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  • 1.
    Blennow, Mats
    et al.
    Karolinska Univ Hosp, Dept Pediat, Huddinge, Sweden; Karolinska Inst, Dept Clin Invest Intervent & Technol, Stockholm, Sweden.
    Ewald, Uwe
    ppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.
    Fritz, Tomas
    Sahlgrens Univ Hosp, Dept Obstet & Gynecol, S-41345 Gothenburg, Sweden.
    Holmgren, Per Åke
    Umea Univ, Dept Clin Sci Obstetr & Gynecol, Umea, Sweden.
    Jeppsson, Annika
    Linkoping Univ, Dept Obstet & Gynecol, Linkoping, Sweden.
    Lindberg, Eva
    Örebro universitet, Hälsoakademin.
    Lundqvist, Anita
    Lund Univ, Dept Hlth Sci, Lund, Sweden.
    Lindeberg, Solveig Nordén
    Uppsala Univ, Dept Obstet & Gynecol, Uppsala, Sweden.
    Olhager, Elisabeth
    Linkoping Univ, Dept Pediat, S-58183 Linkoping, Sweden.
    Östlund, Ingrid
    Orebro Univ Hosp, Dept Obstet & Gynecol, Orebro, Sweden.
    Simic, Marija
    Karolinska Univ Hosp Solna, Dept Obstet & Gynecol, Stockholm, Sweden.
    Sjoers, Gunnar
    Uppsala Univ, Dept Pediat, Uppsala, Sweden.
    Stigson, Lennart
    Sahlgrens Univ Hosp, Dept Pediat, Gothenburg, Sweden.
    Fellman, Vineta
    Lund Univ, Dept Pediat, S-22100 Lund, Sweden.
    Hellstrom-Westas, Lena
    Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden.
    Norman, Mikael
    Karolinska Inst, Dept Clin Invest Intervent & Technol, Stockholm, Sweden; Karolinska Univ Hosp, Dept Pediat, Huddinge, Sweden.
    Westgren, Magnus
    Karolinska Univ Hosp Huddinge, Dept Obstet & Gynecol, Stockholm, Sweden.
    Holmstrom, Gerd
    Uppsala Univ, Dept Ophthalmol, Uppsala, Sweden.
    Laurini, Ricardo
    Nordland Hosp, Dept Pathol, Bodo, Norway.
    Stjernqvist, Karin
    Lund Univ, Dept Psychol, S-22100 Lund, Sweden.
    Kallén, Karin
    Lund Univ, Ctr Reprod Epidemiol, S-22100 Lund, Sweden.
    Lagercrantz, Hugo
    Karolinska Inst, Dept Women & Child Hlth, Stockholm, Sweden; Astrid Lindgren Childrens Hosp, Stockholm, Sweden.
    Marsal, Karel
    Lund Univ, Dept Obstet & Gynecol, S-22100 Lund, Sweden.
    Serenius, Fredrik
    Umea Univ, Dept Clin Sci, S-90187 Umea, Sweden.
    Wennergren, Margareta
    Sahlgrens Univ Hosp, Dept Obstet & Gynecol, Gothenburg, Sweden.
    Nilstun, Tore
    Lund Univ, Dept Med Eth, S-22100 Lund, Sweden.
    Olausson, Petra Otterblad
    Natl Board Hlth & Welf, Ctr Epidemiol, Stockholm, Sweden.
    Stromberg, Bo
    Uppsala Univ, Dept Pediat, Uppsala, Sweden.
    One-year survival of extremely preterm infants after active perinatal care in sweden2009Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 301, nr 21, s. 2225-2233Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context Up-to-date information on infant survival after extremely preterm birth is needed for assessing perinatal care services, clinical guidelines, and parental counseling. Objective To determine the 1-year survival in all infants born before 27 gestational weeks in Sweden during 2004-2007. Design, Setting, and Patients Population-based prospective observational study of extremely preterm infants (707 live-born and 304 stillbirths) born to 887 mothers in 904 deliveries (102 multiple births) in all obstetric and neonatal units in Sweden from April 1, 2004, to March 31, 2007. Main Outcome Measures Infant survival to 365 days and survival without major neonatal morbidity (intraventricular hemorrhage grade > 2, retinopathy of prematurity stage > 2, periventricular leukomalacia, necrotizing enterocolitis, severe bronchopulmonary dysplasia). Associations between perinatal interventions and survival. Results The incidence of extreme prematurity was 3.3 per 1000 infants. Overall perinatal mortality was 45% (from 93% at 22 weeks to 24% at 26 weeks), with 30% stillbirths, including 6.5% intrapartum deaths. Of live-born infants, 91% were admitted to neonatal intensive care and 70% survived to 1 year of age (95% confidence interval [CI], 67%-73%). The Kaplan-Meier survival estimates for 22, 23, 24, 25, and 26 weeks were 9.8% (95% CI, 4%-23%), 53% ( 95% CI, 44%-63%), 67% (95% CI, 59%-75%), 82% (95% CI, 76%-87%), and 85% ( 95% CI, 81%-90%), respectively. Lower risk of infant death was associated with tocolytic treatment (adjusted for gestational age odds ratio [ OR], 0.43; 95% CI, 0.36-0.52), antenatal corticosteroids (OR, 0.44; 95% CI, 0.24-0.81), surfactant treatment within 2 hours after birth ( OR, 0.47; 95% CI, 0.32-0.71), and birth at a level III hospital (OR, 0.49; 95% CI, 0.32-0.75). Among 1-year survivors, 45% had no major neonatal morbidity. Conclusion During 2004 to 2007, 1-year survival of infants born alive at 22 to 26 weeks of gestation in Sweden was 70% and ranged from 9.8% at 22 weeks to 85% at 26 weeks. JAMA. 2009;301(21):2225-2233 www.jama.com

