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  • 1.
    Al-Jebari, Yahia
    et al.
    Lund Univ, Mol Reprod Med, Dept Translat Med, Malmo, Sweden.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Div Clin Epidemiol, Dept Med, Stockholm, Sweden.
    Nord, Carina Berglund
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Cohn-Cedermark, Gabriella
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Stahl, Olof
    Skane Univ Hosp, Dept Oncol, Lund, Sweden.
    Tandstad, Torgrim
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Fac Med & Hlth Sci, Trondheim, Norway;St Olavs Univ Hosp, Canc Clin, Trondheim, Norway.
    Jensen, Allan
    Danish Canc Soc Res Ctr, Virus Lifestyle & Genes, Copenhagen, Denmark.
    Haugnes, Hege Sagstuen
    Univ Hosp North Norway, Dept Oncol, Tromso, Norway;UiT Arctic Univ Norway, Inst Clin Med, Tromso, Norway.
    Daugaard, Gedske
    Rigshosp, Dept Oncol, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Rylander, Lars
    Lund Univ, Div Occupat & Environm Med, Lund, Sweden.
    Giwercman, Aleksander
    Lund Univ, Mol Reprod Med, Dept Translat Med, Malmo, Sweden.
    Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 6, article id e1002816Article in journal (Refereed)
    Abstract [en]

    Background Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. Methods and findings In this nationwide register study, all singletons born in Sweden 1994-2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19-1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment-to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54-1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25-4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995-2000-both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. Conclusions No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.

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  • 2.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    A LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated Wnt/β-catenin signaling2007In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 4, no 11, p. 1829-1841Article in journal (Refereed)
    Abstract [en]

    Background Hyperparathyroidism (HPT) is a common endocrine disorder with incompletely understood etiology, characterized by enlarged hyperactive parathyroid glands and increased serum concentrations of parathyroid hormone and ionized calcium. We have recently reported activation of the Wnt signaling pathway by accumulation of beta-catenin in all analyzed parathyroid tumors from patients with primary HPT (pHPT) and in hyperplastic parathyroid glands from patients with uremia secondary to HPT (sHPT). Mechanisms that may account for this activation have not been identified, except for a few cases of beta-catenin (CTNNB1) stabilizing mutation in pHPT tumors. Methods and Findings Reverse transcription PCR and Western blot analysis showed expression of an aberrantly spliced internally truncated WNT coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) in 32 out of 37 pHPT tumors (86%) and 20 out of 20 sHPT tumors (100%). Stabilizing mutation of CTNNB1 and expression of the internally truncated LRP5 receptor was mutually exclusive. Expression of the truncated LRP5 receptor was required to maintain the nonphosphorylated active beta-catenin level, transcription activity of beta-catenin, MYC expression, parathyroid cell growth in vitro, and parathyroid tumor growth in a xenograft severe combined immunodeficiency ( SCID) mouse model. WNT3 ligand and the internally truncated LRP5 receptor strongly activated transcription, and the internally truncated LRP5 receptor was insensitive to inhibition by DKK1. Conclusions The internally truncated LRP5 receptor is strongly implicated in deregulated activation of the WNT/beta-catenin signaling pathway in hyperparathyroid tumors, and presents a potential target for therapeutic intervention.

  • 3. Bugiardini, Raffaele
    et al.
    Badimon, Lina
    Collins, Peter
    Erbel, Raimund
    Fox, Kim
    Hamm, Christian
    Pinto, Fausto
    Rosengren, Annika
    Stefanadis, Christodoulos
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Van de Werf, Frans
    Angina, "normal" coronary angiography, and vascular dysfunction: risk assessment strategies2007In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 4, no 2, p. e12-Article in journal (Refereed)
    Abstract [en]

    Chest pain may be associated with coronary arteries that appear "normal". Normal is defined here as no visible disease or luminal irregularities (less than 50%) as judged visually at coronary angiography. Normal angiography in patients with chest pain is five times more common in women than in men [1]. Among patients with chest pain and normal angiography, an unknown number are suffering from cardiac pain of ischemic origin. Uncertainty is often difficult to allay, for medical attendants as well as for patients, resulting in perpetuation of symptoms, difficulties in management, and establishment of risk of subsequent coronary events [2]. In this article, we discuss how to stratify risk in patients with chest pain and a normal coronary angiogram.

  • 4. Carrasquilla, Germán D
    et al.
    Frumento, Paolo
    Berglund, Anita
    Borgfeldt, Christer
    Bottai, Matteo
    Chiavenna, Chiara
    Eliasson, Mats
    Engström, Gunnar
    Hallmans, Göran
    Jansson, Jan-Håkan
    Magnusson, Patrik K
    Nilsson, Peter M
    Pedersen, Nancy L
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Leander, Karin
    Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies.2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 11, article id e1002445Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.

    METHODS AND FINDINGS: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.

    CONCLUSIONS: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.

  • 5.
    Censin, J. C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nowak, Christoph
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cooper, Nicholas
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Todd, John A.
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England.;Univ Oxford, NIHR Oxford Biomed Res Ctr, Wellcome Trust Ctr Human Genet,Nuffield Dept Med, JDRF,Wellcome Trust Diabet & Inflammat Lab, Oxford, England..
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 8, article id e1002362Article in journal (Refereed)
    Abstract [en]

    Background The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations. Methods and findings We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study. Conclusions This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.

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  • 6.
    Dalberg, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, Johan
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Birth outcome in women with previously treated breast cancer: a population-based cohort study from Sweden2006In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 3, no 9, p. 1597-1602Article in journal (Refereed)
    Abstract [en]

    Background: Data on birth outcome and offspring health after the appearance of breast cancer are limited. The aim of this study was to assess the risk of adverse birth outcomes in women previously treated for invasive breast cancer compared with the general population of mothers. Methods and Findings: Of all 2,870,932 singleton births registered in the Swedish Medical Birth Registry during 1973-2002, 331 first births following breast cancer surgery - with a mean time to pregnancy of 37 mo (range 7-163) - were identified using linkage with the Swedish Cancer Registry. Logistic regression analysis was used. The estimates were adjusted for maternal age, parity, and year of delivery. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate infant health and mortality, delivery complications, the risk of preterm birth, and the rates of instrumental delivery and cesarean section. The large majority of births from women previously treated for breast cancer had no adverse events. However, births by women exposed to breast cancer were associated with an increased risk of delivery complications (OR 1.5, 95% CI 1.2-1.9), cesarean section (OR 1.3, 95% CI 1.0-1.7), very preterm birth (<32 wk) (OR 3.2, 95% CI 1.7-6.0), and low birth weight (<1500 g) (OR 2.9, 95% CI 1.4-5.8). A tendency towards an increased risk of malformations among the infants was seen especially in the later time period (1988-2002) (OR 2.1, 95% CI 1.2-3.7). Conclusions: It is reassuring that births overall were without adverse events, but our findings indicate that pregnancies in previously treated breast cancer patients should possibly be regarded as higher risk pregnancies, with consequences for their surveillance and management.

     

  • 7. Faggiano, Fabrizio
    et al.
    Allara, Elias
    Giannotta, Fabrizia
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Molinar, Roberta
    Sumnall, Harry
    Wiers, Reinout
    Michie, Susan
    Collins, Linda
    Conrod, Patricia
    Europe Needs a Central, Transparent, and Evidence-Based Approval Process for Behavioural Prevention Interventions2014In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 11, no 10, p. e1001740-Article in journal (Refereed)
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  • 8.
    Fall, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maegi, Reedik
    Ploner, Alexander
    Fischer, Krista
    Horikoshi, Momoko
    Sarin, Antti-Pekka
    Thorleifsson, Gudmar
    Ladenvall, Claes
    Kals, Mart
    Kuningas, Maris
    Draisma, Harmen H. M.
    Ried, Janina S.
    van Zuydam, Natalie R.
    Huikari, Ville
    Mangino, Massimo
    Sonestedt, Emily
    Benyamin, Beben
    Nelson, Christopher P.
    Rivera, Natalia V.
    Kristiansson, Kati
    Shen, Huei-yi
    Havulinna, Aki S.
    Dehghan, Abbas
    Donnelly, Louise A.
    Kaakinen, Marika
    Nuotio, Marja-Liisa
    Robertson, Neil
    de Bruijn, Renee F. A. G.
    Ikram, M. Arfan
    Amin, Najaf
    Balmforth, Anthony J.
    Braund, Peter S.
    Doney, Alexander S. F.
    Doering, Angela
    Elliott, Paul
    Esko, Tonu
    Franco, Oscar H.
    Gretarsdottir, Solveig
    Hartikainen, Anna-Liisa
    Heikkila, Kauko
    Herzig, Karl-Heinz
    Holm, Hilma
    Hottenga, Jouke Jan
    Hypponen, Elina
    Illig, Thomas
    Isaacs, Aaron
    Isomaa, Bo
    Karssen, Lennart C.
    Kettunen, Johannes
    Koenig, Wolfgang
    Kuulasmaa, Kari
    Laatikainen, Tiina
    Laitinen, Jaana
    Lindgren, Cecilia
    Lyssenko, Valeriya
    Laara, Esa
    Rayner, Nigel W.
    Mannisto, Satu
    Pouta, Anneli
    Rathmann, Wolfgang
    Rivadeneira, Fernando
    Ruokonen, Aimo
    Savolainen, Markku J.
    Sijbrands, Eric J. G.
    Small, Kerrin S.
    Smit, Jan H.
    Steinthorsdottir, Valgerdur
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Taanila, Anja
    Tobin, Martin D.
    Uitterlinden, Andre G.
    Willems, Sara M.
    Willemsen, Gonneke
    Witteman, Jacqueline
    Perola, Markus
    Evans, Alun
    Ferrieres, Jean
    Virtamo, Jarmo
    Kee, Frank
    Tregouet, David-Alexandre
    Arveiler, Dominique
    Amouyel, Philippe
    Ferrario, Marco M.
    Brambilla, Paolo
    Hall, Alistair S.
    Heath, AndrewC.
    Madden, Pamela A. F.
    Martin, Nicholas G.
    Montgomery, Grant W.
    Whitfield, John B.
    Jula, Antti
    Knekt, Paul
    Oostra, Ben
    van Duijn, Cornelia M.
    Penninx, Brenda W. J. H.
    Smith, George Davey
    Kaprio, Jaakko
    Samani, Nilesh J.
    Gieger, Christian
    Peters, Annette
    Wichmann, H. -Erich
    Boomsma, Dorret I.
    de Geus, Eco J. C.
    Tuomi, TiinaMaija
    Power, Chris
    Hammond, Christopher J.
    Spector, Tim D.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Orho-Melander, Marju
    Palmer, Colin Neil Alexander
    Morris, Andrew D.
    Groop, Leif
    Jarvelin, Marjo-Riitta
    Salomaa, Veikko
    Vartiainen, Erkki
    Hofman, Albert
    Ripatti, Samuli
    Metspalu, Andres
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Pedersen, Nancy L.
    McCarthy, Mark I.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Prokopenko, Inga
    The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 6, p. e1001474-Article in journal (Refereed)
    Abstract [en]

    Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

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  • 9.
    Gunnarsdottir, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health).
    Cnattingius, Sven
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Lundgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Ekholm Selling, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Högberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhood2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 13, no 2, article id e0192514Article in journal (Refereed)
    Abstract [en]

    Background Preeclampsia is associated with low birth weight, both because of increased risks of preterm and of small-for-gestational-age (SGA) births. Low birth weight is associated with accelerated childhood height gain and cardiovascular diseases later in life. The aim was to investigate if prenatal exposure to preeclampsia is associated with accelerated childhood height gain, also after adjustments for SGA-status and gestational age at birth. Methods In a cohort of children prenatally exposed to preeclampsia (n = 865) or unexposed (n = 22,898) we estimated height gain between birth and five years of age. The mean difference in height gain between exposed and unexposed children was calculated and adjustments were done with linear regression models. Results Children exposed to preeclampsia were on average born shorter than unexposed. Exposed children grew on average two cm more than unexposed from birth to five years of age. After adjustments for maternal characteristics including socioeconomic factors, height, body mass index (BMI) and diabetes, as well as for parents smoking habits, infant's breastfeeding and childhood obesity, the difference was 1.6 cm (95% CI 1.3-1.9 cm). Further adjustment for SGA birth only slightly attenuated this estimate, but adjustment for gestational age at birth decreased the estimate to 0.5 cm (95% CI 0.1-0.7 cm). Conclusion Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhood. The association seemed independent on SGA-status, but partly related to shorter gestational age at birth.

