneus, medial frontal, and temporal cortex. Furthermore, network measures showed additive value over established biomarkers in predicting cognitive decline. Our results suggest that gray matter network measures might have use in identifying patients who will show fast disease progression.

PMID: 29111486 [PubMed - as supplied by publisher]

The use of cerebrospinal fluid in biomarker studies.

Wed, 11/08/2017 - 14:02
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The use of cerebrospinal fluid in biomarker studies.

Handb Clin Neurol. 2017;146:3-20

Authors: Teunissen CE, Verheul C, Willemse EAJ

Abstract
Cerebrospinal fluid (CSF) is an extremely useful matrix for biomarker research for several purposes, such as diagnosis, prognosis, monitoring, and identification of prominent leads in pathways of neurologic diseases. Such biomarkers can be identified based on a priori hypotheses around prominent protein changes, but also by applying -omics technologies. Proteomics is widely used, but metabolomics and transcriptomics are rapidly revealing their potential for CSF studies. The basis of such studies is the availability of high-quality biobanks. Furthermore, profound knowledge and consequent optimization of all aspects in biomarker development are needed. Here we discuss current knowledge and recently developed protocols for successful biomarker studies, from collection of CSF by lumbar puncture, processing, and biobanking protocols, preanalytic confounding factors, and cost-efficient development and validation of assays for implementation into clinical practice or research.

PMID: 29110777 [PubMed - in process]

Multiethnic polygenic risk scores improve risk prediction in diverse populations.

Wed, 11/08/2017 - 14:02
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Multiethnic polygenic risk scores improve risk prediction in diverse populations.

Genet Epidemiol. 2017 Nov 07;:

Authors: Márquez-Luna C, Loh PR, South Asian Type 2 Diabetes (SAT2D) Consortium, SIGMA Type 2 Diabetes Consortium, Price AL

Abstract
Methods for genetic risk prediction have been widely investigated in recent years. However, most available training data involves European samples, and it is currently unclear how to accurately predict disease risk in other populations. Previous studies have used either training data from European samples in large sample size or training data from the target population in small sample size, but not both. Here, we introduce a multiethnic polygenic risk score that combines training data from European samples and training data from the target population. We applied this approach to predict type 2 diabetes (T2D) in a Latino cohort using both publicly available European summary statistics in large sample size (Neff  = 40k) and Latino training data in small sample size (Neff  = 8k). Here, we attained a >70% relative improvement in prediction accuracy (from R(2 ) = 0.027 to 0.047) compared to methods that use only one source of training data, consistent with large relative improvements in simulations. We observed a systematically lower load of T2D risk alleles in Latino individuals with more European ancestry, which could be explained by polygenic selection in ancestral European and/or Native American populations. We predict T2D in a South Asian UK Biobank cohort using European (Neff  = 40k) and South Asian (Neff  = 16k) training data and attained a >70% relative improvement in prediction accuracy, and application to predict height in an African UK Biobank cohort using European (N = 113k) and African (N = 2k) training data attained a 30% relative improvement. Our work reduces the gap in polygenic risk prediction accuracy between European and non-European target populations.

PMID: 29110330 [PubMed - as supplied by publisher]

Consent process for US-based family reference DNA samples.

Tue, 11/07/2017 - 12:55

Consent process for US-based family reference DNA samples.

Forensic Sci Int Genet. 2017 Oct 29;32:71-79

Authors: Katsanis SH, Snyder L, Arnholt K, Mundorff AZ

Abstract
DNA collection from family members of the missing is a tenet for missing persons' and mass fatality investigations. Procedures for consenting family members are disparate, depending on the context supporting the reason for sample collection. While guidelines and best practices have been developed for handling mass fatalities and for identification of the missing, these guidelines do not address standard consent practices for living family members of potential victims. We examined the relevant U.S. laws, international guidelines and best practices, sampled consent forms currently used for DNA collection of family members, and drafted model language for a consent form to communicate the required and recommended information. We modeled the consent form on biobank consenting practices and tested the consent language among students and the general population for constructive feedback and readability. We also asked respondents to consider the options for DNA collection and either hypothetically agree or disagree. The model language presented here highlights information important to relay in consent processes and can serve as a foundation for future consent practices in mass fatalities and missing persons' investigations.