  • 2.
    Chang, Zheng
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, England.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Långström, Niklas
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fazel, Seena
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, England.
    Association Between Prescription of Major Psychotropic Medications and Violent Reoffending After Prison Release2016Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 316, nr 17, s. 1798-1807Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Importance: Individuals released from prison have high rates of violent reoffending, and there is uncertainty about whether pharmacological treatments reduce reoffending risk.

    Objective: To investigate the associations between major classes of psychotropic medications and violent reoffending.

    Design, Setting, and Participants: This cohort study included all released prisoners in Sweden from July 1, 2005, to December 31, 2010, through linkage of population-based registers. Rates of violent reoffending during medicated periods were compared with rates during nonmedicated periods using within-individual analyses. Follow-up ended December 31, 2013.

    Exposures: Periods with or without dispensed prescription of psychotropic medications (antipsychotics, antidepressants, psychostimulants, drugs used in addictive disorders, and antiepileptic drugs) after prison release. Prison-based psychological treatments were investigated as a secondary exposure.

    Main Outcomes and Measures: Violent crime after release from prison.

    Results: The cohort included 22 275 released prisoners (mean [SD] age, 38 [13] years; 91.9% male). During follow-up (median, 4.6 years; interquartile range, 3.0-6.4 years), 4031 individuals (18.1%) had 5653 violent reoffenses. The within-individual hazard ratio (HR) associated with dispensed antipsychotics was 0.58 (95% CI, 0.39-0.88), based on 100 events in 1596 person-years during medicated periods and 1044 events in 11 026 person-years during nonmedicated periods, equating to a risk difference of 39.7 (95% CI, 11.3-57.7) fewer violent reoffenses per 1000 person-years. The within-individual HR associated with dispensed psychostimulants was 0.62 (95% CI, 0.40-0.98), based on 94 events in 1648 person-years during medicated periods and 513 events in 4553 person-years during nonmedicated periods, equating to a risk difference of 42.8 (95% CI, 2.2-67.6) fewer violent reoffenses per 1000 person-years. The within-individual HR associated with dispensed drugs for addictive disorders was 0.48 (95% CI, 0.23-0.97), based on 46 events in 1168 person-years during medicated periods and 1103 events in 15 725 person-years during nonmedicated periods, equating to a risk difference of 36.4 (95% CI, 2.1-54.0) fewer violent reoffenses per 1000 person-years. In contrast, antidepressants and antiepileptics were not significantly associated with violent reoffending rates (HR = 1.09 [95% CI, 0.83-1.43] and 1.14 [95% CI, 0.79-1.65], respectively). The most common prison-based program was psychological treatments for substance abuse, associated with an HR of 0.75 (95% CI, 0.63-0.89), which equated to a risk difference of 23.2 (95% CI, 10.3-34.1) fewer violent reoffenses per 1000 person-years.

    Conclusions and Relevance: Among released prisoners in Sweden, rates of violent reoffending were lower during periods when individiduals were dispensed antipsychotics, psychostimulants, and drugs for addictive disorders, compared with periods in which they were not dispensed these medications. Further research is needed to understand the causal nature of this association.