  • 10.
    Holmberg, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Vickers, Andrew
    Evaluation of Prediction Models for Decision-Making: Beyond Calibration and Discrimination2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 7, p. e1001491-Article in journal (Other academic)
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  • 11.
    Imamura, Fumiaki
    et al.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.
    Fretts, Amanda
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Marklund, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Korat, Andres V. Ardisson
    Harvard TH Chan Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA USA.
    Yang, Wei-Sin
    Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol & Prevent Med, Taipei, Taiwan.
    Lankinen, Maria
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland.
    Qureshi, Waqas
    Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Bowman Gray Ctr,Sect Cardiovasc Med, Winston Salem, NC 27103 USA.
    Helmer, Catherine
    Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France.
    Chen, Tzu-An
    USDA ARS, Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX USA.
    Wong, Kerry
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Bassett, Julie K.
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Murphy, Rachel
    Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Ctr Excellence Canc Prevent, Vancouver, BC, Canada.
    Tintle, Nathan
    Dordt Coll, Dept Math & Stat, Sioux Ctr, IA USA.
    Yu, Chaoyu Ian
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA.
    Brouwer, Ingeborg A.
    Vrije Univ Amsterdam, Amsterdam Publ Hlth Res Inst, Fac Earth & Life Sci, Dept Hlth Sci, Amsterdam, Netherlands.
    Chien, Kuo-Liong
    Natl Taiwan Univ, Coll Publ Hlth, Inst Epidemiol & Prevent Med, Taipei, Taiwan.
    Frazier-Wood, Alexis C.
    USDA ARS, Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX USA.
    del Gobbo, Liana C.
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA USA.
    Djousse, Luc
    Brigham & Womens Hosp, Dept Med, Div Aging, 75 Francis St, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA USA.
    Geleijnse, Johanna M.
    Wageningen Univ, Div Human Nutr, Wageningen, Netherlands.
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia;Univ Melbourne, Ctr Epidemiol & Biostat, Parkville, Vic, Australia.
    de Goede, Janette
    Wageningen Univ, Div Human Nutr, Wageningen, Netherlands.
    Gudnason, Vilmundur
    Iceland Heart Assoc Res Inst, Kopavogur, Iceland.
    Harris, William S.
    Univ South Dakota, Sanford Sch Med, Dept Internal Med, Sioux Falls, SD USA;OmegaQuant Analyt LLC, Sioux Falls, SD USA.
    Hodge, Allison
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia;Univ Melbourne, Ctr Epidemiol & Biostat, Parkville, Vic, Australia.
    Hu, Frank
    Harvard TH Chan Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA USA.
    Koulman, Albert
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England;Univ Cambridge, Addenbrookes Hosp, Natl Inst Hlth Res Biomed Res Ctr Core Nutr Bioma, Cambridge, England;Univ Cambridge, Addenbrookes Hosp, Natl Inst Hlth Res Biomed Res Ctr Core Metabol &, Cambridge, England;MRC, Elsie Widdowson Lab, Cambridge, England;Univ Eastern Finland, Inst Clin Med, Internal Med, Kuopio, Finland.
    Laakso, Markku
    Kuopio Univ Hosp, Dept Med, Kuopio, Finland.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lin, Hung-Ju
    Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan.
    McKnight, Barbara
    Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA.
    Rajaobelina, Kalina
    Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala Univ, Dept Publ Hlth & Caring Sci, Clin Nutr & Metab, Uppsala, Sweden.
    Robinson, Jennifer G.
    Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA;Univ Iowa, Dept Med, Coll Publ Hlth, Iowa City, IA 52242 USA.
    Samieri, Cecilia
    Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, INSERM, UMR 1219, Bordeaux, France.
    Siscovick, David S.
    New York Acad Med, New York, NY USA.
    Soedamah-Muthu, Sabita S.
    Tilburg Univ, Ctr Res Psychol Somat Dis, Dept Med & Clin Psychol, Tilburg, Netherlands.
    Sotoodehnia, Nona
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Sun, Qi
    Harvard TH Chan Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA USA.
    Tsai, Michael Y.
    Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA.
    Uusitupa, Matti
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland.
    Wagenknecht, Lynne E.
    Wake Forest Sch Med, Publ Hlth Sci, Winston Salem, NC USA.
    Wareham, Nick J.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.
    Wu, Jason H. Y.
    Univ New South Wales, George Inst Global Hlth, Sydney, NSW, Australia;Univ New South Wales, Fac Med, Sydney, NSW, Australia.
    Micha, Renata
    Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
    Forouhi, Nita G.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.
    Lemaitre, Rozenn N.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA.
    Mozaffarian, Dariush
    Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA.
    Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 10, article id e1002670Article in journal (Refereed)
    Abstract [en]

    Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15: 0 and 17: 0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from Europe, 1 from Australia, 1 from Taiwan) performed new harmonised individual-level analysis for the prospective associations according to a standardised plan. In total, 63,682 participants with a broad range of baseline ages and BMIs and 15,180 incident cases of T2D over the average of 9 years of follow-up were evaluated. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Prespecified interactions by age, sex, BMI, and race/ethnicity were explored in each cohort and were meta-analysed. Potential heterogeneity by cohort-specific characteristics (regions, lipid compartments used for fatty acid assays) was assessed with metaregression. After adjustment for potential confounders, including measures of adiposity (BMI, waist circumference) and lipogenesis (levels of palmitate, tri-glycerides), higher levels of 15:0, 17:0, and t16:1n-7 were associated with lower incidence of T2D. In the most adjusted model, the hazard ratio (95% CI) for incident T2D per cohort-specific 10th to 90th percentile range of 15:0 was 0.80 (0.73-0.87); of 17:0, 0.65 (0.59-0.72); of t16:1n7, 0.82 (0.70-0.96); and of their sum, 0.71 (0.63-0.79). In exploratory analyses, similar associations for 15:0, 17:0, and the sum of all three fatty acids were present in both genders but stronger in women than in men ((pinteraction) < 0.001). Whereas studying associations with biomarkers has several advantages, as limitations, the biomarkers do not distinguish between different food sources of dairy fat (e.g., cheese, yogurt, milk), and residual confounding by unmeasured or imprecisely measured confounders may exist. Conclusions In a large meta-analysis that pooled the findings from 16 prospective cohort studies, higher levels of 15:0, 17:0, and t16:1n-7 were associated with a lower risk of T2D.

