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1.  Implementing Direct Access to Low-Dose Computed Tomography in General Practice—Method, Adaption and Outcome 
PLoS ONE  2014;9(11):e112162.
Background
Early detection of lung cancer is crucial as the prognosis depends on the disease stage. Chest radiographs has been the principal diagnostic tool for general practitioners (GPs), but implies a potential risk of false negative results, while computed tomography (CT) has a higher sensitivity. The aim of this study was to describe the implementation of direct access to low-dose CT (LDCT) from general practice.
Methods
We conducted a cohort study nested in a randomised study. A total of 119 general practices with 266 GPs were randomised into two groups. Intervention GPs were offered direct access to chest LDCT combined with a Continuing Medical Education (CME) meeting on lung cancer diagnosis.
Results
During a 19-month period, 648 patients were referred to LDCT (0.18/1000 adults on GP list/month). Half of the patients needed further diagnostic work-up, and 15 (2.3%, 95% CI: 1.3–3.8%) of the patients had lung cancer; 60% (95% CI: 32.3–83.7%) in a localised stage. The GP referral rate was 61% higher for CME participants compared to non-participants.
Conclusion
Of all patients referred to LDCT, 2.3% were diagnosed with lung cancer with a favourable stage distribution. Half of the referred patients needed additional diagnostic work-up. There was an association between participation in CME and use of CT scan. The proportion of cancers diagnosed through the usual fast-track evaluation was 2.2 times higher in the group of CME-participating GPs. The question remains if primary care case-finding with LDCT is a better option for patients having signs and symptoms indicating lung cancer than a screening program. Whether open access to LDCT may provide earlier diagnosis of lung cancer is yet unknown and a randomised trial is required to assess any effect on outcome.
Trial Registration
Clinicaltrials.gov NCT01527214
doi:10.1371/journal.pone.0112162
PMCID: PMC4226510  PMID: 25383780
2.  Examining Psychiatric Disorder as a Risk Factor for Cancer in a Prospective Cohort Study of 1,165,039 Swedish Men: Different Analytical Strategies Reveal Different Findings 
Epidemiology (Cambridge, Mass.)  2012;23(4):543-550.
Background
Associations between psychiatric disorders and cancer incidence are inconsistent, with studies reporting cancer rates in psychiatric patients that are higher, similar, or lower than the general population. Exploration of these associations is complicated by difficulties in establishing the timing of onset of psychiatric disorders and cancer, and the associated possibility of reverse causality. Some studies have dealt with this problem by excluding patients with cancers pre-dating their psychiatric illness; others have not considered the issue.
Methods
We examined associations between psychiatric hospitalization and cancer incidence in a cohort of 1,165,039 Swedish men, and explored the impact of different analytical strategies on these associations using real and simulated data.
Results
Relative to men without psychiatric hospitalization, we observed consistent increases in smoking-related cancers in those with psychiatric hospitalizations, regardless of analytical approach (for example, hazard ratio (95% confidence interval): 1.73 (1.52, 1.96)). However, associations with nonsmoking-related cancers were highly dependent on analytical strategy. In analyses based on the full cohort, we observed no association or a modest increase in cancer incidence in those with psychiatric hospitalizations (1.14 (1.07, 1.22)). In contrast, analyses excluding men whose cancer predated their psychiatric hospitalizations, resulted in a reduction in future cancer incidence in psychiatric patients (0.72; 0.67, 0.78). Results from simulated data suggest that even modest exclusions of this type can lead to strong artefactual associations.
Conclusions
Psychiatric disorder-cancer incidence associations are complex and influenced by analytical strategy. A greater understanding of the temporal relationship between psychiatric disorder and cancer incidence is required.
doi:10.1097/EDE.0b013e3182547094
PMCID: PMC4176762  PMID: 22488410
3.  Mental disorders in early adulthood and later psychiatric hospital admissions in relation to mortality in a cohort study of a million men 
Archives of general psychiatry  2012;69(8):823-831.
Context
Mental disorders have been associated with increased mortality, but the evidence is primarily based on hospital admissions for psychoses. The underlying mechanisms are unclear.
Objective
To investigate whether the risks of death associated with mental disorders diagnosed in young men are similar to those associated with admission for these disorders, and to examine the role of confounding or mediating factors.
Design
Prospective cohort study in which mental disorders were assessed by psychiatric interview during a medical examination on conscription for military service at a mean age of 18.3 years and data on psychiatric hospital admissions and mortality during a mean 22.6 years of follow-up were obtained from national registers.
Setting
Sweden.
Participants
1,095,338 men conscripted between 1969 and 1994.