  • 3.
    Ekelund, Ulf
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, United Kingdom; Department of Sport Medicine, Norwegian School of Sport Science, Oslo, Norway .
    Luan, Jian'an
    MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, United Kingdom .
    Sherar, Lauren B.
    College of Kinesiology, University of Saskatchewan, Saskatoon, Canada; School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom.
    Esliger, Dale W.
    College of Kinesiology, University of Saskatchewan, Saskatoon, Canada; School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, United Kingdom.
    Griew, Pippa
    School of Sport and Health Sciences, University of Exeter, Exeter, United Kingdom.
    Cooper, Ashley
    Exercise, Nutrition and Health Sciences, School for Policy Studies, University of Bristol, Bristol, United Kingdom.
    Moderate to vigorous physical activity and sedentary time and cardiometabolic risk factors in children and adolescents2012Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 307, nr 7, s. 704-712Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Sparse data exist on the combined associations between physical activity and sedentary time with cardiometabolic risk factors in healthy children.

    Objective: To examine the independent and combined associations between objectively measured time in moderate- to vigorous-intensity physical activity (MVPA) and sedentary time with cardiometabolic risk factors.

    Design, Setting, and Participants: Pooled data from 14 studies between 1998 and 2009 comprising 20 871 children (aged 4-18 years) from the International Children's Accelerometry Database. Time spent in MVPA and sedentary time were measured using accelerometry after reanalyzing raw data. The independent associations between time in MVPA and sedentary time, with outcomes, were examined using meta-analysis. Participants were stratified by tertiles of MVPA and sedentary time.

    Main Outcome Measures: Waist circumference, systolic blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and insulin.

    Results: Times (mean [SD] min/d) accumulated by children in MVPA and being sedentary were 30 (21) and 354 (96), respectively. Time in MVPA was significantly associated with all cardiometabolic outcomes independent of sex, age, monitor wear time, time spent sedentary, and waist circumference (when not the outcome). Sedentary time was not associated with any outcome independent of time in MVPA. In the combined analyses, higher levels of MVPA were associated with better cardiometabolic risk factors across tertiles of sedentary time. The differences in outcomes between higher and lower MVPA were greater with lower sedentary time. Mean differences in waist circumference between the bottom and top tertiles of MVPA were 5.6 cm (95% CI, 4.8-6.4 cm) for high sedentary time and 3.6 cm (95% CI, 2.8-4.3 cm) for low sedentary time. Mean differences in systolic blood pressure for high and low sedentary time were 0.7 mm Hg (95% CI, -0.07 to 1.6) and 2.5 mmHg (95% CI, 1.7-3.3), and for high-density lipoprotein cholesterol, differences were -2.6 mg/dL(95% CI, -1.4 to -3.9) and -4.5 mg/dL(95% CI, -3.3 to -5.6), respectively. Geometric mean differences for insulin and triglycerides showed similar variation. Those in the top tertile of MVPA accumulated more than 35 minutes per day in this intensity level compared with fewer than 18 minutes per day for those in the bottom tertile. In prospective analyses (N=6413 at 2.1 years' follow-up), MVPA and sedentary time were not associated with waist circumference at follow-up, but a higher waist circumference at baseline was associated with higher amounts of sedentary time at follow-up.

    Conclusion: Higher MVPA time by children and adolescents was associated with better cardiometabolic risk factors regardless of the amount of sedentary time.

  • 4. Friberg, Örjan
    et al.
    Svedjeholm, Rolf
    Söderquist, Bo
    Örebro universitet, Hälsoakademin.
    Treating sternal wound infections after cardiac surgery with an implantable gentamicin-collagen sponge2010Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 304, nr 19, s. 2123-2124Artikkel i tidsskrift (Fagfellevurdert)
  • 5.
    Jansen, Willemijn J.
    et al.
    Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands.
    Ossenkoppele, Rik
    Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands; Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands; Department of Neurology, Memory and Aging Center, University of California, San Francisco; Helen Wills Neuroscience Institute, University of California, Berkeley.
    Knol, Dirk L.
    Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
    Tijms, Betty M.
    Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
    Scheltens, Philip
    Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
    Verhey, Frans R. J.
    Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands.
    Visser, Pieter Jelle
    Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands; Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
    The Amyloid Biomarker Study Group,
    Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis2015Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 313, nr 19, s. 1924-1938Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Importance  Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.