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  • 12.
    Johansson, Mattias
    et al.
    IARC, Lyon, France.
    Carreras-Torres, Robert
    IARC, Lyon, France.
    Scelo, Ghislaine
    IARC, Lyon, France.
    Purdue, Mark P.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Mariosa, Daniela
    IARC, Lyon, France.
    Muller, David C.
    Imperial Coll, London, England.
    Timpson, Nicolas J.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
    Haycock, Philip C.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England.
    Brown, Kevin M.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Wang, Zhaoming
    St Jude Childrens Res Hosp, Memphis, TN USA.
    Ye, Yuanqing
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX USA.
    Hofmann, Jonathan N.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Foll, Matthieu
    IARC, Lyon, France.
    Gaborieau, Valerie
    IARC, Lyon, France.
    Machiela, Mitchell J.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Colli, Leandro M.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Li, Peng
    IARC, Lyon, France;Max Planck Inst Demog Res, Rostock, Germany.
    Garnier, Jean-Guillaume
    Ctr Energie Atom & Energies Alternat, Inst Genom, Ctr Natl Genotypage, Evry, France; Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, Paris, France.
    Blanche, Helene
    Ctr Energie Atom & Energies Alternat, Inst Genom, Ctr Natl Genotypage, Evry, France.
    Boland, Anne
    Ctr Energie Atom & Energies Alternat, Inst Genom, Ctr Natl Genotypage, Evry, France.
    Burdette, Laurie
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Prokhortchouk, Egor
    Russian Acad Sci, Fed Res Ctr Fundamentals Biotechnol, Moscow, Russia.
    Skryabin, Konstantin G.
    Russian Acad Sci, Fed Res Ctr Fundamentals Biotechnol, Moscow, Russia; Kurchatov Sci Ctr, Moscow, Russia.
    Yeager, Meredith
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Radojevic-Skodric, Sanja
    Univ Belgrade Sch Med, Inst Pathol, Belgrade, Serbia; Clin Ctr Serbia, Clin Urol, Belgrade, Serbia.
    Ognjanovic, Simona
    Mayo Clin, Grad Sch Biomed Sci, Rochester, MN USA; IOCPR, Belgrade, Serbia.
    Foretova, Lenka
    Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic.
    Holcatova, Ivana
    Charles Univ Prague, Fac Med 2, Inst Publ Hlth & Prevent Med, Prague, Czech Republic.
    Janout, Vladimir
    Palacky Univ, Fac Med, Dept Prevent Med, Olomouc, Czech Republic.
    Mates, Dana
    Natl Inst Publ Hlth, Bucharest, Romania.
    Mukeriya, Anush
    Russian NN Blokhin Canc Res Ctr, Moscow, Russia.
    Rascu, Stefan
    Carol Davila Univ Med & Pharm, Th Burghele Hosp, Bucharest, Romania.
    Zaridze, David
    Russian NN Blokhin Canc Res Ctr, Moscow, Russia.
    Bencko, Vladimir
    Charles Univ Prague, Fac Med 1, Inst Hyg & Epidemiol, Prague, Czech Republic.
    Cybulski, Cezary
    Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland.
    Fabianova, Eleonora
    Reg Author Publ Hlth Banska Bystr, Banska Bystrica, Slovakia.
    Jinga, Viorel
    Carol Davila Univ Med & Pharm, Th Burghele Hosp, Bucharest, Romania.
    Lissowska, Jolanta
    M Sklodowska Curie Canc Ctr, Warsaw, Poland; Inst Oncol, Warsaw, Poland.
    Lubinski, Jan
    Pomeranian Med Univ, Dept Genet & Pathol, Int Hereditary Canc Ctr, Szczecin, Poland.
    Navratilova, Marie
    Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic.
    Rudnai, Peter
    Natl Publ Hlth Ctr, Natl Directorate Environm Hlth, Budapest, Hungary.
    Benhamou, Simone
    INSERM, U946, Paris, France; CNRS, Inst Gustave Roussy, UMR 8200, Villejuif, France.
    Cancel-Tassin, Geraldine
    CeRePP, Paris, France; UPMC Univ Paris 06, Inst Univ Cancerol, GRC 5, Paris, France.
    Cussenot, Olivier
    CeRePP, Paris, France; UPMC Univ Paris 06, Inst Univ Cancerol, GRC 5, Paris, France; Hopitaux Univ Est Parisien Tenon, AP HP, Dept Urol, Paris, France.
    Weiderpass, Elisabete
    Canc Registry Norway, Inst Population Based Canc Res, Dept Res, Oslo, Norway; Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden; Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki, Finland; Arctic Univ Norway, Univ Tromso, Dept Community Med, Tromso, Norway.
    Ljungberg, Borje
    Umeå Univ, Dept Surg & Perioperat Sci Urol & Androl, Umeå, Sweden.
    Sitaram, Raviprakash Tumkur
    Umeå Univ, Dept Surg & Perioperat Sci Urol & Androl, Umeå, Sweden.
    Häggström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Umeå Univ, Dept Biobank Res, Umeå, Sweden.
    Bruinsma, Fiona
    Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia.
    Jordan, Susan J.
    QIMR Berghofer Med Res Inst, Herston, Qld, Australia; Univ Queensland, Sch Publ Hlth, Brisbane, Qld, Australia.
    Severi, Gianluca
    Univ Paris Saclay, Univ Paris Sud, Hlth Generat Team, CESP,INSERM,Fac Med,UVSQ,Gustave Roussy, Villejuif, France; Human Genet Fdn HuGeF, Turin, Italy.
    Winship, Ingrid
    Univ Melbourne, Royal Melbourne Hosp, Dept Med, Melbourne, Vic, Australia.
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth, KG Jebsen Ctr Genet Epidemiol, Trondheim, Norway.
    Vatten, Lars J.
    Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth & Gen Practice, Trondheim, Norway.
    Fletcher, Tony
    Univ London, London Sch Hyg & Trop Med, London, England.
    Larsson, Susanna C.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Wolk, Alicja
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
    Banks, Rosamonde E.
    Univ Leeds, St Jamess Univ Hosp, Leeds Inst Canc & Pathol, Leeds, W Yorkshire, England.
    Selby, Peter J.
    Imperial Coll London, St Marys Hosp, Div Surg, Natl Inst Hlth Res Diagnost Evidence Cooperat, London, England.
    Easton, Douglas F.
    Univ Cambridge, Dept Oncol, Cambridge, England; Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.
    Andreotti, Gabriella
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA.
    Freeman, Laura E. Beane
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Koutros, Stella
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Mannisto, Satu
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Weinstein, Stephanie
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Clark, Peter E.
    Vanderbilt Ingram Canc Ctr, Nashville, TN USA.
    Edwards, Todd L.
    Vanderbilt Genet Inst, Vanderbilt Ingram Canc Ctr, Div Epidemiol, Dept Med, Nashville, TN USA.
    Lipworth, Loren
    Vanderbilt Ingram Canc Ctr, Nashville, TN USA.
    Gapstur, Susan M.
    Amer Canc Soc, Atlanta, GA 30329 USA.
    Stevens, Victoria L.
    Amer Canc Soc, Atlanta, GA 30329 USA.
    Carol, Hallie
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Freedman, Matthew L.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Pomerantz, Mark M.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Cho, Eunyoung
    Brown Univ, Providence, RI 02912 USA.
    Wilson, Kathryn M.
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA.
    Gaziano, J. Michael
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA.
    Sesso, Howard D.
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA; Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.
    Freedman, Neal D.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Parker, Alexander S.
    Mayo Clin, Dept Hlth Sci Res, Jacksonville, FL 32224 USA.
    Eckel-Passow, Jeanette E.
    Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA.
    Huang, Wen-Yi
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Kahnoski, Richard J.
    Spectrum Hlth, Div Urol, Grand Rapids, MI USA.
    Lane, Brian R.
    Spectrum Hlth, Div Urol, Grand Rapids, MI USA; Michigan State Univ, Coll Human Med, Grand Rapids, MI USA.
    Noyes, Sabrina L.
    Van Andel Res Inst, Ctr Canc Genom & Quantitat Biol, Grand Rapids, MI USA; Spectrum Hlth, Grand Rapids, MI USA.
    Petillo, David
    Van Andel Res Inst, Ctr Canc Genom & Quantitat Biol, Grand Rapids, MI USA; Ferris State Univ, Diagnost Program, Grand Rapids, MI USA.
    Teh, Bin Tean
    Van Andel Res Inst, Ctr Canc Genom & Quantitat Biol, Grand Rapids, MI USA; Natl Univ Singapore, Med Sch, Program Canc & Stem Cell Biol, Duke Natl, Singapore, Singapore; ASTAR, Inst Mol & Cell Biol, Singapore, Singapore; Natl Canc Ctr Singapore, Div Med Sci, Lab Canc Epigenome, Singapore, Singapore; Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore.
    Peters, Ulrike
    Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA.
    White, Emily
    Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1124 Columbia St, Seattle, WA 98104 USA.
    Anderson, Garnet L.
    Fred Hutchinson Canc Res Ctr, WHI Clin Coordinating Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
    Johnson, Lisa
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA.
    Luo, Juhua
    Indiana Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Bloomington, IN USA.
    Buring, Julie
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA; Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.
    Lee, I-Min
    Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA; Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA.
    Chow, Wong-Ho
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA.
    Moore, Lee E.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Eisen, Timothy
    Univ Cambridge, Cambridge, England.
    Henrion, Marc
    Inst Canc Res, London, England; Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA.
    Larkin, James
    Royal Marsden NHS Fdn Trust, London, England.
    Barman, Poulami
    Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA.
    Leibovich, Bradley C.
    Mayo Clin, Dept Urol, Rochester, MN USA.
    Choueiri, Toni K.
    Dana Farber Canc Inst, Boston, MA 02115 USA.
    Lathrop, G. Mark
    McGill Univ, Montreal, PQ, Canada;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.
    Deleuze, Jean-Francois
    Ctr Energie Atom & Energies Alternat, Inst Genom, Ctr Natl Genotypage, Evry, France; Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, Paris, France.
    Gunter, Marc
    IARC, Lyon, France.
    McKay, James D.
    IARC, Lyon, France.
    Wu, Xifeng
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Div Canc Prevent & Populat Sci, Houston, TX 77030 USA.
    Houlston, Richard S.
    Inst Canc Res, London, England.
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA.
    Relton, Caroline
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England; Univ Bristol, Sch Social & Community Med, Bristol, Avon, England.
    Richards, J. Brent
    McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ, Canada;McGill Univ, Jewish Gen Hosp, Dept Human Genet, Montreal, PQ, Canada;McGill Univ, Jewish Gen Hosp, Dept Epidemiol & Biostat, Montreal, PQ, Canada.
    Martin, Richard M.
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England; Univ Bristol, Sch Social & Community Med, Bristol, Avon, England; Univ Bristol, Univ Hosp Bristol NHS Fdn Trust, Natl Inst Hlth Res, Bristol Nutr Biomed Res Unit, Bristol, Avon, England.
    Smith, George Davey
    Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England; Univ Bristol, Sch Social & Community Med, Bristol, Avon, England.
    Brennan, Paul
    IARC, Lyon, France.
    The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 1, article id e1002724Article in journal (Refereed)
    Abstract [en]

    Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.

    Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.

    Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

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  • 13.
    Karmali, Kunal N.
    et al.
    Northwestern Univ, Dept Med, Chicago, IL 60611 USA..
    Lloyd-Jones, Donald M.
    Northwestern Univ, Dept Med, Chicago, IL 60611 USA..
    van der Leeuw, Joep
    Univ Med Ctr Utrecht, Dept Vasc Med, Utrecht, Netherlands..
    Goff, David C., Jr.
    NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA..
    Yusuf, Salim
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Zanchetti, Alberto
    Ist Auxol Italiano, Milan, Italy..
    Glasziou, Paul
    Bond Univ, Ctr Res Evidence Based Practice, Robina, Australia..
    Jackson, Rodney
    Univ Auckland, Sch Populat Hlth, Fac Med & Hlth Sci, Auckland, New Zealand..
    Woodward, Mark
    Univ Oxford, George Inst Global Hlth, Oxford, England.;George Inst Global Hlth, Sydney, NSW, Australia..
    Rodgers, Anthony
    George Inst Global Hlth, Sydney, NSW, Australia..
    Neal, Bruce C.
    George Inst Global Hlth, Sydney, NSW, Australia..
    Berge, Eivind
    Oslo Univ Hosp, Dept Cardiol, Oslo, Norway..
    Teo, Koon
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Davis, Barry R.
    Univ Texas Dallas, Sch Publ Hlth, Dallas, TX USA..
    Chalmers, John
    George Inst Global Hlth, Sydney, NSW, Australia..
    Pepine, Carl
    Univ Florida, Div Cardiovasc Med, Gainesville, FL USA..
    Rahimi, Kazem
    Univ Oxford, George Inst Global Hlth, Oxford, England..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Blood pressure-lowering treatment strategies based on cardiovascular risk versus blood pressure: A meta-analysis of individual participant data2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 3, article id e1002538Article in journal (Refereed)
    Abstract [en]

    Background: Clinical practice guidelines have traditionally recommended blood pressure treatment based primarily on blood pressure thresholds. In contrast, using predicted cardiovascular risk has been advocated as a more effective strategy to guide treatment decisions for cardiovascular disease (CVD) prevention. We aimed to compare outcomes from a blood pressure-lowering treatment strategy based on predicted cardiovascular risk with one based on systolic blood pressure (SBP) level.

    Methods and findings: We used individual participant data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) from 1995 to 2013. Trials randomly assigned participants to either blood pressure-lowering drugs versus placebo or more intensive versus less intensive blood pressure-lowering regimens. We estimated 5-y risk of CVD events using a multivariable Weibull model previously developed in this dataset. We compared the two strategies at specific SBP thresholds and across the spectrum of risk and blood pressure levels studied in BPLTTC trials. The primary outcome was number of CVD events avoided per persons treated. We included data from 11 trials (47,872 participants). During a median of 4.0 y of follow-up, 3,566 participants (7.5%) experienced a major cardiovascular event. Areas under the curve comparing the two treatment strategies throughout the range of possible thresholds for CVD risk and SBP demonstrated that, on average, a greater number of CVD events would be avoided for a given number of persons treated with the CVD risk strategy compared with the SBP strategy (area under the curve 0.71 [95% confidence interval (CI) 0.70-0.72] for the CVD risk strategy versus 0.54 [95% CI 0.53-0.55] for the SBP strategy). Compared with treating everyone with SBP >= 150 mmHg, a CVD risk strategy would require treatment of 29% (95% CI 26%-31%) fewer persons to prevent the same number of events or would prevent 16% (95% CI 14%-18%) more events for the same number of persons treated. Compared with treating everyone with SBP >= 140 mmHg, a CVD risk strategy would require treatment of 3.8% (95% CI 12.5% fewer to 7.2% more) fewer persons to prevent the same number of events or would prevent 3.1% (95% CI 1.5%-5.0%) more events for the same number of persons treated, although the former estimate was not statistically significant. In subgroup analyses, the CVD risk strategy did not appear to be more beneficial than the SBP strategy in patients with diabetes mellitus or established CVD.

    Conclusions: A blood pressure-lowering treatment strategy based on predicted cardiovascular risk is more effective than one based on blood pressure levels alone across a range of thresholds. These results support using cardiovascular risk assessment to guide blood pressure treatment decision-making in moderate- to high-risk individuals, particularly for primary prevention.