PMID: 29107870 [PubMed - as supplied by publisher]

Evidence for M2 macrophages in granulomas from pulmonary sarcoidosis: a new aspect of macrophage heterogeneity.

Tue, 11/07/2017 - 12:55

Evidence for M2 macrophages in granulomas from pulmonary sarcoidosis: a new aspect of macrophage heterogeneity.

Hum Immunol. 2017 Oct 26;:

Authors: Shamaei M, Mortaz E, Pourabdollah M, Garssen J, Tabarsi P, Velayati A, Adcock IM

Abstract
BACKGROUND: Sarcoidosis is a granulomatous disease of unknown etiology. Macrophages play a key role in granuloma formation with the T cells, having a significant impact on macrophage polarization (M1 and M2) and the cellular composition of the granuloma. This study evaluates macrophage polarization in granulomas in pulmonary sarcoidosis.
MATERIALS AND METHODS: Tissue specimens from the Department of Pathology biobank at the Masih Daneshvari Hospital were obtained. Paraffin sections from 10 sarcoidosis patients were compared with those from 12 cases of tuberculosis using immunohistochemical staining. These sections consisted of mediastinal lymph nodes and transbronchial lung biopsy (TBLB) for sarcoidosis patients versus pleural tissue, neck, axillary lymph nodes and TBLB for tuberculosis patients. The sections were stained for T-cells (CD4+, CD8+) and mature B lymphocytes (CD22+). CD14+ and CD68+ staining was used as a marker of M1 macrophages and CD163+ as a marker for M2 macrophages.
RESULTS: Immunohistochemical staining revealed a 4/1 ratio of CD4+/CD8+ T-cells in sarcoidosis granuloma sections and a 3/1 ratio in tuberculosis sections. There was no significance difference in single CD4+, CD8+, CD22+, CD14+ and CD68+ staining between sarcoidosis and tuberculosis sections. CD163 expression was significantly increased in sarcoidosis sections compared with those from tuberculosis subjects.
CONCLUSION: Enhanced CD163+ staining indicates a shift towards M2 macrophage subsets in granulomas from sarcoidosis patients. Further research is required to determine the functional role of M2 macrophages in the immunopathogenesis of sarcoidosis.

PMID: 29107084 [PubMed - as supplied by publisher]

A small amount of precisely measured high-intensity habitual physical activity predicts bone health in pre- and post-menopausal women in UK Biobank.

Tue, 11/07/2017 - 12:55

A small amount of precisely measured high-intensity habitual physical activity predicts bone health in pre- and post-menopausal women in UK Biobank.

Int J Epidemiol. 2017 Jun 29;:

Authors: Stiles VH, Metcalf BS, Knapp KM, Rowlands AV

Abstract
Background: Physical inactivity is a highly modifiable risk factor for the development of osteoporosis but, due to a lack of research that has precisely and objectively meaured physical activity (PA) relevant to bone, the specific contribution that PA can make to bone health is poorly understood. This study examined whether a more precise measure of PA relelvant to bone was associated with meaures of bone health in pre- and post-menopausal women in UK Biobank.
Methods: Time spent at intensities specific to bone health [≥750 milli-gravitational units ( mg ) and ≥1000 mg ] were analysed from raw tri-axial acceleration data averaged over 1-second epochs from 7-day monitoring of habitual PA using accelerometry-based activity monitors (100 Hz; AX3, Axivity, UK) of 1218 pre- and 1316 post-menopausal healthy women. In a cross-sectional analysis, associations between categories of time (<1, 1-2 and ≥2 minutes) spent above the intensity thresholds and calcaneal quantitative ultrasound measures of bone health (bone mineral density T-score, BMDT-score; speed of sound, SOS; and broadband ultrasound attenuation, BUA) were examined.
Results: Compared with <1 minute, spending 1-2 or ≥2 minutes/day at intensities ≥1000  mg in pre-menopausal and ≥750  mg in post-menopausal women was positively associated with BMDT-score, SOS and BUA.
Conclusion: Brief bursts of high-intensity PA relevant to bone health can be captured by applying bone-specific thresholds of intensity to raw tri-axial accelerations averaged over 1-second epochs. Accumulating 1-2 minutes/day of high-intensity PA, equivalent to running in pre-menopausal women and slow jogging in post-menopausal women, is associated with better bone health.