Main outcome measure
All-cause mortality according to diagnoses of schizophrenia, other non-affective psychoses, bipolar or depressive disorders, neurotic/adjustment disorders, personality disorders, alcohol-related or other substance use disorders at conscription and on hospital admission.
Results
Diagnosis of mental disorder at conscription or on hospital admission was associated with increased mortality. Age-adjusted hazard ratios (95% confidence intervals) according to diagnoses at conscription ranged from 1.81 (1.54, 2.10) (depressive disorders) to 5.55 (1.79, 17.2) (bipolar disorders). The equivalent figures according to hospital diagnoses ranged from 5.46 (5.06, 5.89) (neurotic/adjustment disorders) to 11.2 (10.4, 12.0) (other substance use disorders) in men born 1951-8 and increased in men born later. Adjustment for early-life socioeconomic status, body mass index and blood pressure had little effect on these associations, but they were partially attenuated by adjustment for smoking, alcohol intake, intelligence, education and late-life socioeconomic position. These associations were not primarily due to deaths from suicide.
Conclusions
The increased risk of premature death associated with mental disorder is not confined to those whose illness is severe enough for hospitalisation or to those with psychotic or substance-use disorders.
doi:10.1001/archgenpsychiatry.2011.2000
PMCID: PMC4170756  PMID: 22868936
4.  Intelligence in early adulthood and subsequent hospitalisation and admission rates for the whole range of mental disorders: longitudinal study of 1,049,663 men 
Background
Lower intelligence is a risk factor for several specific mental disorders, but it is unclear whether it is a risk factor for all mental disorder or whether it is associated with illness severity. We examined the relation between pre-morbid intelligence and risk of hospital admission and total admission rates for the whole range of mental disorders.
Methods
Participants were 1,049,663 Swedish men who took tests of intelligence on conscription into military service and were followed up for hospital admissions for mental disorder for a mean of 22.6 years. International Classification of Diseases diagnoses were recorded at discharge from hospital.
Results
Risk of hospital admission for all categories of disorder rose with each point decrease in the nine-point IQ score. For a standard deviation decrease in IQ, age-adjusted hazard ratios (95% CI) were 1.60 (1.55, 1.65) for schizophrenia, 1.49 (1.45, 1.53) for other non-affective psychoses, 1.50 (1.47, 1.51) for mood disorders, 1.51 (1.48, 1.54) for neurotic disorders, 1.60 (1.56, 1.64) for adjustment disorders, 1.75 (1.70, 1.80) for personality disorders, 1.75 (1.73, 1.77) for alcohol-related and 1.85 (1.82, 1.88) for other substance use disorders. Lower intelligence was associated with greater comorbidity. Associations changed little on adjustment for potential confounders. Men with lower intelligence had higher total admission rates, a possible marker of clinical severity.
Conclusions
Lower intelligence is a risk factor for the whole range of mental disorders and for illness severity. Understanding the underlying mechanisms is crucial if we are to find ways to reduce the burden of mental illness.
doi:10.1097/EDE.0b013e3181c17da8
PMCID: PMC4170757  PMID: 19907333
5.  Intelligence in early adulthood and subsequent risk of unintentional injury over two decades: cohort study of 1,109,475 Swedish men 
Background
There is growing evidence of an inverse association between intelligence (IQ) and unintentional injuries.
Methods
Analyses are based on a cohort of 1,109,475 Swedish men with IQ measured in early adulthood. Men were followed-up for an average 24 years and hospital admissions for unintentional injury were recorded.
Results
198,133 (17.9%) men had at least one hospital admission for any unintentional injury during follow-up. The most common cause of unintentional injury was falling, followed by road accidents, poisoning, fire and drowning. In addition, 14,637 (1.3%) men had at least one admission for complications of medical care. After adjusting for confounding variables, lower IQ scores were associated with an elevated risk of any unintentional injury (Hazard ratio (95% confidence interval) per standard deviation decrease in IQ: 1.15 (1.14, 1.15)), and of cause-specific injuries other than drowning (poisoning (1.53 (1.49, 1.57)), fire (1.36 (1.31, 1.41)), road traffic accidents (1.25 (1.23, 1.26)), medical complications (1.20 (1.18, 1.22)), and falling (1.17 (1.16, 1.18)). These gradients were stepwise across the full IQ range.
Conclusions
Low IQ scores in early adulthood were associated with a subsequently increased risk of unintentional injury. A greater understanding of mechanisms underlying these associations may provide opportunities and strategies for prevention.
doi:10.1136/jech.2009.100669
PMCID: PMC4170759  PMID: 19955099
IQ; injury; socioeconomic status; cohort
6.  Physical stature and method-specific attempted suicide: cohort study of one million men 
Psychiatry research  2010;179(1):116-118.