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  • 14.
    KC, Ashish
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Ewald, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Basnet, Omkar
    Golden Community, Jawgal, Lalitpur, Nepal.
    Gurung, Abhishek
    Golden Community, Jawgal, Lalitpur, Nepal.
    Pyakuryal, Sushil Nath
    Nepal Hlth Res Council, Kathmandu, Nepal.
    Jha, Bijay Kumar
    Govt Nepal, Minist Hlth & Populat, Kathmandu, Nepal.
    Bergström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. UCL, UCL Inst Global Hlth IGH, London, England.
    Eriksson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Paudel, Prajwal
    Nepal Hlth Res Council, Kathmandu, Nepal.
    Karki, Sushil
    Life Line Nepal, Kathmandu, Nepal.
    Gajurel, Sunil
    Kamana Hlth Nepal, Kathmandu, Nepal.
    Brunell, Olivia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Wrammert, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Litorp, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Målqvist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), Global Health Research on Implementation and Sustainability.
    Effect of a scaled-up neonatal resuscitation quality improvement package on intrapartum-related mortality in Nepal: A stepped-wedge cluster randomized controlled trial2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 9, article id e1002900Article in journal (Refereed)
    Abstract [en]

    Background Improving quality of intrapartum care will reduce intrapartum stillbirth and neonatal mortality, especially in resource-poor settings. Basic neonatal resuscitation can reduce intrapartum stillbirth and early neonatal mortality, if delivered in a high-quality health system, but there is a dearth of evidence on how to scale up such evidence-based interventions. We evaluated the scaling up of a quality improvement (QI) package for neonatal resuscitation on intrapartum-related mortality (intrapartum stillbirth and first day mortality) at hospitals in Nepal. Methods and findings We conducted a stepped-wedge cluster randomized controlled trial in 12 hospitals over a period of 18 months from April 14, 2017, to October 17, 2018. The hospitals were assigned to one of four wedges through random allocation. The QI package was implemented in a stepped-wedge manner with a delay of three months for each step. The QI package included improving hospital leadership on intrapartum care, building health workers' competency on neonatal resuscitation, and continuous facilitated QI processes in clinical units. An independent data collection system was set up at each hospital to gather data on mortality through patient case note review and demographic characteristics of women using semi-structured exit interviews. The generalized linear mixed model (GLMM) and multivariate logistic regression were used for analyses. During this study period, a total of 89,014 women-infant pairs were enrolled. The mean age of the mother in the study period was 24.0 +/- 4.3 years, with 54.9% from disadvantaged ethnic groups and 4.0% of them illiterate. Of the total birth cohort, 54.4% were boys, 16.7% had gestational age less than 37 weeks, and 17.1% had birth weight less than 2,500 grams. The incidence of intrapartum-related mortality was 11.0 per 1,000 births during the control period and 8.0 per 1,000 births during the intervention period (adjusted odds ratio [aOR], 0.79; 95% CI, 0.69-0.92; p = 0.002; intra-cluster correlation coefficient [ICC], 0.0286). The incidence of early neonatal mortality was 12.7 per 1,000 live births during the control period and 10.1 per 1,000 live births during the intervention period (aOR, 0.89; 95% CI, 0.78-1.02; p = 0.09; ICC, 0.1538). The use of bag-and-mask ventilation for babies with low Apgar score (<7 at 1 minute) increased from 3.2% in the control period to 4.0% in the intervention period (aOR, 1.52; 95% CI, 1.32-1.77, p = 0.003). There were two major limitations to the study; although a large sample of women-infant pairs were enrolled in the study, the clustering reduced the power of the study. Secondly, the study was not sufficiently powered to detect reduction in early neonatal mortality with the number of clusters provided. Conclusion These results suggest scaled-up implementation of a QI package for neonatal resuscitation can reduce intrapartum-related mortality and improve clinical care. The QI intervention package is likely to be effective in similar settings. More implementation research is required to assess the sustainability of QI interventions and quality of care.

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  • 15. Kloprogge, Frank
    et al.
    Workman, Lesley
    Borrmann, Steffen
    Tékété, Mamadou
    Lefèvre, Gilbert
    Hamed, Kamal
    Piola, Patrice
    Ursing, Johan
    Kofoed, Poul Erik
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Ngasala, Billy
    Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
    Björkman, Anders
    Ashton, Michael
    Friberg Hietala, Sofia
    Aweeka, Francesca
    Parikh, Sunil
    Mwai, Leah
    Davis, Timothy M. E.
    Karunajeewa, Harin
    Salman, Sam
    Checchi, Francesco
    Fogg, Carole
    Newton, Paul N.
    Mayxay, Mayfong
    Deloron, Philippe
    Faucher, Jean François
    Nosten, François
    Ashley, Elizabeth A.
    McGready, Rose
    van Vugt, Michele
    Proux, Stephane
    Price, Ric N.
    Karbwang, Juntra
    Ezzet, Farkad
    Bakshi, Rajesh
    Stepniewska, Kasia
    White, Nicholas J.
    Guerin, Philippe J.
    Barnes, Karen I.
    Tarning, Joel
    Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 6, article id e1002579Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.

    METHODS AND FINDINGS: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.

    CONCLUSIONS: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

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  • 16.
    Launonen, Antti P.
    et al.
    Univ Tampere, Fac Med & Hlth Technol, Tampere, Finland;Tampere Univ Hosp, Tampere, Finland.
    Sumrein, Bakir O.
    Univ Tampere, Fac Med & Hlth Technol, Tampere, Finland;Tampere Univ Hosp, Tampere, Finland.
    Reito, Aleksi
    Cent Finland Cent Hosp, Dept Orthopaed, Jyvaskyla, Finland.
    Lepola, Vesa
    Univ Tampere, Fac Med & Hlth Technol, Tampere, Finland;Tampere Univ Hosp, Tampere, Finland.
    Paloneva, Juha
    Cent Finland Cent Hosp, Dept Orthopaed, Jyvaskyla, Finland.
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolf, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ström, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Berg, Hans E.
    Karolinska Inst, Div Orthoped & Biotechnol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Orthoped, Huddinge, Sweden.
    Fellander-Tsai, Li
    Karolinska Inst, Div Orthoped & Biotechnol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Orthoped, Huddinge, Sweden.
    Jansson, Karl-Ake
    Karolinska Inst, Div Orthoped & Biotechnol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Orthoped, Huddinge, Sweden.
    Fell, Daniel
    Karolinska Inst, Div Orthoped & Biotechnol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Orthoped, Huddinge, Sweden.
    Mechlenburg, Inger
    Aarhus Univ Hosp, Dept Orthopaed Surg, Aarhus, Denmark;Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Dossing, Kaj
    Viborg Reg Hosp, Orthoped Dept, Viborg, Denmark.
    Ostergaard, Helle
    Viborg Reg Hosp, Orthoped Dept, Viborg, Denmark.
    Martson, Aare
    Tartu Univ Hosp, Dept Traumatol & Orthoped, Tartu, Estonia;Tartu Univ, Tartu, Estonia.
    Laitinen, Minna K.
    Univ Tampere, Fac Med & Hlth Technol, Tampere, Finland;Tampere Univ Hosp, Tampere, Finland.
    Mattila, Ville M.
    Univ Tampere, Fac Med & Hlth Technol, Tampere, Finland;Tampere Univ Hosp, Tampere, Finland.
    Operative versus non-operative treatment for 2-part proximal humerus fracture: A multicenter randomized controlled trial2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 7, article id e1002855Article in journal (Refereed)
    Abstract [en]

    Background

    Although increasingly used, the benefit of surgical treatment of displaced 2-part proximal humerus fractures has not been proven. This trial evaluates the clinical effectiveness of surgery with locking plate compared with non-operative treatment for these fractures.

    Methods and findings

    The NITEP group conducted a superiority, assessor-blinded, multicenter randomized trial in 6 hospitals in Finland, Estonia, Sweden, and Denmark. Eighty-eight patients aged 60 years or older with displaced (more than 1 cm or 45 degrees) 2-part surgical or anatomical neck proximal humerus fracture were randomly assigned in a 1:1 ratio to undergo either operative treatment with a locking plate or non-operative treatment. The mean age of patients was 72 years in the non-operative group and 73 years in the operative group, with a female sex distribution of 95% and 87%, respectively. Patients were recruited between February 2011 and April 2016. The primary outcome measure was Disabilities of Arm, Shoulder, and Hand (DASH) score at 2-year follow-up. Secondary outcomes included Constant–Murley score, the visual analogue scale for pain, the quality of life questionnaire 15D, EuroQol Group’s 5-dimension self-reported questionnaire EQ-5D, the Oxford Shoulder Score, and complications. The mean DASH score (0 best, 100 worst) at 2 years was 18.5 points for the operative treatment group and 17.4 points for the non-operative group (mean difference 1.1 [95% CI −7.8 to 9.4], p = 0.81). At 2 years, there were no statistically or clinically significant between-group differences in any of the outcome measures. All 3 complications resulting in secondary surgery occurred in the operative group. The lack of blinding in patient-reported outcome assessment is a limitation of the study. Our assessor physiotherapists were, however, blinded.

    Conclusions

    This trial found no significant difference in clinical outcomes at 2 years between surgery and non-operative treatment in patients 60 years of age or older with displaced 2-part fractures of the proximal humerus. These results suggest that the current practice of performing surgery on the majority of displaced proximal 2-part fractures of the humerus in older adults may not be beneficial.

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  • 17.
    Lei, Jiayao
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Ploner, Alexander
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Lagheden, Camilla
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Eklund, Carina
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Kleppe, Sara Nordqvist
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Andrae, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Elfström, K. Miriam
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden;Reg Canc Ctr Stockholm Gotland, Stockholm, Sweden.
    Dillner, Joakim
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Stockholm, Sweden.
    Sparén, Pär
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Sundström, Karin
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Stockholm, Sweden.
    High-risk human papillomavirus status and prognosis in invasive cervical cancer: A nationwide cohort study2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 10, article id e1002666Article in journal (Refereed)
    Abstract [en]

    Background: High-risk human papillomavirus (hrHPV) infection is established as the major cause of invasive cervical cancer (ICC). However, whether hrHPV status in the tumor is associated with subsequent prognosis of ICC is controversial. We aim to evaluate the association between tumor hrHPV status and ICC prognosis using national registers and comprehensive human papillomavirus (HPV) genotyping.

    Methods and findings: In this nationwide population-based cohort study, we identified all ICC diagnosed in Sweden during the years 2002-2011 (4,254 confirmed cases), requested all archival formalin-fixed paraffin-embedded blocks, and performed HPV genotyping. Twenty out of 25 pathology bio-banks agreed to the study, yielding a total of 2,845 confirmed cases with valid HPV results. Cases were prospectively followed up from date of cancer diagnosis to 31 December 2015, migration from Sweden, or death, whichever occurred first. The main exposure was tumor hrHPV status classified as hrHPV-positive and hrHPV-negative. The primary outcome was all-cause mortality by 31 December 2015. Five-year relative survival ratios (RSRs) were calculated, and excess hazard ratios (EHRs) with 95% confidence intervals (CIs) were estimated using Poisson regression, adjusting for education, time since cancer diagnosis, and clinical factors including age at cancer diagnosis and International Federation of Gynecology and Obstetrics (FIGO) stage. Of the 2,845 included cases, hrHPV was detected in 2,293 (80.6%), and we observed 1,131 (39.8%) deaths during an average of 6.2 years follow-up. The majority of ICC cases were diagnosed at age 30-59 years (57.5%) and classified as stage IB (40.7%). hrHPV positivity was significantly associated with screen-detected tumors, young age, high education level, and early stage at diagnosis (p < 0.001). The 5-year RSR compared to the general female population was 0.74 (95% CI 0.72-0.76) for hrHPV-positive cases and 0.54 (95% CI 0.50-0.59) for hrHPV-negative cases, yielding a crude EHR of 0.45 (95% CI 0.38-0.52) and an adjusted EHR of 0.61 (95% CI 0.52-0.71). Risk of all-cause mortality as measured by EHR was consistently and statistically significantly lower for cases with hrHPV-positive tumors for each age group above 29 years and each FIGO stage above IA. The difference in prognosis by hrHPV status was highly robust, regardless of the clinical, histological, and educational characteristics of the cases. The main limitation was that, except for education, we were not able to adjust for lifestyle factors or other unmeasured confounders.