    Objective  To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).

    Data Sources  Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.

    Study Selection  Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.

    Data Extraction and Synthesis  Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.

    Main Outcomes and Measures  Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.

    Results  The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.

    Conclusions and Relevance  Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

  • 6. Johansson, Jan-Erik
    et al.
    Andrén, Ove
    Örebro universitet, Hälsoakademin.
    Andersson, Swen-Olof
    Dickman, Paul W.
    Holmberg, Lars
    Magnuson, Anders
    Adami, Hans-Olov
    Natural history of early, localized prostate cancer2004Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 291, nr 22, s. 2713-2719Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context Among men with early prostate cancer, the natural history without initial therapy determines the potential for survival benefit following radical local treatment. However, little is known about disease progression and mortality beyond 10 to 15 years of watchful waiting. Objective To examine the long-term natural history of untreated, early stage prostatic cancer. Design Population-based, cohort study with a mean observation period of 21 years. Setting Regionally well-defined catchment area in central Sweden (recruitment March 1977 through February 1984). Patients A consecutive sample of 223 patients (98% of all eligible) with early-stage (T0-T2 NX MO classification), initially untreated prostatic cancer. Patients with tumor progression were hormonally treated (either by orchiectomy or estrogens) if they had symptoms. Main Outcome Measures Progression-free, cause-specific, and overall survival. Results After complete follow-up, 39 (17%) of all patients experienced generalized disease. Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 (when 49 patients were still alive) to 20 years, revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer-specific survival (from 78.7% to 54.4%). The prostate cancer mortality rate increased from 15 per 1000 person-years (95% confidence interval, 10-21) during the first 15 years to 44 per 1000 person-years (95% confidence interval, 22-88) beyond 15 years of follow-up (P=.01). Conclusion Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.

  • 7.
    Lebwohl, Benjamin
    et al.
    Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, USA; Mailman School of Public Health, Department of Epidemiology, Columbia University, New York, USA.
    Green, Peter H. R.
    Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, USA.
    Söderling, Jonas
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Roelstraete, Björn
    Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ludvigsson, Jonas F.
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, USA; Department Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden.
    Association Between Celiac Disease and Mortality Risk in a Swedish Population2020Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 323, nr 13, s. 1277-1285Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Question: Is celiac disease associated with increased mortality?

    Findings: In this population-based cohort study of 49 & x202f;829 patients in Sweden with celiac disease followed up for a median of 12.5 years, the mortality rate compared with general population controls was 9.7 vs 8.6 deaths per 1000 person-years, a difference that was statistically significant.

    Meaning: In a Swedish population, celiac disease was associated with a small but statistically significant increased mortality risk.

    Importance: Celiac disease may be associated with a modest but persistent increased long-term mortality risk. It is uncertain whether this risk has changed in the era of wider diagnosis rates, less severe clinical disease, and more widespread availability of gluten-free food.

    Objective: To evaluate the association between celiac disease and mortality risk in a population-based cohort in Sweden.

    Design, Setting, and Participants: All individuals in Sweden with celiac disease diagnosed between 1969 and 2017 were identified through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort. Participants (n = 49 & x202f;829) were observed starting on the day of the biopsy. The final date of follow-up was December 31, 2017.

    Exposures: Celiac disease was defined by the presence of small intestinal villus atrophy on histopathology specimens during the years 1969-2017 from Sweden's 28 pathology departments. Each individual was matched with as many as 5 control participants in the general population by age, sex, county, and calendar period.

    Main Outcomes and Measures: The primary outcome was all-cause mortality, and the secondary outcome was cause-specific mortality. Patients with celiac disease were compared with controls using stratified Cox proportional modeling, stratifying by year of diagnosis.