Adult height, a marker of early-life environment, has been sporadically associated with suicide risk. We have examined adult height and attempted suicide risk in a cohort of 1,102,293 Swedish men and, in fully-adjusted analyses, found decreasing stepwise associations between height and attempted suicides by any means and most specific means.
doi:10.1016/j.psychres.2010.06.011
PMCID: PMC4170761  PMID: 20627206
Attempted suicide; Height; Cohort
7.  Intelligence in early adulthood and subsequent risk of assault: cohort study of 1,120,998 Swedish men 
Psychosomatic medicine  2010;72(4):390-396.
Objective
There is growing evidence of an association between low intelligence (IQ) and increased risk of assault. However, previous studies are relatively small, do not adjust for socioeconomic status, and have not examined method-specific assaults.
Method
Cox proportional hazards regression was used to explore IQ associations with assault by any means and by four specific methods in a large prospective cohort of 1,120,988 Swedish men. Study members had IQ measured in early adulthood and were well characterised for socioeconomic status in childhood and adulthood. Men were followed-up for an average of 24 years and hospital admissions for injury due to assault were recorded.
Results
16,512 (1.5%) men had at least one hospital admission for injury due to assault by any means during follow-up. The most common assault was during a fight (N=13,144), followed by stabbing (N=1,211), blunt instrument (N=352), and firearms assaults (N=51). After adjusting for confounding variables, lower IQ scores were associated with an elevated risk of hospitalisation for assaults by any means (Hazard ratio (95% confidence interval) per standard deviation decrease in IQ: 1.51 (1.49, 1.54)), and for each of the cause-specific assaults (fight: 1.48 (1.45, 1.51); stabbing: 1.68 (1.58, 1.79); blunt instrument: 1.65 (1.47, 1.85); and firearms: 1.34 (1.00, 1.80)). These gradients were stepwise across the full IQ range.
Conclusions
Low IQ scores in early adulthood were associated with a subsequently increased risk of assault. A greater understanding of mechanisms underlying these associations may provide opportunities and strategies for prevention.
doi:10.1097/PSY.0b013e3181d137e9
PMCID: PMC4170781  PMID: 20190131
IQ; assault; socioeconomic status; cohort
8.  Mental disorders across the adult life course and future coronary heart disease: evidence for general susceptibility 
Circulation  2013;129(2):186-193.
Background
Depression, anxiety and psychotic disorders have been associated with an increased risk of coronary heart disease (CHD). It is unclear whether this association between mental health and CHD is present across a wider range of mental disorders.
Methods and Results
Participants were 1,107,524 Swedish men conscripted at mean age 18.3 years. Mental disorders were assessed by psychiatric interview on conscription and data on hospital admissions for mental disorder and CHD were obtained from national registers during 22.6 years of follow-up. Increased risk of incident CHD was evident across a range of mental disorders whether diagnosed at conscription or on later hospital admission. Age-adjusted hazard ratios (95% confidence intervals) according to diagnoses at conscription ranged from 1.30 (1.05, 1.60) (depressive disorders) to 1.92 (1.60, 2.31) (alcohol-related disorders). The equivalent figures according to diagnoses during hospital admission ranged from 1.49 (1.24, 1.80) (schizophrenia) to 2.82 (2.53, 3.13) (other substance use disorders). Associations were little changed by adjustment for parental socioeconomic status, or body mass index, diabetes and blood pressure measured at conscription, but were partially attenuated by adjustment for smoking, alcohol intake, and intelligence measured at conscription, and for education and own socioeconomic position.
Conclusions
Increased risk of incident CHD is present across a range of mental disorders and is observable when disorders are diagnosed at a young age.
doi:10.1161/CIRCULATIONAHA.113.002065
PMCID: PMC4107269  PMID: 24190959
epidemiology; heart disease; mental disorder; men; cohort study
9.  Characterization of pulmonary lesions in patients with suspected lung cancer: computed tomography versus [18F]fluorodeoxyglucose-positron emission tomography/computed tomography 
Cancer Imaging  2012;12(3):437-446.