PMID: 29106579 [PubMed - as supplied by publisher]

Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer.

Tue, 11/07/2017 - 12:55

Whole exome sequencing reveals intertumor heterogeneity and distinct genetic origins of sporadic synchronous colorectal cancer.

Int J Cancer. 2017 Nov 06;:

Authors: Di J, Yang H, Jiang B, Wang Z, Ji J, Su X

Abstract
Sporadic synchronous colorectal cancer (CRC) refers to more than one primary tumor detected in a single patient at the time of the first diagnosis without predisposition of cancer development. Given the same genetic and microenvironment they raise, sporadic synchronous CRC is a unique model to study CRC tumorigenesis. We performed whole exome sequencing in 32 fresh frozen tumor lesions from 15 patients with sporadic synchronous CRC to compare their genetic alterations. This approach identified ubiquitously mutated genes in the range from 0.34% to 4.22% and from 0.8% to 7.0% in non-hypermutated tumors and hypermutated tumors, respectively, in a single patient. We show that both ubiquitously mutated genes and candidate cancer genes from different tumors in the same patient mutated at different sites. Consistently, obvious differences in somatic copy number variations (SCNV) were found in most patients with non-hypermutated tumor lesions, which had ubiquitous copy number amplification rates ranging from 0% to 8.8% and ubiquitous copy number deletion rates ranging from 0% to 8.2%. Hypermutated lesions were nearly diploid with 0% to 18.8% common copy number aberrations. Accordingly, clonal structures, altered signaling pathways, and druggable genes in a single patient with synchronous CRC varied significantly. Taken together, the disparate SCNVs and mutations in synchronous CRC supported the field effect theory of tumorigenesis. Moreover, the intertumor heterogeneity of synchronous CRCs implies that analysis of all tumor lesions from the same patient is necessary for appropriate clinical treatment decisions. This article is protected by copyright. All rights reserved.

PMID: 29105743 [PubMed - as supplied by publisher]

Validation of a Machine Learning Approach for Venous Thromboembolism Risk Prediction in Oncology.

Tue, 11/07/2017 - 12:55
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Validation of a Machine Learning Approach for Venous Thromboembolism Risk Prediction in Oncology.

Dis Markers. 2017;2017:8781379

Authors: Ferroni P, Zanzotto FM, Scarpato N, Riondino S, Guadagni F, Roselli M

Abstract
Using kernel machine learning (ML) and random optimization (RO) techniques, we recently developed a set of venous thromboembolism (VTE) risk predictors, which could be useful to devise a web interface for VTE risk stratification in chemotherapy-treated cancer patients. This study was designed to validate a model incorporating the two best predictors and to compare their combined performance with that of the currently recommended Khorana score (KS). Age, sex, tumor site/stage, hematological attributes, blood lipids, glycemic indexes, liver and kidney function, BMI, performance status, and supportive and anticancer drugs of 608 cancer outpatients were all entered in the model, with numerical attributes analyzed as continuous values. VTE rate was 7.1%. The VTE risk prediction performance of the combined model resulted in 2.30 positive likelihood ratio (+LR), 0.46 negative LR (-LR), and 4.88 HR (95% CI: 2.54-9.37), with a significant improvement over the KS [HR 1.73 (95% CI: 0.47-6.37)]. These results confirm that a ML approach might be of clinical value for VTE risk stratification in chemotherapy-treated cancer outpatients and suggest that the ML-RO model proposed could be useful to design a web service able to provide physicians with a graphical interface helping in the critical phase of decision making.

PMID: 29104344 [PubMed - in process]

Talin and vinculin are downregulated in atherosclerotic plaque; Tampere Vascular Study.

Tue, 11/07/2017 - 12:55
Related Articles

Talin and vinculin are downregulated in atherosclerotic plaque; Tampere Vascular Study.