    Conclusions: In this study, women with hrHPV-positive cervical tumors had a substantially better prognosis than women with hrHPV-negative tumors. hrHPV appears to be a biomarker for better prognosis in cervical cancer independent of age, FIGO stage, and histological type, extending information from already established prognostic factors. The underlying biological mechanisms relating lack of detectable tumor hrHPV to considerably worse prognosis are not known and should be further investigated.

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  • 18.
    Mascalzoni, Deborah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hicks, Andrew
    Pramstaller, Peter
    Wjst, Matthias
    Informed consent in the genomics era.2008In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 5, no 9, p. e192-194Article in journal (Refereed)
  • 19.
    Mendelson, Michael M.
    et al.
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;Boston Univ, Sch Med, Boston, MA 02118 USA.;Boston Childrens Hosp, Dept Cardiol, Boston, MA USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA.;Boston Univ, Dept Biostat, Boston, MA USA..
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Aslibekyan, Stella
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Demerath, Ellen W.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Guan, Weihua
    Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA..
    Zhi, Degui
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA..
    Yao, Chen
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Huan, Tianxiao
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Willinger, Christine
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Chen, Brian
    NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Courchesne, Paul
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Multhaup, Michael
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Lrvin, Marguerite R.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Cohain, Ariella
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA..
    Grove, Megan L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    Bressler, Jan
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA..
    North, Kari
    Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Shah, Sonia
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    McRae, Allan F.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Harris, Sarah E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland..
    Gibson, Jude
    Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH8 9YL, Midlothian, Scotland..
    Redmond, Paul
    Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Coriey, Janie
    Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Murphy, Lee
    Univ Edinburgh, Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH8 9YL, Midlothian, Scotland..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland..
    Kleinbrink, Erica
    Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA.;Wayne State Univ, Dept Neurol, Detroit, MI USA..
    Lipovich, Leonard
    Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA.;Wayne State Univ, Dept Neurol, Detroit, MI USA..
    Visscher, Peter M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Wray, Naomi R.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Krauss, Ronald M.
    Childrens Hosp Oakland Res Inst, Oakland, CA USA..
    Fallin, Daniele
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Feinberg, Andrew
    Johns Hopkins Univ, Sch Med, Ctr Epigenet, Baltimore, MD USA..
    Absher, Devin M.
    HudsonAlpha Inst Biotechnol, Huntsville, AL USA..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Univ Texas Houston, Brown Fdn Inst Mol Med, Houston, TX USA..
    Pankow, James S.
    Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Fox, Caroline
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Arnett, Donna K.
    Univ Kentucky, Coll Publ Hlth, Lexington, KY USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX 77030 USA.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Liang, Liming
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.;NHLBI, Populat Sci Branch, NIH, Bethesda, MD 20892 USA..
    Deary, Lan J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 1, article id e1002215Article in journal (Refereed)
    Abstract [en]

    Background The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.

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  • 20.
    Michaëlsson, Karl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Jensevik, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Leisure physical activity and the risk of fracture in men2007In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 4, no 6, p. 1094-1100Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Data from previous studies are inconsistent, and it is therefore uncertain whether, to what extent, and at what level leisure physical activity influences the risk of osteoporotic fractures in men. METHODS AND FINDINGS: A cohort of 2,205 men, 49-51 y of age, was enrolled in a longitudinal, population-based study. Leisure physical activity and other lifestyle habits were established at baseline and at ages 60, 70, 77, and 82 y. During 35 y of follow-up, 482 men had at least one fracture. Cox's proportional hazards regression was used to determine hazard ratios (HRs) of fracture associated with time-dependent physical activity habits and covariates. Men with a sedentary lifestyle (HR 2.56, 95% confidence interval 1.55-4.24) or men who walked or bicycled only for pleasure (HR 1.61, 95% confidence interval 1.10-2.36) had an increased adjusted risk of hip fracture compared with men who participated in regular sports activities for at least 3 h/wk. At the end of follow-up, 8.4% of the men with a high physical activity, 13.3% of the men with a medium physical activity, and 20.5% of the men with a low physical activity had suffered a hip fracture. According to the estimation of population-attributable risk, one third of all hip fractures could be prevented by participation in regular sports activities. High activity also conferred a reduced overall fracture risk. CONCLUSIONS: Our data indicate that regular sports activities can reduce the risk of fractures in older men.

  • 21.
    Persson, Lars-Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Nga, Nguyen Thu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Målqvist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Thi Phuong Hoa, Dinh
    Hanoi School of Public Health, Hanoi, Viet Nam.
    Eriksson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Wallin, Lars
    Department of Neurobiology, Care Sciences and Society, Division of Nursing, Karolinska Institutet, Stockholm.
    Selling, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Huy, Tran Q
    Ministry of Health, Hanoi, Viet Nam.
    Duc, Duong M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Tiep, Tran V
    Vietnam-Sweden Uong Bi General Hospital, Uong Bi, Viet Nam.
    Thi Thu Thuy, Vu
    Provincial Health Bureau, Quang Ninh Province, Viet Nam.
    Ewald, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Effect of Facilitation of Local Maternal-and-Newborn Stakeholder Groups on Neonatal Mortality: Cluster-Randomized Controlled Trial2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 5, p. e1001445-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Facilitation of local women's groups may reportedly reduce neonatal mortality. It is not known whether facilitation of groups composed of local health care staff and politicians can improve perinatal outcomes. We hypothesised that facilitation of local stakeholder groups would reduce neonatal mortality (primary outcome) and improve maternal, delivery, and newborn care indicators (secondary outcomes) in Quang Ninh province, Vietnam.

    METHODS AND FINDINGS:

    In a cluster-randomized design 44 communes were allocated to intervention and 46 to control. Laywomen facilitated monthly meetings during 3 years in groups composed of health care staff and key persons in the communes. A problem-solving approach was employed. Births and neonatal deaths were monitored, and interviews were performed in households of neonatal deaths and of randomly selected surviving infants. A latent period before effect is expected in this type of intervention, but this timeframe was not pre-specified. Neonatal mortality rate (NMR) from July 2008 to June 2011 was 16.5/1,000 (195 deaths per 11,818 live births) in the intervention communes and 18.4/1,000 (194 per 10,559 live births) in control communes (adjusted odds ratio [OR] 0.96 [95% CI 0.73-1.25]). There was a significant downward time trend of NMR in intervention communes (p = 0.003) but not in control communes (p = 0.184). No significant difference in NMR was observed during the first two years (July 2008 to June 2010) while the third year (July 2010 to June 2011) had significantly lower NMR in intervention arm: adjusted OR 0.51 (95% CI 0.30-0.89). Women in intervention communes more frequently attended antenatal care (adjusted OR 2.27 [95% CI 1.07-4.8]).

    CONCLUSIONS:

    A randomized facilitation intervention with local stakeholder groups composed of primary care staff and local politicians working for three years with a perinatal problem-solving approach resulted in increased attendance to antenatal care and reduced neonatal mortality after a latent period.

    TRIAL REGISTRATION:

    Current Controlled Trials ISRCTN44599712

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  • 22. Richmond, Rebecca C.
    et al.
    Smith, George Davey
    Ness, Andy R.
    den Hoed, Marcel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    McMahon, George
    Timpson, Nicholas J.
    Assessing Causality in the Association between Child Adiposity and Physical Activity Levels: A Mendelian Randomization Analysis2014In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 11, no 3Article in journal (Refereed)
    Abstract [en]

    Background Cross-sectional studies have shown that objectively measured physical activity is associated with childhood adiposity, and a strong inverse dose-response association with body mass index (BMI) has been found. However, few studies have explored the extent to which this association reflects reverse causation. We aimed to determine whether childhood adiposity causally influences levels of physical activity using genetic variants reliably associated with adiposity to estimate causal effects. Methods and Findings The Avon Longitudinal Study of Parents and Children collected data on objectively assessed activity levels of 4,296 children at age 11 y with recorded BMI and genotypic data. We used 32 established genetic correlates of BMI combined in a weighted allelic score as an instrumental variable for adiposity to estimate the causal effect of adiposity on activity. In observational analysis, a 3.3 kg/m(2) (one standard deviation) higher BMI was associated with 22.3 (95% CI, 17.0, 27.6) movement counts/min less total physical activity (p = 1.6x10(-16)), 2.6 (2.1, 3.1) min/d less moderate-to-vigorous-intensity activity (p = 3.7x10(-29)), and 3.5 (1.5, 5.5) min/d more sedentary time (p = 5.0x10(-4)). In Mendelian randomization analyses, the same difference in BMI was associated with 32.4 (0.9, 63.9) movement counts/min less total physical activity (p = 0.04) (similar to 5.3% of the mean counts/minute), 2.8 (0.1, 5.5) min/d less moderate-to-vigorous-intensity activity (p = 0.04), and 13.2 (1.3, 25.2) min/d more sedentary time (p = 0.03). There was no strong evidence for a difference between variable estimates from observational estimates. Similar results were obtained using fat mass index. Low power and poor instrumentation of activity limited causal analysis of the influence of physical activity on BMI. Conclusions Our results suggest that increased adiposity causes a reduction in physical activity in children and support research into the targeting of BMI in efforts to increase childhood activity levels. Importantly, this does not exclude lower physical activity also leading to increased adiposity, i.e., bidirectional causation. Please see later in the article for the Editors' Summary Editors' Summary Background The World Health Organization estimates that globally at least 42 million children under the age of five are obese. The World Health Organization recommends that all children undertake at least one hour of physical activity daily, on the basis that increased physical activity will reduce or prevent excessive weight gain in children and adolescents. In practice, while numerous studies have shown that body mass index (BMI) shows a strong inverse correlation with physical activity (i.e., active children are thinner than sedentary ones), exercise programs specifically targeted at obese children have had only very limited success in reducing weight. The reasons for this are not clear, although environmental factors such as watching television and lack of exercise facilities are traditionally blamed. Why Was This Study Done? ? One of the reasons why obese children do not lose weight through exercise might be that being fat in itself leads to a decrease in physical activity. This is termed reverse causation, i.e. , obesity causes sedentary behavior, rather than the other way around. The potential influence of environmental factors (e.g., lack of opportunity to exercise) makes it difficult to prove this argument. Recent research has demonstrated that specific genotypes are related to obesity in children. Specific variations within the DNA of individual genes (single nucleotide polymorphisms, or SNPs) are more common in obese individuals and predispose to greater adiposity across the weight distribution. While adiposity itself can be influenced by many environmental factors that complicate the interpretation of observed associations, at the population level, genetic variation is not related to the same factors, and over the life course cannot be changed. Investigations that exploit these properties of genetic associations to inform the interpretation of observed associations are termed Mendelian randomization studies. This research technique is used to reduce the influence of confounding environmental factors on an observed clinical condition. The authors of this study use Mendelian randomization to determine whether a genetic tendency towards high BMI and fat mass is correlated with reduced levels of physical activity in a large cohort of children. What Did the Researchers Do and Find? ? The researchers looked at a cohort of children from a large long-term health research project (the Avon Longitudinal Study of Parents and Children). BMI and total body fat were recorded. Total daily activity was measured via a small movement-counting device. In addition, the participants underwent genotyping to detect the presence of several SNPs known to be linked to obesity. For each child a total BMI allelic score was determined based on the number of obesity-related genetic variants carried by that individual. The association between obesity and reduced physical activity was then studied in two ways. Direct correlation between actual BMI and physical activity was measured (observational data). Separately, the link between BMI allelic score and physical activity was also determined (Mendelian randomization or instrumental variable analysis). The observational data showed that boys were more active than girls and had lower BMI. Across both sexes, a higher-than-average BMI was associated with lower daily activity. In genetic analyses, allelic score had a positive correlation with BMI, with one particular SNP being most strongly linked to high BMI and total fat mass. A high allelic score for BMI was also correlated with lower levels of daily physical activity. The authors conclude that children who are obese and have an inherent predisposition to high BMI also have a propensity to reduced levels of physical activity, which may compound their weight gain. What Do These Findings Mean? ? This study provides evidence that being fat is in itself a risk factor for low activity levels, separately from external environmental influences. This may be an example of "reverse causation," i.e., high BMI causes a reduction in physical activity. Alternatively, there may be a bidirectional causality, so that those with a genetic predisposition to high fat mass exercise less, leading to higher BMI, and so on, in a vicious circle. A significant limitation of the study is that validated allelic scores for physical activity are not available. Thus, it is not possible to determine whether individuals with a high allelic score for BMI also have a propensity to exercise less, or whether it is simply the circumstance of being overweight that discourages activity. This study does suggest that trying to persuade obese children to lose weight by exercising more is likely to be ineffective unless additional strategies to reduce BMI, such as strict diet control, are also implemented. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001618. The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States A more worldwide view is given by the World Health Organization The UK National Health Service website gives information on physical activity guidelines for different age groups The International Obesity Task Force is a network of organizations that seeks to alert the world to the growing health crisis threatened by soaring levels of obesity MedlinePlus-which brings together authoritative information from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations-has a page on obesity Additional information on the Avon Longitudinal Study of Parents and Children is available The British Medical Journal has an article that describes <ext-link ext-link-type="uri" xlink:href="http://www.bmj.com/content/345/bmj. e7325" xlink:type="simple">Mendelian randomization