Abstract
Pulmonary nodules are of high clinical importance, given they may prove to be an early manifestation of lung cancer. Pulmonary nodules are small, focal, radiographic opacities that may be solitary or multiple. A solitary pulmonary nodule is a single, small (≤30 mm in diameter) opacity. Larger opacities are called masses and are often malignant. As imaging techniques improve and more nodules are detected, the optimal management of pulmonary nodules remains unclear. However, the question of malignancy of any given nodule remains the same. A standard contrast-enhanced computed tomography (CT) scan is often the first examination, followed by a number of other examinations. The purpose of this study was to examine the clinical feasibility of CT versus integrated [18F]fluorodeoxyglucose-positron emission tomography (PET)/low-dose CT scan in patients with suspected lung cancer and pulmonary lesions on CT. All results were controlled for reproducibility. We found that when used early in the work-up of the lesions, CT raised the prevalence of lung cancer in the population to the point where further diagnostic imaging examination could be considered futile. We also found that the overall diagnostic accuracy, as well as the classification probabilities and predictive values of the two modalities were not significantly different; the reproducibility of these results was substantial.
doi:10.1102/1470-7330.2012.0035
PMCID: PMC3478790  PMID: 23092816
Lung neoplasms; radiography; radionuclide imaging; multidetector computed tomography, positron emission tomography/computed tomography, sensitivity, specificity
10.  Mediastinal staging in non-small-cell lung carcinoma: computed tomography versus F-18-fluorodeoxyglucose positron-emission tomography and computed tomography 
Cancer Imaging  2014;14(1):23.
Background
After the diagnosis Non-Small-Cell Lung Carcinoma (NSCLC) has been established, consideration must turn toward the stage of disease, because this will impact directly on management and prognosis. Staging is used to predict survival and to guide the patient toward the most appropriate treatment regimen or clinical trial. Distinguishing malignant involvement of the mediastinal lymph nodes (N2 or N3) from the hilar lymph nodes, or no lymph nodes (N0 or N1) is critical, because malignant involvement of N2 or N3 lymph nodes usually indicates non–surgically resectable disease. The purpose of this study was to examine and compare CT versus integrated F18-FDG PET/low dose CT (FDG PET/CT) for mediastinal staging in NSCLC, and the desire was to safely distinguish between malignant and benign lesions without the need for invasive procedures. All results were controlled for reproducibility.
Methods
114 participants with NSCLC were included in a prospective cohort study. Blinded CT and FDG PET/CT images were reviewed. The participants’ mediastinums were staged based on lymph node sizes (CT), or on FDG uptake (FDG PET/CT). Reference standard was tissue sampling.
Results
We found that there was no measureable difference between CT and FDG PET/CT mediastinal staging results; overall two-thirds of the participants in the study were correctly staged, and almost one-third of the participants were falsely staged.
Conclusion
Neither CT nor FDG PET/CT could obviate the need for further invasive staging prior to thoracotomy in patients with NSCLC; for that purpose, the results of both modalities were too meagre. Therefore, these patients still depend on invasive staging methods. In our study, invasive staging was accomplished by mediastinoscopy. However, today this is increasingly replaced by EBUS or EUS.
doi:10.1186/1470-7330-14-23
PMCID: PMC4331828  PMID: 25608616
Carcinoma; Non-small-cell lung/radiography; Carcinoma; Non-small-cell lung/radionuclide imaging; Mediastinal neoplasms/secondary; Computed tomography; X-ray/methods; Positron-emission tomography and computed tomography/methods; Sensitivity and specificity; Roc curve
11.  Impacts of mobility disability and high and increasing body mass index on health-related quality of life and participation in society: a population-based cohort study from Sweden 
BMC Public Health  2014;14:381.
Background
Increasing obesity in adults with mobility disability has become a considerable health problem, similar to the increasing trend of obesity in the general population. The aims of this study were to investigate the association of mobility disability with overweight status and obesity in a large population-based Swedish cohort of adults, and to investigate whether mobility disability, high body mass index (BMI), and increasing BMI over time are predictors of health-related quality of life and participation in society after 8 years of follow-up.
Methods
The study cohort included 13,549 individuals aged 18–64 years who answered questions about mobility disability, weight, height, health-related quality of life and participation in society in the Stockholm Public Health Survey 2002 and 2010. The cohort was randomly selected from the population of Stockholm County, and divided into six subgroups based on data for mobility disability and overweight status. Multiple binary logistic regression analyses were performed to assess the likelihood for low health-related quality of life and lack of participation.
Results
Respondents with mobility disability had a higher mean BMI than those without mobility disability. Respondents both with and without mobility disability increased in BMI, but with no significant difference in the longitudinal changes (mean difference: 0.078; 95% CI: -0.16 - 0.32). Presence of mobility disability increased the risk of low health-related quality of life and lack of participation in 2010, irrespective of low health-related quality of life and lack of participation in 2002. The risk of pain and low general health (parts of health-related quality of life) increased for every 5 units of higher BMI reported in 2010. In respondents without low general health at baseline, the risk of obtaining low general health increased for every 5 units of higher BMI in 2010 (OR:1.60; CI: 1.47 - 1.74).