Atherosclerosis. 2016 Dec;255:43-53

Authors: von Essen M, Rahikainen R, Oksala N, Raitoharju E, Seppälä I, Mennander A, Sioris T, Kholová I, Klopp N, Illig T, Karhunen PJ, Kähönen M, Lehtimäki T, Hytönen VP

Abstract
BACKGROUND AND AIMS: Focal adhesions (FA) play an important role in the tissue remodeling and in the maintenance of tissue integrity and homeostasis. Talin and vinculin proteins are among the major constituents of FAs contributing to cellular well-being and intercellular communication.
METHODS: Microarray analysis (MA) and qRT-PCR low-density array were implemented to analyze talin-1, talin-2, meta-vinculin and vinculin gene expression in circulating blood and arterial plaque.
RESULTS: All analyzed genes were significantly and consistently downregulated in plaques (carotid, abdominal aortic and femoral regions) compared to left internal thoracic artery (LITA) control. The use of LITA samples as controls for arterial plaque samples was validated using immunohistochemistry by comparing LITA samples with healthy arterial samples from a cadaver. Even though the differences in expression levels between stable and unstable plaques were not statistically significant, we observed further negative tendency in the expression in unstable atherosclerotic plaques. The confocal tissue imaging revealed gradient of talin-1 expression in plaque with reduction close to the vessel lumen. Similar gradient was observed for talin-2 expression in LITA controls but was not detected in plaques. This suggests that impaired tissue mechanostability affects the tissue remodeling and healing capabilities leading to development of unstable plaques.
CONCLUSIONS: The central role of talin and vinculin in cell adhesions suggests that the disintegration of the tissue in atherosclerosis could be partially driven by downregulation of these genes, leading to loosening of cell-ECM interactions and remodeling of the tissue.

PMID: 27816808 [PubMed - indexed for MEDLINE]

Germline variations at JAK2, TERT, HBS1L-MYB and MECOM and the risk of myeloproliferative neoplasms in Taiwanese population.

Sun, 11/05/2017 - 22:00
Related Articles

Germline variations at JAK2, TERT, HBS1L-MYB and MECOM and the risk of myeloproliferative neoplasms in Taiwanese population.

Oncotarget. 2017 Sep 29;8(44):76204-76213

Authors: Chiang YH, Chang YC, Lin HC, Huang L, Cheng CC, Wang WT, Cheng HI, Su NW, Chen CG, Lin J, Chang YF, Chang MC, Hsieh RK, Chou WC, Lim KH, Kuo YY

Abstract
Germline variations at JAK2, TERT, HBS1L-MYB and MECOM have been found to associate with myeloproliferative neoplasms (MPNs) in European populations. Whether these germline variations are associated with MPNs in Taiwanese population is obscure. Here we aimed to evaluate the association of five germline variations (JAK2 46/1 haplotype tagged by rs12343867, JAK2 intron 8 rs12339666, TERT rs2736100, HBS1L-MYB rs9376092 and MECOM rs2201862) and the risk of MPNs in Taiwanese population. A total of 178 MPN patients (109 essential thrombocythemia, 54 polycythemia vera and 15 primary myelofibrosis) were enrolled into this study. The information of 17033 control subjects was obtained from Taiwan Biobank database. The JAK2 46/1 haplotype, JAK2 rs12339666 and TERT rs2736100 were significantly associated with Taiwanese MPNs (P = 3.6×10(-19), 1.9×10(-19) and 3.1×10(-6), respectively), and JAK2(V617F)-positive MPNs (n=121) (P = 5.6×10(-21), 4.4×10(-21) and 8.6×10(-7), respectively). In JAK2(V617F)-negative cases (n=55), only the JAK2 46/1 haplotype and JAK2 rs12339666 remained statistically significant (P= 0.009 and 0.007, respectively). When stratified by disease subtypes, the JAK2 46/1 haplotype and JAK2 rs12339666 were significantly associated with all three MPN subtypes, but TERT rs2736100 was only associated with essential thrombocythemia and polycythemia vera. We did not find any association of these five SNPs with CALR mutations in our cohort. Furthermore, the risk alleles of MECOM rs2201862 and HBS1L-MYB rs9376092 were demonstrated to be negatively associated with the risk of developing polycythemia vera. In conclusion, germline variations at JAK2 (both the 46/1 haplotype and rs12339666) and TERT rs2736100 were associated with MPNs in Taiwanese population.

PMID: 29100304 [PubMed]