    Results: There were 49 & x202f;829 patients with celiac disease, including 24% who were diagnosed between the years 2010 and 2017. The mean (SD) age at diagnosis was 32.2 (25.2) years and 62.4% were women. During a median follow-up time of 12.5 years, 13.2% (n = 6596) died. Compared with controls (n = 246 & x202f;426), overall mortality was increased in those with celiac disease (9.7 vs 8.6 deaths per 1000 person-years; absolute difference, 1.2 per 1000 person-years; hazard ratio [HR], 1.21 [95% CI, 1.17-1.25]). The relative increase in mortality risk was present in all age groups and was greatest in those diagnosed in the age range of 18 to 39 years (1.9 vs 1.1 per 1000 person-years; HR, 1.69 [95% CI, 1.47-1.94]; P values for heterogeneity comparing 18-39 years with 40-59 years and with >= 60 years were both <.001). Individuals with celiac disease were at increased risk of death from cardiovascular disease (3.5 vs 3.4 per 1000 person-years; HR, 1.08 [95% CI, 1.02-1.13]), cancer (2.7 vs 2.2 per 1000 person-years; HR, 1.29 [95% CI, 1.22-1.36]), and respiratory disease (0.6 vs 0.5 per 1000 person-years; HR, 1.21 [95% CI, 1.08-1.37]). When compared with controls, the overall mortality risk was greatest in the first year after diagnosis (15.3 vs 6.5 per 1000 person-years; HR, 2.34 [95% CI, 2.14-2.55]) but persisted beyond 10 years after diagnosis (10.5 vs 10.1 per 1000 person-years; HR, 1.15 [95% CI, 1.10-1.20]). The mortality risk was likewise present for patients diagnosed during the years 2010-2017 (7.5 vs 5.5 per 1000 person-years; HR, 1.35 [95% CI, 1.21-1.51]).

    Conclusions and Relevance: In a Swedish population studied between 1969 and 2017, a diagnosis of celiac disease compared with the general population was associated with a small but statistically significant increased mortality risk. This population epidemiology study used Swedish histopathology registry data to estimate mortality risk in patients with vs without celiac disease.

  • 8.
    Ludvigsson, Jonas F.
    et al.
    Örebro universitet, Hälsoakademin.
    Montgomery, Scott M.
    Örebro universitet, Hälsoakademin.
    Ekbom, Anders
    Brandt, Lena
    Granath, Fredrik
    Small-intestinal histopathology and mortality risk in celiac disease2009Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 302, nr 11, s. 1171-1178Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Studies of mortality in celiac disease have not taken small-intestinal pathology into account. OBJECTIVE: To examine mortality in celiac disease according to small-intestinal histopathology. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study. We collected data from duodenal/jejunal biopsies taken between July 1969 and February 2008 on celiac disease (Marsh stage 3: villous atrophy; n = 29,096 individuals) and inflammation (Marsh stage 1-2; n = 13,306) from all 28 pathology departments in Sweden. A third cohort consisted of individuals with latent celiac disease from 8 university hospitals (n = 3719). Latent celiac disease was defined as positive celiac disease serology in individuals with normal mucosa (Marsh stage 0). Through linkage with the Swedish Total Population Register, we estimated the risk of death through August 31, 2008, compared with age- and sex-matched controls from the general population. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: There were 3049 deaths among patients with celiac disease, 2967 with inflammation, and 183 with latent celiac disease. We found an increased hazard ratio (HR) for death in celiac disease (HR, 1.39; 95% confidence interval [CI], 1.33-1.45; median follow-up, 8.8 years), inflammation (HR, 1.72; 95% CI, 1.64-1.79; median follow-up, 7.2 years), and latent celiac disease (HR, 1.35; 95% CI, 1.14-1.58; median follow-up, 6.7 years). The absolute mortality rate was 10.4 (95% CI, 10.0-10.8) per 1000 person-years in celiac disease, 25.9 (95% CI, 25.0-26.8) in inflammation, and 6.7 (95% CI, 5.7-7.6) in latent celiac disease. Excess mortality was 2.9 per 1000 person-years in celiac disease, 10.8 in inflammation, and 1.7 in latent celiac disease. This risk increase was also seen in children. Excluding the first year of follow-up, HRs decreased somewhat. CONCLUSION: Risk of death among patients with celiac disease, inflammation, or latent celiac disease is modestly increased.

  • 9.
    Sandin, Sven
    et al.
    Department of Psychiatry, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Hultman, Christina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Reichenberg, Abraham
    Department of Psychiatry, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
    The Heritability of Autism Spectrum Disorder2017Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 318, nr 12, s. 1182-1184Artikkel i tidsskrift (Fagfellevurdert)
  • 10.
    Sandin, Sven
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychosis Studies, Institute of Psychiatry, King’s College, London, United Kingdom.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Kuja-Halkola, Ralf
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Hultman, Christina M.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Reichenberg, Abraham
    Department of Psychiatry, Ichan School of Medicine at Mount Sinai, New York, USA; Department of Preventive Medicine, Ichan School of Medicine at Mount Sinai, New York, USA; Seaver Autism Center and Friedman Brain Institute, Ichan School of Medicine at Mount Sinai, New York, USA.
    The familial risk of autism2014Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, nr 17, s. 1770-1777Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Importance: Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved.