Conclusions
The greatest risk of low general health after 8 years was observed for respondents with both mobility disability and high BMI. These results indicate the importance of working preventively with persons with mobility disability and overweight status or obesity based on the risk of further weight gain.
doi:10.1186/1471-2458-14-381
PMCID: PMC4036728  PMID: 24742257
Mobility disability; Overweight; Obesity; Prevalence; Population study; Health-related quality of life (HRQoL); Participation
12.  Primary prevention of childhood obesity through counselling sessions at Swedish child health centres: design, methods and baseline sample characteristics of the PRIMROSE cluster-randomised trial 
BMC Public Health  2014;14:335.
Background
Childhood obesity is a growing concern in Sweden. Children with overweight and obesity run a high risk of becoming obese as adults, and are likely to develop comorbidities. Despite the immense demand, there is still a lack of evidence-based comprehensive prevention programmes targeting pre-school children and their families in primary health care settings. The aims are to describe the design and methodology of the PRIMROSE cluster-randomised controlled trial, assess the relative validity of a food frequency questionnaire, and describe the baseline characteristics of the eligible young children and their mothers.
Methods/Design
The PRIMROSE trial targets first-time parents and their children at Swedish child health centres (CHC) in eight counties in Sweden. Randomisation is conducted at the CHC unit level. CHC nurses employed at the participating CHC received training in carrying out the intervention alongside their provision of regular services. The intervention programme, starting when the child is 8-9 months of age and ending at age 4, is based on social cognitive theory and employs motivational interviewing. Primary outcomes are children’s body mass index and waist circumference at four years. Secondary outcomes are children’s and mothers’ eating habits (assessed by a food frequency questionnaire), and children’s and mothers’ physical activity (measured by accelerometer and a validated questionnaire), and mothers’ body mass index and waist circumference.
Discussion
The on-going population-based PRIMROSE trial, which targets childhood obesity, is embedded in the regular national (routine) preventive child health services that are available free-of-charge to all young families in Sweden. Of the participants (n = 1369), 489 intervention and 550 control mothers (75.9%) responded to the validated physical activity and food frequency questionnaire at baseline (i.e., before the first intervention session, or, for children in the control group, before they reached 10 months of age). The food frequency questionnaire showed acceptable relative validity when compared with an 8-day food diary. We are not aware of any previous RCT, concerned with the primary prevention of childhood obesity through sessions at CHC that addresses healthy eating habits and physical activity in the context of a routine child health services programme.
Trial registration
ISRCTN16991919
doi:10.1186/1471-2458-14-335
PMCID: PMC3995501  PMID: 24717011
Childhood obesity; Primary prevention; Motivational interviewing; Primary care setting; Intervention study
13.  Surgically Induced Interpregnancy Weight Loss and Prevalence of Overweight and Obesity in Offspring 
PLoS ONE  2013;8(12):e82247.
Introduction
According to the fetal overnutrition hypothesis, obesity in pregnancy predisposes the offspring to obesity. Previous studies have suggested that after biliopancreatic surgery for obesity, the offspring is less likely to be obese. This study aims to further compare the BMI development of children born before and after maternal surgical weight loss.
Method
Women with at least one child born before and one child born after bariatric surgery were identified by record-linkage. Information about maternal BMI was extracted from medical records, as was information about the children's BMI from birth to 10 years of age. We retrieved BMI data at four years of age for 340 children, born to 223 women (164 children born before surgery (BS), 176 children born after surgery (AS)). We evaluated prevalence of overweight/obesity and mean BMI in children born BS and AS at the ages of four, six and ten using GEE regression models. For 71 families, where we had complete data on mother and both children, we used a fixed-effects regression model to explore the association between differences in maternal BMI in w10 of the pre- and post-operative pregnancies with siblings' BMI differences at age four.
Results
In no age group did we see a significantly reduced prevalence of overweight/obesity AS. For 10-year-old girls, the AS group had significantly higher rates of obesity. There was no association between differences in maternal BMI in early pregnancy and differences in siblings' BMI at four years of age (β = −0.01, CI 95% = −0.11; 0.09).
Conclusions
We have been unable to demonstrate any effect of bariatric surgery on weight development in offspring. It seems unlikely that restrictive bariatric surgery conveys a protective effect in offspring with regards to obesity.
doi:10.1371/journal.pone.0082247
PMCID: PMC3861408  PMID: 24349234
14.  Metastatic renal cell cancer 
Cancer Imaging  2013;13(3):374-380.