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  • 23.
    Sewankambo, Nelson
    et al.
    Principal, College of Health Sciences, Makerere University, Kampala, Uganda.
    Tumwine, James K
    Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda.
    Tomson, Göran
    Department of Learning, Informatics, Management and Ethics, Karolinska Institutet, Stockholm, Sweden.
    Obua, Celestino
    School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda.
    Bwanga, Freddie
    Department of Medical Microbiology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda.
    Waiswa, Peter
    Department of Public Health Sciences, Global Health, Karolinska Institutet, Stockholm, Sweden.
    Katabira, Elly
    Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda.
    Akuffo, Hannah
    Unit for Research Cooperation, Swedish International Development cooperation Agency (Sida), Stockholm, Sweden.
    Persson, Kristina
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Enabling Dynamic Partnerships through Joint Degrees between Low- and High-Income Countries for Capacity Development in Global Health Research: Experience from the Karolinska Institutet/Makerere University Partnership2015In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 12, no 2, p. e1001784-Article in journal (Refereed)
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  • 24.
    Svensson, J. Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Stalpers, L.J.
    Esveldt-van Lange, R.E.
    Franken, N.
    Haveman, J.
    Klein, B.
    Turesson, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Vrieling, I.
    Giphart-Gassler, M.
    Analysis of gene expression using gene sets discriminates cancer patients with and without late radiation toxicity2006In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 3, no 10, p. 1904-1914Article in journal (Refereed)
    Abstract [en]

    Background Radiation is an effective anti-cancer therapy but leads to severe late radiation toxicity in 5%-10% of patients. Assuming that genetic susceptibility impacts this risk, we hypothesized that the cellular response of normal tissue to X-rays could discriminate patients with and without late radiation toxicity.

    Methods and Findings Prostate carcinoma patients without evidence of cancer 2 y after curative radiotherapy were recruited in the study. Blood samples of 21 patients with severe late complications from radiation and 17 patients without symptoms were collected. Stimulated peripheral lymphocytes were mock-irradiated or irradiated with 2-Gy X-rays. The 24-h radiation response was analyzed by gene expression profiling and used for classification. Classification was performed either on the expression of separate genes or, to augment the classification power, on gene sets consisting of genes grouped together based on function or cellular colocalization. X- ray irradiation altered the expression of radio-responsive genes in both groups. This response was variable across individuals, and the expression of the most significant radio-responsive genes was unlinked to radiation toxicity. The classifier based on the radiation response of separate genes correctly classified 63% of the patients. The classifier based on affected gene sets improved correct classification to 86%, although on the individual level only 21/38 (55%) patients were classified with high certainty. The majority of the discriminative genes and gene sets belonged to the ubiquitin, apoptosis, and stress signaling networks. The apoptotic response appeared more pronounced in patients that did not develop toxicity. In an independent set of 12 patients, the toxicity status of eight was predicted correctly by the gene set classifier.

    Conclusions Gene expression profiling succeeded to some extent in discriminating groups of patients with and without severe late radiotherapy toxicity. Moreover, the discriminative power was enhanced by assessment of functionally or structurally related gene sets. While prediction of individual response requires improvement, this study is a step forward in predicting susceptibility to late radiation toxicity.

  • 25. Valdimarsdottir, Unnur
    et al.
    Hultman, Christina M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Harlow, Bernard
    Cnattingius, Sven
    Sparén, Pär
    Psychotic Illness in First-Time Mothers with No Previous Psychiatric Hospitalizations: A Population-Based Study2009In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 6, no 2, p. 194-201Article in journal (Refereed)
    Abstract [en]

    Background Psychotic illness following childbirth is a relatively rare but severe condition with unexplained etiology. The aim of this study was to investigate the impact of maternal background characteristics and obstetric factors on the risk of postpartum psychosis, specifically among mothers with no previous psychiatric hospitalizations. Methods and Findings We investigated incidence rates and potential maternal and obstetric risk factors of psychoses after childbirth in a national cohort of women who were first-time mothers from 1983 through 2000 (n=745,596). Proportional hazard regression models were used to estimate relative risks of psychoses during and after the first 90 d postpartum, among mothers without any previous psychiatric hospitalization and among all mothers. Within 90 d after delivery, 892 women (1.2 per 1,000 births; 4.84 per 1,000 person-years) were hospitalized due to psychoses and 436 of these (0.6 per 1,000 births; 2.38 per 1,000 person-years) had not previously been hospitalized for any psychiatric disorder. During follow-up after the 90 d postpartum period, the corresponding incidence rates per 1,000 person-years were reduced to 0.65 for all women and 0.49 for women not previously hospitalized. During (but not after) the first 90 d postpartum the risk of psychoses among women without any previous psychiatric hospitalization was independently affected by: maternal age (35 y or older versus 19 y or younger; hazard ratio 2.4, 95% confidence interval [CI] 1.2 to 4.7); high birth weight (>= 4,500 g; hazard ratio 0.3, 95% CI 0.1 to 1.0); and diabetes (hazard ratio 0). Conclusions The incidence of psychotic illness peaks immediately following a first childbirth, and almost 50% of the cases are women without any previous psychiatric hospitalization. High maternal age increases the risk while diabetes and high birth weight are associated with reduced risk of first-onset psychoses, distinctly during the postpartum period.

  • 26. Vimaleswaran, Karani S.
    et al.
    Berry, Diane J.
    Lu, Chen
    Tikkanen, Emmi
    Pilz, Stefan
    Hiraki, Linda T.
    Cooper, Jason D.
    Dastani, Zari
    Li, Rui
    Houston, Denise K.
    Wood, Andrew R.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Vandenput, Liesbeth
    Zgaga, Lina
    Yerges-Armstrong, Laura M.
    McCarthy, Mark I.
    Dupuis, Josee
    Kaakinen, Marika
    Kleber, Marcus E.
    Jameson, Karen
    Arden, Nigel
    Raitakari, Olli
    Viikari, Jorma
    Lohman, Kurt K.
    Ferrucci, Luigi
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ingelsson, Erik
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lorentzon, Mattias
    Salomaa, Veikko
    Campbell, Harry
    Dunlop, Malcolm
    Mitchell, Braxton D.
    Herzig, Karl-Heinz
    Pouta, Anneli
    Hartikainen, Anna-Liisa
    Streeten, Elizabeth A.
    Theodoratou, Evropi
    Jula, Antti
    Wareham, Nicholas J.
    Ohlsson, Claes
    Frayling, Timothy M.
    Kritchevsky, Stephen B.
    Spector, Timothy D.
    Richards, J. Brent
    Lehtimaki, Terho
    Ouwehand, Willem H.
    Kraft, Peter
    Cooper, Cyrus
    Maerz, Winfried
    Power, Chris
    Loos, Ruth J. F.
    Wang, Thomas J.
    Jaervelin, Marjo-Riitta
    Whittaker, John C.
    Hingorani, Aroon D.
    Hyppoenen, Elina
    Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 2, p. e1001383-Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH) D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. Methods and Findings: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH) D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH) D (p = 6.52x10(-27)). The BMI allele score was associated both with BMI (p = 6.30x10(-62)) and 25(OH) D (20.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH) D (p <= 8.07x10(-57) for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH) D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH) D with BMI, a finding that was confirmed using data from the GIANT consortium (p >= 0.57 for both vitamin D scores). Conclusions: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH) D, while any effects of lower 25(OH) D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.

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  • 27.
    Wainberg, Michael
    et al.
    Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.
    Mahajan, Anubha
    Univ Oxford, Wellcome Ctr Human Genet, Oxford, England;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Oxford, England.
    Kundaje, Anshul
    Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA.
    McCarthy, Mark I.
    Univ Oxford, Wellcome Ctr Human Genet, Oxford, England;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Oxford, England;Churchill Hosp, NIHR Oxford Biomed Res Ctr, Oxford, England;Genentech Inc, OMNI Human Genet, San Francisco, CA 94080 USA.
    Ingelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Sinnott-Armstrong, Nasa
    Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
    Rivas, Manuel A.
    Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA.
    Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study2019In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 16, no 12, article id e1002982Article in journal (Refereed)
    Abstract [en]

    Background: Lifestyle interventions to reduce body mass index (BMI) are critical public health strategies for type 2 diabetes prevention. While weight loss interventions have shown demonstrable benefit for high-risk and prediabetic individuals, we aimed to determine whether the same benefits apply to those at lower risk.