    Objective: To provide estimates of familial aggregation and heritability of ASD.

    Design, setting and participants: A population-based cohort including 2,049,973 Swedish children born 1982 through 2006. We identified 37,570 twin pairs, 2,642,064 full sibling pairs, 432,281 maternal and 445,531 paternal half sibling pairs, and 5,799,875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained.

    Main outcomes and measures: The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors.

    Results: In the sample, 14,516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100,000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64).

    Conclusions and relevance: Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.

  • 11.
    Sjöström, Lars
    et al.
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Peltonen, Markku
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Jacobson, Peter
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Ahlin, Sofie
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Andersson-Assarsson, Johanna
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Anveden, Asa
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Bouchard, Claude
    Pennington Biomed Res Ctr, Louisiana State Univ Syst, Baton Rouge LA, USA..
    Carlsson, Bjorn
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Karason, Kristjan
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Lönroth, Hans
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Näslund, Ingmar
    Region Örebro län. Department of Surgery, Örebro University Hospital, Örebro, Sweden.
    Sjöström, Elisabeth
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Taube, Magdalena
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Wedel, Hans
    Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden; Nord Sch Publ Hlth, Gothenburg, Sweden.
    Svensson, Per-Arne
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Sjöholm, Kajsa
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Carlsson, Lena M. S.
    Inst Med, Univ Gothenburg, Gothenburg, Sweden.
    Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications2014Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 311, nr 22, s. 2297-2304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    IMPORTANCE Short-term studies show that bariatric surgery causes remission of diabetes. The long-term outcomes for remission and diabetes-related complications are not known.

    OBJECTIVES: To determine the long-term diabetes remission rates and the cumulative incidence of microvascular and macrovascular diabetes complications after bariatric surgery.

    DESIGN, SETTING, AND PARTICIPANTS: The Swedish Obese Subjects (SOS) is a prospective matched cohort study conducted at 25 surgical departments and 480 primary health care centers in Sweden. Of patients recruited between September 1,1987, and January 31, 2001, 260 of 2037 control patients and 343 of 2010 surgery patients had type 2 diabetes at baseline. For the current analysis, diabetes status was determined at SOS health examinations until May 22, 2013. Information on diabetes complications was obtained from national health registers until December 31, 2012. Participation rates at the 2-, 10-, and 15-year examinations were 81%, 58%, and 41% in the control group and 90%, 76%, and 47% in the surgery group. For diabetes assessment, the median follow-up time was 10 years (interquartile range [IQR], 2-15) and 10 years (IQR, 10-15) in the control and surgery groups, respectively. For diabetes complications, the median follow-up time was 17.6 years (IQR, 14.2-19.8) and 18.1 years (IQR, 15.2-21.1) in the control and surgery groups, respectively.

    INTERVENTIONS: Adjustable or nonadjustable banding (n = 61), vertical banded gastroplasty (n = 227), or gastric bypass (n = 55) procedures were performed in the surgery group, and usual obesity and diabetes care was provided to the control group.

    MAIN OUTCOMES AND MEASURES: Diabetes remission, relapse, and diabetes complications. Remission was defined as blood glucose <110 mg/dL and no diabetes medication.

    RESULTS: The diabetes remission rate 2 years after surgery was 16.4% (95% CL, 11.7%-22.2%; 34/207) for control patients and 72.3% (95% Cl, 66.9%-77.2%; 219/303) for bariatric surgery patients (odds ratio [OR], 13.3; 95% Cl, 8.5-20.7; P < .001). At 15 years, the diabetes remission rates decreased to 6.5% (4/62) for control patients and to 30.4% (35/115) for bariatric surgery patients (OR, 6.3; 95% Cl, 2.1-18.9; P < .001). With long-term follow-up, the cumulative incidence of microvascular complications was 41.8 per 1000 person-years (95% Cl, 35.3-49.5) for control patients and 20.6 per 1000 person-years (95% Cl, 17.0-24.9) in the surgery group (hazard ratio [HR], 0.44; 95% Cl, 0.34-0.56; P < .001). Macrovascular complications were observed in 44.2 per 1000 person-years (95% Cl, 37.5-52.1) in control patients and 31.7 per 1000 person-years (95% Cl, 27.0-37.2) for the surgical group (HR, 0.68; 95% Cl, 0.54-0.85; P = .001).