Abstract
Targeted therapy is the treatment of choice in patients with metastatic renal cell cancer (mRCC) at most institutions although a combination of cytokine therapy and targeted therapy still is being investigated. Morphological size-based criteria (RECIST) has failed in monitoring the effect of targeted therapy in patients with mRCC, as successful therapy often does not result in a decrease in tumour size. Modifications of size-based criteria and criteria based on computed tomography (CT) contrast enhancement has been introduced. Different imaging modalities that rely on characteristics other than size such as dynamic contrast-enhanced (DCE) ultrasonography, DCE CT, DCE magnetic resonance imaging (MRI), diffusion-weighted MRI, positron emission tomography and texture analysis seem to contribute with prognostic information, even at baseline scans, and can predict tumour response early after initiating therapy. No new standard for the imaging follow-up of targeted therapy in mRCC has been established.
doi:10.1102/1470-7330.2013.9035
PMCID: PMC3783114  PMID: 24061106
Targeted therapy; renal cell carcinoma; mRCC
16.  Is bipolar disorder more common in highly intelligent people? A cohort study of a million men 
Molecular psychiatry  2012;18(2):190-194.
Anecdotal and biographical reports have long suggested that bipolar disorder is more common in people with exceptional cognitive or creative ability. Epidemiological evidence for such a link is sparse. We investigated the relationship between intelligence and subsequent risk of hospitalisation for bipolar disorder in a prospective cohort study of 1,049,607 Swedish men. Intelligence was measured on conscription for military service at a mean age of 18.3 years and data on psychiatric hospital admissions over a mean follow-up period of 22.6 years was obtained from national records. Risk of hospitalization with any form of bipolar disorder fell in a stepwise manner as intelligence increased (p for linear trend <0.0001). However, when we restricted analyses to men with no psychiatric comorbidity, there was a ‘reversed-J’ shaped association: men with the lowest intelligence had the greatest risk of being admitted with pure bipolar disorder, but risk was also elevated among men with the highest intelligence (p for quadratic trend = 0.03), primarily in those with the highest verbal (p for quadratic trend=0.009) or technical ability (p for quadratic trend <0.0001). At least in men, high intelligence may indeed be a risk factor for bipolar disorder, but only in the minority of cases who have the disorder in a pure form with no psychiatric comorbidity.
doi:10.1038/mp.2012.26
PMCID: PMC3705611  PMID: 22472877
17.  Associations of mortality with own height using son's height as an instrumental variable 
Economics and Human Biology  2013;11(3):351-359.
Highlights
► Associations of exposures with mortality may be confounded by existing ill health. ► We used a son's height as an instrument for parents’ height to avoid confounding. ► Parents of taller sons had lower cardiovascular and respiratory disease mortality. ► Parents of taller sons had higher mortality from cancer. ► Previous studies of height are not substantially confounded by existing ill health.
Height is associated with mortality from many diseases, but it remains unclear whether the association is causal or due to confounding by social factors, genetic pleiotropy,1 or existing ill-health. The authors investigated whether the association of height with mortality is causal by using a son's height as an instrumental variable (IV) for parents’ height among the parents of a cohort of 1,036,963 Swedish men born between 1951 and 1980 who had their height measured at military conscription, aged around 18, between 1969 and 2001. In a two-sample IV analysis adjusting for son's age at examination and secular trends in height, as well as parental age, and socioeconomic position, the hazard ratio (HR) for all-cause paternal mortality per standard deviation (SD, 6.49 cm) of height was 0.96 (95% confidence interval (CI): 0.95, 0.96). The results of IV analyses of mortality from all causes, cardiovascular disease (CVD), respiratory disease, cancer, external causes and suicide were comparable to those obtained using son's height as a simple proxy for own height and to conventional analyses of own height in the present data and elsewhere, suggesting that such conventional analyses are not substantially confounded by existing ill-health.
doi:10.1016/j.ehb.2012.04.003
PMCID: PMC3685807  PMID: 22560304
IV, instrumental variable; HR, hazard ratio; SD, standard deviation; CI, confidence interval; CVD, cardiovascular disease; BMI, body mass index; SEP, socioeconomic position; CHD, coronary heart disease; Body height; Mortality; Confounding factor; Causality; Cohort studies
18.  Association of Birth Order with Cardiovascular Disease Risk Factors in Young Adulthood: A Study of One Million Swedish Men 
PLoS ONE  2013;8(5):e63361.
Background
Birth order has been suggested to be linked to several cardiovascular disease (CVD) risk factors, but the evidence is still inconsistent. We aim to determine the associations of birth order with body mass index (BMI), muscle strength and blood pressure. Further we will analyse whether these relationships are affected by family characteristics.