    Methods and findings: We performed a multi-stratum Mendelian randomization study of the effect size of BMI on diabetes odds in 287,394 unrelated individuals of self-reported white British ancestry in the UK Biobank, who were recruited from across the United Kingdom from 2006 to 2010 when they were between the ages of 40 and 69 years. Individuals were stratified on the following diabetes risk factors: BMI, diabetes family history, and genome-wide diabetes polygenic risk score. The main outcome measure was the odds ratio of diabetes per 1-kg/m(2) BMI reduction, in the full cohort and in each stratum. Diabetes prevalence increased sharply with BMI, family history of diabetes, and genetic risk. Conversely, predicted risk reduction from weight loss was strikingly similar across BMI and genetic risk categories. Weight loss was predicted to substantially reduce diabetes odds even among lower-risk individuals: for instance, a 1-kg/m(2) BMI reduction was associated with a 1.37-fold reduction (95% CI 1.12-1.68) in diabetes odds among non-overweight individuals (BMI < 25 kg/m(2)) without a family history of diabetes, similar to that in obese individuals (BMI >= 30 kg/m(2)) with a family history (1.21-fold reduction, 95% CI 1.13-1.29). A key limitation of this analysis is that the BMI-altering DNA sequence polymorphisms it studies represent cumulative predisposition over an individual's entire lifetime, and may consequently incorrectly estimate the risk modification potential of weight loss interventions later in life.

    Conclusions In a population-scale cohort, lower BMI was consistently associated with reduced diabetes risk across BMI, family history, and genetic risk categories, suggesting all individuals can substantially reduce their diabetes risk through weight loss. Our results support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk. 

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  • 28.
    Wang, Jiangrong
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Andrae, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Sundstrom, Karin
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden..
    Ploner, Alexander
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Strom, Peter
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Elfstrom, K. Miriam
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden..
    Dillner, Joakim
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.;Karolinska Univ Hosp, Karolinska Univ Lab, Stockholm, Sweden..
    Sparen, Par
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Effectiveness of cervical screening after age 60 years according to screening history: Nationwide cohort study in Sweden2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 10, article id e1002414Article in journal (Refereed)
    Abstract [en]

    Background The relatively high incidence of cervical cancer in women at older ages is a continuing concern in countries with long-established cervical screening. Controversy remains on when and how to cease screening. Existing population-based studies on the effectiveness of cervical screening at older ages have not considered women's screening history. We performed a nationwide cohort study to investigate the incidence of cervical cancer after age 60 years and its association with cervical screening at age 61-65, stratified by screening history at age 51-60. Methods and findings Using the Total Population Register, we identified 569,132 women born between 1 January 1919 and 31 December 1945, resident in Sweden since age 51. Women's cytological screening records, cervical cancer occurrence, and FIGO stage (for those diagnosed with cancer) were retrieved from national registers and medical charts. We calculated the cumulative incidence of cervical cancer from age 61 to age 80 using a survival function considering competing risk, and estimated the hazard ratio (HR) of cervical cancer in relation to screening status at age 61-65 from Cox models, adjusted for birth cohort and level of education, conditioning on women's screening history in their 50s. In women unscreened in their 50s, the cumulative incidence up to age 80 was 5.0 per 1,000 women, and screening at age 61-65 was associated with a lower risk for cervical cancer (HR = 0.42, 95% CI 0.24-0.72), corresponding to a decrease of 3.3 cancer cases per 1,000 women. A higher cumulative incidence and similarly statistically significant risk decrease was seen for women with abnormal smears in their 50s. In women adequately or inadequately screened with only normal results between age 51 and age 60, the cumulative incidence of cervical cancer from age 61 to 80 was 1.6 and 2.5 per 1,000 women, respectively, and further screening at age 61-65 was not associated with statistically significant decreases of cervical cancer risk up to age 80, but with fewer cancer cases of advanced stages at age 61-65. Adjustment for potential lifestyle confounders was limited. Conclusions In this study, cervical screening with cytology at age 61-65 was associated with a statistically significant reduction of subsequent cervical cancer risk for women who were unscreened, or screened with abnormalities, in their 50s. In women screened with normal results in their 50s, the risk for future cancer was not sizeable, and the risk reduction associated with continued screening appeared limited. These findings should inform the current debate regarding age and criteria to discontinue cervical screening.