    CONCLUSIONS AND RELEVANCE: In this very long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials.

  • 12.
    Song, Huan
    et al.
    Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fang, Fang
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Tomasson, Gunnar
    Department of Epidemiology and Biostatistics, Faculty of Medicine, University of Iceland, Reykjavík, Iceland; Department of Rheumatology, University Hospital, Reykjavík, Iceland; Centre for Rheumatology Research, University Hospital, Reykjavík, Iceland.
    Arnberg, Filip K.
    National Centre for Disaster Psychiatry, Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden; Stress Research Institute, Stockholm University, Stockholm, Sweden.
    Mataix-Cols, David
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    Fernández de la Cruz, Lorena
    Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Fall, Katja
    Örebro universitet, Institutionen för medicinska vetenskaper. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
    Valdimarsdóttir, Unnur A.
    Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
    Association of Stress-Related Disorders With Subsequent Autoimmune Disease2018Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 319, nr 23, s. 2388-2400Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Importance: Psychiatric reactions to life stressors are common in the general population and may result in immune dysfunction. Whether such reactions contribute to the risk of autoimmune disease remains unclear.

    Objective: To determine whether there is an association between stress-related disorders and subsequent autoimmune disease.

    Design, Setting, and Participants: Population- and sibling-matched retrospective cohort study conducted in Sweden from January 1, 1981, to December 31, 2013. The cohort included 106 464 exposed patients with stress-related disorders, with 1 064 640 matched unexposed persons and 126 652 full siblings of these patients.

    Exposures: Diagnosis of stress-related disorders, ie, posttraumatic stress disorder, acute stress reaction, adjustment disorder, and other stress reactions.

    Main Outcomes and Measures: Stress-related disorder and autoimmune diseases were identified through the National Patient Register. The Cox model was used to estimate hazard ratios (HRs) with 95% CIs of 41 autoimmune diseases beyond 1 year after the diagnosis of stress-related disorders, controlling for multiple risk factors.

    Results: The median age at diagnosis of stress-related disorders was 41 years (interquartile range, 33-50 years) and 40% of the exposed patients were male. During a mean follow-up of 10 years, the incidence rate of autoimmune diseases was 9.1, 6.0, and 6.5 per 1000 person-years among the exposed, matched unexposed, and sibling cohorts, respectively (absolute rate difference, 3.12 [95% CI, 2.99-3.25] and 2.49 [95% CI, 2.23-2.76] per 1000 person-years compared with the population- and sibling-based reference groups, respectively). Compared with the unexposed population, patients with stress-related disorders were at increased risk of autoimmune disease (HR, 1.36 [95% CI, 1.33-1.40]). The HRs for patients with posttraumatic stress disorder were 1.46 (95% CI, 1.32-1.61) for any and 2.29 (95% CI, 1.72-3.04) for multiple (≥3) autoimmune diseases. These associations were consistent in the sibling-based comparison. Relative risk elevations were more pronounced among younger patients (HR, 1.48 [95% CI, 1.42-1.55]; 1.41 [95% CI, 1.33-1.48]; 1.31 [95% CI, 1.24-1.37]; and 1.23 [95% CI, 1.17-1.30] for age at ≤33, 34-41, 42-50, and ≥51 years, respectively; P for interaction < .001). Persistent use of selective serotonin reuptake inhibitors during the first year of posttraumatic stress disorder diagnosis was associated with attenuated relative risk of autoimmune disease (HR, 3.64 [95% CI, 2.00-6.62]; 2.65 [95% CI, 1.57-4.45]; and 1.82 [95% CI, 1.09-3.02] for duration ≤179, 180-319, and ≥320 days, respectively; P for trend = .03).

    Conclusions and Relevance: In this Swedish cohort, exposure to a stress-related disorder was significantly associated with increased risk of subsequent autoimmune disease, compared with matched unexposed individuals and with full siblings. Further studies are needed to better understand the underlying mechanisms.

  • 13.
    Sujan, Ayesha C.
    et al.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Rickert, Martin E.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Öberg, Sara
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA.
    Quinn, Patrick D.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA.
    Hernandez-Diaz, Sonia
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA.
    Almqvist, Catarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    D'Onofrio, Brian M.
    Department of Psychological and Brain Sciences, Indiana University, Bloomington, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring2017Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 317, nr 15, s. 1553-1562Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    IMPORTANCE: Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding.

    OBJECTIVE: To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems.

    DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations.

    EXPOSURES: Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations.