Methods
BMI, elbow flexion, hand grip and knee extension strength and systolic and diastolic blood pressure were measured at conscription examination in 1 065 710 Swedish young men born between 1951 and 1975. The data were analysed using linear multivariate and fixed effects regression models; the latter compare siblings and account for genetic and social factors shared by brothers.
Results
Fixed effect regression analysis showed that birth order was inversely associated with BMI: second and third born had 0.8% and 1.1% (p<0.001) lower BMI than first-born, respectively. The association pattern differed among muscle strengths. After adjustment for BMI, first-born presented lower elbow flexion and hand grip strength than second-born (−5.9 N and −3.8 N, respectively, p<0.001). Knee extension strength was inversely related to birth order though not always significantly. The association between birth order and blood pressure was not significant.
Conclusions
Birth order is negatively associated with BMI and knee extension strength, positively with elbow flexion and hand grip strength, and is not associated with blood pressure among young men. Although the effects are small, the link between birth order and some CVD risk factors is already detectable in young adulthood.
doi:10.1371/journal.pone.0063361
PMCID: PMC3656047  PMID: 23696817
19.  A Life-Course Study on Effects of Parental Markers of Morbidity and Mortality on Offspring’s Suicide Attempt 
PLoS ONE  2012;7(12):e51585.
Background
Research on the temporal relationship of parental risk factors with offspring’s suicide attempt is scarce and a life course approach has not been applied to date. We investigated the temporal relationship of parental morbidity and mortality with offspring’s suicide attempt and whether any such association was modified by offspring’s age at attempt.
Methods
We designed a case-control study through linkage of Swedish registers. Cases comprised all individuals in Sweden born 1973–1983 with inpatient care due to suicide attempt (15–31 years of age) and with information on both biological parents (N = 15 193). Ten controls were matched to each case (National Patient register with national complete coverage). Conditional logistic and spline regressions were applied.
Results
Particularly for women, most parental markers showed the strongest effect sizes if exposure was short-term (within 2 years after exposure) and related to the mother. Especially short-term exposure to maternal inpatient care due to psychiatric diagnoses had a significantly stronger effect on suicide attempt risk in women compared to men. Regarding exposure to parental inpatient care due to psychiatric diagnoses, short-term as opposed to long-term (exceeding 2 years after exposure) effects were highest during adolescence and decreased significantly with age for female and male offspring, respectively.
Conclusions
Although limited by the fact that data on parental morbidity and the outcome of suicidality were based on in-patient data only, the data suggest that the high risks of suicide attempt in case of exposure to parental psychopathology and suicidal behavior particularly during adolescence and the strong short-term effects associated with maternal psychopathology for female offspring are of direct clinical importance.
doi:10.1371/journal.pone.0051585
PMCID: PMC3520946  PMID: 23251584
20.  Focused sonographic examination of the heart, lungs and deep veins in an unselected population of acute admitted patients with respiratory symptoms: a protocol for a prospective, blinded, randomised controlled trial 
BMJ Open  2012;2(3):e001369.
Introduction
Patients admitted to hospital with acute respiratory symptoms remain a diagnostic challenge for the emergency physician. The use of focused sonography may improve the initial diagnostics, as most of the diseases, commonly seen and misdiagnosed in patients with acute respiratory symptoms, can be diagnosed with sonography. The protocol describes a prospective, blinded, randomised controlled trial that aims to assess the diagnostic impact of a pragmatic implementation of focused sonography of the heart, lungs and deep veins as a diagnostic modality in acute admitted patients with respiratory symptoms.
Methods and analysis
The primary outcome of the study is the number of patients with a correct presumptive diagnosis within 4 h of admission to the emergency department. The patient is randomised to either an intervention or a control group. In the intervention group, the usual initial diagnostic work up is supplemented by focused sonographic examination of the heart, lungs and deep veins of the legs. In the control group, usual diagnostic work up is performed. The χ2 test, alternatively the Fischer exact test will be used, to establish whether there is a difference in the distribution of the total number of patients with a correct/incorrect ‘4 h’ presumptive diagnosis in the control group and in the intervention group.
Ethics and dissemination
This clinical trial is performed according to the Declaration of Helsinki and has been approved by the Regional Scientific Ethical Committee for Southern Denmark and the Danish Data Protection Agency. The results of the trial will be published according to the CONSORT statement with the extension for pragmatic trials. The results of the trial will be published in a peer-reviewed scientific journal regardless of the outcome.
Trial registration number
This study is registered at http://clinicaltrials.gov, registration number NCT01486394.
Article summary
Article focus
Focused sonography of the heart, lungs and deep veins.
Initial diagnostics of acute admitted patients with respiratory symptoms.