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  • 29.
    Wheeler, Eleanor
    et al.
    Wellcome Trust Sanger Inst, Dept Human Genet, Genome Campus, Cambridge, England..
    Leong, Aaron
    Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA.;Harvard Med Sch, Boston, MA USA..
    Liu, Ching-Ti
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Hivert, Marie-France
    Harvard Pilgrim Hlth Care Inst, Harvard Med Sch, Dept Populat Med, Boston, MA USA.;Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Jukhuset, Ctr Mol Med, Solna, Sweden..
    Podmore, Clara
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;Lausanne Univ Hosp CHUV, Dept Internal Med, Lausanne, Switzerland..
    Li, Man
    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.;Univ Utah, Div Nephrol, Salt Lake City, UT USA.;Univ Utah, Dept Human Genet, Salt Lake City, UT USA..
    Yao, Jie
    LABioMed Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA USA..
    Sim, Xueling
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Hong, Jaeyoung
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA..
    Chu, Audrey Y.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Zhang, Weihua
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Wang, Xu
    Natl Univ Singapore, Life Sci Inst, Singapore, Singapore..
    Chen, Peng
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA.;Jilin Univ, Minist Educ, Key Lab Pathobiol, Jilin, Jilin, Peoples R China.;Jilin Univ, Coll Basic Med Sci, Changchun, Jilin, Peoples R China..
    Maruthur, Nisa M.
    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA.;Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA.;Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore..
    Porneala, Bianca C.
    Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA..
    Sharp, Stephen J.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Jia, Yucheng
    LABioMed Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA USA..
    Kabagambe, Edmond K.
    Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Chang, Li-Ching
    Acad Sinica, Inst Biomed Sci, Taipei, Taiwan..
    Chen, Wei-Min
    Univ Virginia, Ctr Publ Hlth Gen, Charlottesville, VA USA..
    Elks, Cathy E.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;AstraZeneca, Innovat Med & Early Dev Biotech Unit, Personalised Healthcare & Biomarkers, Cambridge, England..
    Evans, Daniel S.
    Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA..
    Fan, Qiao
    Duke NUS Med Sch, Ctr Quantitat Med, Singapore, Singapore..
    Giulianini, Franco
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Go, Min Jin
    Korean Natl Inst Hlth, Ctr Genome Sci, Div Struct & Funct Genom, Osong, Chungchungbuk D, South Korea..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam, Netherlands..
    Hu, Yao
    Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci,Key Lab Nutr & Metab, Shanghai, Peoples R China..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Kanoni, Stavroula
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England..
    Kim, Young Jin
    Korean Natl Inst Hlth, Ctr Genome Sci, Div Struct & Funct Genom, Osong, Chungchungbuk D, South Korea..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Ladenvall, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Lund Univ Diabet Ctr, Lund, Sweden..
    Lecoeur, Cecile
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Lim, Sing-Hui
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Marzi, Carola
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res DZD eV, Partner Munich, Munich, Germany..
    Nalls, Mike A.
    Data Tecn Int, Glen Echo, MD USA.;NIA, Neurogenet Lab, Bethesda, MD 20892 USA..
    Navarro, Pau
    Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Rybin, Denis V.
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA 02215 USA..
    Sanna, Serena
    CNR, IRGB, Monserrato, Italy..
    Shi, Yuan
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore..
    Stram, Daniel O.
    Univ Southern Calif, Dept Prevent Med, Los Angeles, CA USA..
    Takeuchi, Fumihiko
    Natl Ctr Global Hlth & Med, Dept Gene Diagnost & Therapeut, Res Inst, Tokyo, Japan..
    Tan, Shu Pei
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Van Vliet-Ostaptchouk, Jana V.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Wong, Andrew
    MRC Unit Lifelong Hlth & Ageing, London, England..
    Yengo, Loic
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Zhao, Wanting
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore..
    Goel, Anuj
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England..
    Martinez Larrad, Maria Teresa
    Spanish Biomed Res Ctr Diabet & Assoc Metab Disor, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Madrid, Spain..
    Radke, Doert
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Salo, Perttu
    Natl Inst Hlth & Welf THL, Helsinki, Finland.;Univ Helsinki, Inst Mol Med, Finland FIMM & Diabet & Obes Res Program, Helsinki, Finland..
    Tanaka, Toshiko
    NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA..
    van Iperen, Erik P. A.
    Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands.;Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, ICIN, Utrecht, Netherlands..
    Abecasis, Goncalo
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Afaq, Saima
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England..
    Alizadeh, Behrooz Z.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Bertoni, Alain G.
    Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA..
    Bonnefond, Amelia
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Boettcher, Yvonne
    Univ Leipzig, Integrated Res & Treatment IFB Ctr Adipos Dis, Leipzig, Germany..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland..
    Carlson, Olga D.
    NIA, Clin Invest Lab, Baltimore, MD 21224 USA..
    Chen, Chien-Hsiun
    Acad Sinica, Inst Biomed Sci, Taipei, Taiwan.;China Med Univ, Sch Chinese Med, Taichung, Taiwan..
    Cho, Yoon Shin
    Korean Natl Inst Hlth, Ctr Genome Sci, Div Struct & Funct Genom, Osong, Chungchungbuk D, South Korea.;Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea..
    Garvey, W. Timothy
    Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA.;Univ Alabama Birmingham, Birmingham Vet Affairs Med Ctr, Birmingham, AL USA..
    Gieger, Christian
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol 2, Neuherberg, Germany..
    Goodarzi, Mark O.
    Cedars Sinai Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA..
    Grallert, Harald
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol 2, Neuherberg, Germany.;German Ctr Diabet Res DZD eV, Partner Munich, Munich, Germany..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Jukhuset, Ctr Mol Med, Solna, Sweden..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Herder, Christian
    Univ Dusseldorf, German Diabet Ctr, Leibniz Inst Diabet Res Heinrich Heine, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Hsiung, Chao Agnes
    Ohio State Univ, Wexner Med Ctr, Dept Internal Med, Div Endocrinol Diabet Metab, Columbus, OH 43210 USA..
    Huang, Jie
    Boston VA Res Inst Inc, Boston, MA USA..
    Igase, Michiya
    Ehime Univ, Grad Sch Med, Dept Geriatr Med, Matsuyama, Ehime, Japan..
    Isono, Masato
    Natl Ctr Global Hlth & Med, Dept Gene Diagnost & Therapeut, Res Inst, Tokyo, Japan..
    Katsuya, Tomohiro
    Osaka Univ, Grad Sch Med, Dept Clin Gene Therapy, Suita, Osaka, Japan.;Osaka Univ, Grad Sch Med, Dept Geriatr Med & Nephrol, Suita, Osaka, Japan..
    Khor, Chiea-Chuen
    Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore..
    Kiess, Wieland
    Univ Leipzig, Univ Hosp Children & Adolescents, Dept Womens & Child Hlth, Ctr Pediat Res, Leipzig, Germany.;Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, LIFE Child, Leipzig, Germany..
    Kohara, Katsuhiko
    Ehime Univ, Fac Collaborat Reg Innovat, Matsuyama, Ehime, Japan..
    Kovacs, Peter
    Univ Leipzig, Integrated Res & Treatment IFB Ctr Adipos Dis, Leipzig, Germany..
    Lee, Juyoung
    Korean Natl Inst Hlth, Ctr Genome Sci, Div Struct & Funct Genom, Osong, Chungchungbuk D, South Korea..
    Lee, Wen-Jane
    Taichung Vet Gen Hosp, Dept Med Res, Taichung, Taiwan..
    Lehne, Benjamin
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England..
    Li, Huaixing
    Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci,Key Lab Nutr & Metab, Shanghai, Peoples R China..
    Liu, Jianjun
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore..
    Lobbens, Stephane
    Univ Lille, CNRS, Inst Pasteur Lille, EGID,UMR 8199, Lille, France..
    Luang, Jian'an
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Lyssenko, Valeriya
    Lund Univ, Lund Univ Diabet Ctr, Lund, Sweden..
    Meitinger, Thomas
    Tech Univ Munich, Inst Human Genet, Munich, Germany.;Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany.;Munich Cluster Syst Neurol SyNergy, Munich, Germany.;Singapore Natl Eye Ctr, Singapore, Singapore..
    Miki, Tetsuro
    Ehime Univ, Grad Sch Med, Dept Geriatr Med, Matsuyama, Ehime, Japan..
    Miljkovic, Iva
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA..
    Moon, Sanghoon
    Korean Natl Inst Hlth, Ctr Genome Sci, Div Struct & Funct Genom, Osong, Chungchungbuk D, South Korea..
    Mulas, Antonella
    CNR, IRGB, Monserrato, Italy..
    Mueller, Gabriele
    Univ Hosp & Med Fac Carl Gustav Carus, Ctr Evidence Based Healthcare, Dresden, Germany..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany.;DZHK German Ctr Cardiovasc Res, Partner Site Munich Heart Alliance, Munich, Germany.;King Abdulaziz Univ, Fand Med Res Ctr, Saudi Diabet Res Grp, Jeddah, Saudi Arabia..
    Nagaraja, Ramaiah
    NIA, Genet Lab, Baltimore, MD 21224 USA..
    Nauck, Matthias
    Univ Med Greifswald, Inst Clin Chem, Greifswald, Germany.;Univ Med Greifswald, Lab Med, Greifswald, Germany..
    Pankow, James S.
    Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Polasek, Ozren
    Univ Split, Split, Croatia.;Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland..
    Prokopenko, Inga
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Ramos, Paula S.
    Med Univ South Carolina, Dept Med, Charleston, SC USA..
    Rasmussen-Torvik, Laura
    Northwestern Univ Feinberg Sch Med, Dept Prevent Med, Chicago, IL USA..
    Rathmann, Wolfgang
    German Ctr Diabet Res DZD, Neuherberg, Germany..
    Rich, Stephen S.
    Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA..
    Robertson, Neil R.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Roden, Michael
    Univ Dusseldorf, German Diabet Ctr, Leibniz Inst Diabet Res Heinrich Heine, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany..
    Roussel, Ronan
    Ctr Rech Cordelier, INSERM, UMR S 1138, Paris, France.;Univ Paris Diderot, Sorbonne Paris Cite, UFR Med, Paris, France.;Hop Xavier Bichat, AP HP, DHU FIRE, Dept Diabetol Endocrinol & Nutr, Paris, France..
    Rudan, Igor
    Univ Edinburgh, Edinburgh, Midlothian, Scotland..
    Scott, Robert A.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Scott, William R.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Jukhuset, Ctr Mol Med, Solna, Sweden.;Karolinska Inst, Sci life Lab, Solna, Sweden..
    Siscovick, David S.
    New York Acad Med, New York, NY USA..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Sun, Liang
    Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci,Key Lab Nutr & Metab, Shanghai, Peoples R China..
    Swertz, Morris
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Tajuddin, Salman M.
    NIA, Hlth Dispar Unit, NIH, Baltimore, MD 21224 USA..
    Taylor, Kent D.
    LABioMed Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA USA..
    Teo, Yik-Ying
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Life Sci Inst, Singapore, Singapore.;Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore.;Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore, Singapore..
    Tham, Yih Chung
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore..
    Toenjes, Anke
    Univ Leipzig, Dept Med, Leipzig, Germany..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Willemsen, Gonneke
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam, Netherlands..
    Wilsgaard, Tom
    Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway..
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, London, England..
    Egan, Josephine
    NIA, Clin Invest Lab, Baltimore, MD 21224 USA..
    Ferrucci, Luigi
    NIA, Clin Invest Lab, Baltimore, MD 21224 USA..
    Hovingh, G. Kees
    Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands..
    Jula, Antti
    Natl Inst Hlth & Welf THL, Helsinki, Finland..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London, England..
    Kumari, Meena
    UCL, Dept Epidemiol & Publ Hlth, London, England.;Univ Essex, Inst Social & Econ Res, Colchester, Essex, England..
    Njolstad, Inger
    Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway..
    Palmer, Colin N. A.
    Med Res Inst, Ninewells Hosp & Med Sch, Pat Macpherson Ctr Pharmacogenet & Pharmacogenom, Dundee, Scotland..
    Serrano Rios, Manuel
    Spanish Biomed Res Ctr Diabet & Assoc Metab Disor, Inst Invest Sanitaria Hosp Clin San Carlos IdISSC, Madrid, Spain..
    Stumvoll, Michael
    Univ Leipzig, Dept Med, Leipzig, Germany..
    Watkins, Hugh
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England..
    Aung, Tin
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore.;Duke NUS Med Sch, Ophthalmol & Visual Sci Acad Clin Program Eye ACP, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Blueher, Matthias
    Univ Leipzig, Dept Med, Leipzig, Germany..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam, Netherlands..
    Bornstein, Stefan R.
    Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany..
    Chambers, John C.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Genet, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Broad Inst MIT & Harvard, Cambridge, MA USA..
    Chen, Yii-Der Ida
    LABioMed Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA USA..
    Chen, Yduan-Tsong
    Acad Sinica, Inst Biomed Sci, Taipei, Taiwan..
    Cheng, Ching-Yu
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore.;Duke NUS Med Sch, Ophthalmol & Visual Sci Acad Clin Program Eye ACP, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Cucca, Francesco
    CNR, IRGB, Monserrato, Italy.;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy..
    de Geus, Eco J. C.
    Vrije Univ Amsterdam, Biol Psychol, Amsterdam, Netherlands..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England.;King Abdulaziz Univ, Princess Al Jawhara AI Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Evans, Michele K.
    NIA, Hlth Dispar Unit, NIH, Baltimore, MD 21224 USA..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Div Epidemiol, Brown Fdn Inst Mol Med, Houston, TX 77030 USA..
    Friedlander, Yechiel
    Hebrew Univ Jerusalem, Hadassah Med Ctr, Braun Sch Publ Hlth, Jerusalem, Israel..
    Froguel, Philippe
    Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England.;Lille Univ, CNRS 8199, Lille, France..
    Groop, Leif
    Lund Univ, Lund Univ Diabet Ctr, Lund, Sweden.;Finnish Inst Mol Med, Helsinki, Finland..
    Gross, Myron D.
    Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA..
    Harris, Tamara B.
    NIA, Bethesda, MD 20892 USA..
    Hayward, Caroline
    Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Heng, Chew-Kiat
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Paediat, Singapore, Singapore.;Natl Univ Hlth Syst, Khoo Teck Puat Natl Univ Childrens Med Inst, Singapore, Singapore..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA..
    Kato, Norihiro
    Natl Ctr Global Hlth & Med, Dept Gene Diagnost & Therapeut, Res Inst, Tokyo, Japan..
    Kim, Bong-Jo
    Korean Natl Inst Hlth, Ctr Genome Sci, Div Struct & Funct Genom, Osong, Chungchungbuk D, South Korea..
    Koh, Woon-Puay
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Duke NUS Med Sch Singapore, Singapore, Singapore..
    Kooner, Jaspal S.
    Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Natl Heart & Lung Inst, Hammersmith Hosp Campus, London, England..
    Koerner, Antje
    Univ Leipzig, Univ Hosp Children & Adolescents, Dept Womens & Child Hlth, Ctr Pediat Res, Leipzig, Germany.;Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, LIFE Child, Leipzig, Germany..
    Kuh, Diana
    MRC Unit Lifelong Hlth & Ageing, London, England..
    Kuusisto, Johanna
    Univ Eastern Finland, Inst Clin Med Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Laakso, Markku
    Univ Eastern Finland, Inst Clin Med Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Lin, Xu
    Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci,Key Lab Nutr & Metab, Shanghai, Peoples R China..
    Liu, Yongmei
    Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA..
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    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth Dev Inst, New York, NY 10029 USA..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
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    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria.;Synlab Serv GmbH, Synlab Acad, Mannheim, Germany..
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    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Ong, Ken K.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Pereira, Mark A.
    Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA..
    Peters, Annette
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Inst Epidemiol 2, Neuherberg, Germany..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA.;Harvard Med Sch, Boston, MA USA.;Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA..
    Sabanayagam, Charumathi
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore.;Duke NUS Med Sch, Ophthalmol & Visual Sci Acad Clin Program Eye ACP, Singapore, Singapore..
    Sale, Michele
    Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA..
    Saleheen, Danish
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
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    Cent Finland, Cent Hosp, Dept Med, Jyvaskyla, Finland..
    Schwarz, Peter E. H.
    Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany..
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    Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrine & Metab, Taichung, Taiwan.;Natl Yang Ming Univ, Sch Med, Taipei, Taiwan.;Natl Def Med Ctr, Sch Med, Taipei, Taiwan..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Tabara, Yasuharu
    Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan..
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    Natl Inst Hlth & Welf, Chron Dis Prevent Unit, Helsinki, Finland.;Dasman Diabet Inst, Dasman, Kuwait.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria..
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    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Wilson, James F.
    Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland..
    Wolffenbuttel, Bruce H. R.
    Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, Groningen, Netherlands..
    Wong, Tien Yin
    Singapore Eye Res Inst, Acad Level 6, Discovery Tower, Singapore, Singapore.;Duke NUS Med Sch, Ophthalmol & Visual Sci Acad Clin Program Eye ACP, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore..
    Wu, Jer-Yuarn
    Acad Sinica, Inst Biomed Sci, Taipei, Taiwan.;China Med Univ, Sch Chinese Med, Taichung, Taiwan..
    Yuan, Jian-Min
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA.;Univ Pittsburgh, Inst Canc, Div Canc Control & Populat Sci, Pittsburgh, PA USA..
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    NIA, Lab Epidemiol & Populat Sci, NIH, Baltimore, MD 21224 USA..
    Soranzo, Nicole
    Wellcome Trust Sanger Inst, Dept Human Genet, Genome Campus, Cambridge, England.;Univ Cambridge, Dept Haematol, Cambridge, England.;Univ Cambridge, Natl Inst Hlth Res Blood & Transplant Unit NIHR B, Cambridge, England..
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    LABioMed Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA USA..
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    Univ Oxford, Biomed Res Ctr Oxford Haematol Theme, Headley Way, Oxford, England.;Univ Oxford, John Radcliffe Hosp, Radcliffe Dept Med, Headley Way, Oxford, England.;NHS Blood & Transplant, Oxford, England..
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    Harvard Med Sch, Boston, MA USA.;Massachusetts Gen Hosp, Diabet Unit & Ctr Human Genet Res, Boston, MA 02114 USA.;Broad Inst, Programs Metab & Med & Populat Genet, Cambridge, MA USA..
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    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
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    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Duke NUS Med Sch Singapore, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore..
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    Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA.;Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA.;Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA.;Singapore Natl Eye Ctr, Singapore, Singapore..
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    LABioMed Harbor UCLA Med Ctr, Dept Pediat, Inst Translat Genom & Populat Sci, Torrance, CA USA..
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    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
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    Wellcome Trust Sanger Inst, Dept Human Genet, Genome Campus, Cambridge, England.;Univ Cambridge, Inst Metab Sci, Cambridge, England..
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    Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis2017In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, no 9, article id e1002383Article in journal (Refereed)
    Abstract [en]

    Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

    Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

    Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

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