    MAINOUTCOMES AND MEASURES: Pretermbirth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring.

    RESULTS: Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons.

    CONCLUSIONS AND RELEVANCE: Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

  • 14.
    Walker, Gareth J.
    et al.
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England; IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
    Harrison, James W.
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England; IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
    Heap, Graham A.
    Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands.
    Voskuil, Michiel D.
    Medical Department, Regional Hospital Viborg, Viborg, Denmark.
    Andersen, Vibeke
    Medical Department, Regional Hospital Viborg, Viborg, Denmark.
    Anderson, Carl A.
    Wellcome Trust Sanger Institute, Hinxton, England.
    Ananthakrishnan, Ashwin N.
    Department of Gastroenterology, Massachusetts General Hospital, Boston, USA.
    Barrett, Jeffrey C.
    Wellcome Trust Sanger Institute, Hinxton, England.
    Beaugerie, Laurent
    Department of Gastroenterology, Saint-Antoine Hospital and Sorbonne Universite, Paris, France.
    Bewshea, Claire M.
    IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
    Cole, Andy T.
    Derby Digestive Diseases Centre, Royal Derby Hospital, Derby Teaching Hospitals NHS Foundation Trust, Derby, England.
    Cummings, Fraser R.
    Department of Gastroenterology, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, England.
    Daly, Mark J.
    Broad Institute, Harvard University, Cambridge, Massachusetts, USA.
    Ellul, Pierre
    Department of Gastroenterology, Mater Dei Hospital, Msida, Malta.
    Fedorak, Richard N.
    Division of Gastroenterology, University of Alberta, Edmonton, Canada.
    Festen, Eleonora A. M.
    Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands.
    Florin, Timothy H.
    Mater Research Institute, University of Queensland, South Brisbane, Australia.
    Gaya, Daniel R.
    Department of Gastroenterology, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, Scotland.
    Halfvarson, Jonas
    Örebro universitet, Institutionen för medicinska vetenskaper. Division of Gastroenterology.
    Hart, Ailsa L.
    Department of Gastroenterology, St Mark's Hospital, London North West Healthcare NHS Trust, Harrow, England.
    Heerasing, Neel M.
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England; IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
    Hendy, Peter
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England; IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
    Irving, Peter M.
    Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, England.
    Jones, Samuel E.
    University of Exeter Medical School, Exeter, England.
    Koskela, Jukka
    Broad Institute, Harvard University, Cambridge, Massachusetts, USA.
    Lindsay, James O.
    Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, England.
    Mansfield, John C.
    Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, England.
    McGovern, Dermot
    F. Widjaja Foundation Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
    Parkes, Miles
    Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England.
    Pollok, Richard C. G.
    Department of Gastroenterology, St George's Healthcare NHS Trust, Tooting, England.
    Ramakrishnan, Subramaniam
    Gastrointestinal and Liver Services, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, England.
    Rampton, David S.
    Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, England.
    Rivas, Manuel A.
    Broad Institute, Harvard University, Cambridge, Massachusetts.
    Russell, Richard K.
    Department of Paediatric Gastroenterology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, Scotland.
    Schultz, Michael
    Dunedin Hospital, Dunedin, New Zealand.
    Sebastian, Shaji
    Gastroenterology and Hepatology, Hull and East Yorkshire Hospitals NHS Trust, Hull, England.
    Seksik, Philippe
    Department of Gastroenterology, Saint-Antoine Hospital and Sorbonne Universite, Paris, France.
    Singh, Abhey
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.
    So, Kenji
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.
    Sokol, Harry
    Department of Gastroenterology, Saint-Antoine Hospital and Sorbonne Universite, Paris, France.
    Subramaniam, Kavitha
    Canberra Hospital, Canberra, Australia.
    Todd, Anthony
    Department of Haematology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.
    Annese, Vito
    Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
    Weersma, Rinse K.
    Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands.
    Xavier, Ramnik
    Broad Institute, Harvard University, Cambridge, Massachusetts, USA.
    Ward, Rebecca
    University of Exeter Medical School, Exeter, England.
    Weedon, Michael N.
    University of Exeter Medical School, Exeter, England.
    Goodhand, James R.
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England; IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
    Kennedy, Nicholas A.
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England; IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
    Ahmad, Tariq
    Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England; IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
    Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease2019Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 321, nr 8, s. 773-785Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).

    Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).

    Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.

    Exposures: Genetic variants associated with TIM.

    Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.

    Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.

    Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.

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