Key messages
The results of the study may help to determine whether sonography should be included as a fully integrated part of the primary evaluation in these patients.
Strengths and limitations of this study
First randomised trial to compare the overall diagnostic performance between the conventional approach and an approach including focused sonography to evaluate and diagnose acute admitted patients with respiratory symptoms, admitted to an emergency department.
Pragmatic design with inclusion of most patients with respiratory symptoms.
Single-centre study that could affect external validity.
Study not powered to investigate morbidity or mortality.
doi:10.1136/bmjopen-2012-001369
PMCID: PMC3367153  PMID: 22649177
22.  Genetic and Environmental Contributions to Weight, Height, and BMI from Birth to 19 Years of Age: An International Study of Over 12,000 Twin Pairs 
PLoS ONE  2012;7(2):e30153.
Objective
To examine the genetic and environmental influences on variances in weight, height, and BMI, from birth through 19 years of age, in boys and girls from three continents.
Design and Settings
Cross-sectional twin study. Data obtained from a total of 23 twin birth-cohorts from four countries: Canada, Sweden, Denmark, and Australia. Participants were Monozygotic (MZ) and dizygotic (DZ) (same- and opposite-sex) twin pairs with data available for both height and weight at a given age, from birth through 19 years of age. Approximately 24,036 children were included in the analyses.
Results
Heritability for body weight, height, and BMI was low at birth (between 6.4 and 8.7% for boys, and between 4.8 and 7.9% for girls) but increased over time, accounting for close to half or more of the variance in body weight and BMI after 5 months of age in both sexes. Common environmental influences on all body measures were high at birth (between 74.1–85.9% in all measures for boys, and between 74.2 and 87.3% in all measures for girls) and markedly reduced over time. For body height, the effect of the common environment remained significant for a longer period during early childhood (up through 12 years of age). Sex-limitation of genetic and shared environmental effects was observed.
Conclusion
Genetics appear to play an increasingly important role in explaining the variation in weight, height, and BMI from early childhood to late adolescence, particularly in boys. Common environmental factors exert their strongest and most independent influence specifically in pre-adolescent years and more significantly in girls. These findings emphasize the need to target family and social environmental interventions in early childhood years, especially for females. As gene-environment correlation and interaction is likely, it is also necessary to identify the genetic variants that may predispose individuals to obesity.
doi:10.1371/journal.pone.0030153
PMCID: PMC3275599  PMID: 22347368
23.  A national cohort study of parental socioeconomic status and non-fatal suicidal behaviour-the mediating role of school performance 
BMC Public Health  2012;12:17.
Background
A link between low parental socioeconomic status and mental health problems in offspring is well established in previous research. The mechanisms that explain this link are largely unknown. The present study investigated whether school performance was a mediating and/or moderating factor in the path between parental socioeconomic status and the risk of hospital admission for non-fatal suicidal behaviour.
Methods
A national cohort of 447 929 children born during 1973-1977 was followed prospectively in the National Patient Discharge Register from the end of their ninth and final year of compulsory school until 2001. Multivariate Cox proportional hazards and linear regression analyses were performed to test whether the association between parental socioeconomic status and non-fatal suicidal behaviour was mediated or moderated by school performance.
Results
The results of a series of multiple regression analyses, adjusted for demographic variables, revealed that school performance was as an important mediator in the relationship between parental socioeconomic status and risk of non-fatal suicidal behaviour, accounting for 60% of the variance. The hypothesized moderation of parental socioeconomic status-non-fatal suicidal behaviour relationship by school performance was not supported.
Conclusions
School performance is an important mediator through which parental socioeconomic status translates into a risk for non-fatal suicidal behaviour. Prevention efforts aimed to reduce socioeconomic inequalities in non-fatal suicidal behaviour among young people will need to consider socioeconomic inequalities in school performance.
doi:10.1186/1471-2458-12-17
PMCID: PMC3268709  PMID: 22230577
Non-fatal suicidal behaviour; Socioeconomic status; School performance; Cohort studies
24.  Increasing Genetic Variance of Body Mass Index during the Swedish Obesity Epidemic 
PLoS ONE  2011;6(11):e27135.
Background and Objectives
There is no doubt that the dramatic worldwide increase in obesity prevalence is due to changes in environmental factors. However, twin and family studies suggest that genetic differences are responsible for the major part of the variation in adiposity within populations. Recent studies show that the genetic effects on body mass index (BMI) may be stronger when combined with presumed risk factors for obesity. We tested the hypothesis that the genetic variance of BMI has increased during the obesity epidemic.
Methods
The data comprised height and weight measurements of 1,474,065 Swedish conscripts at age 18–19 y born between 1951 and 1983. The data were linked to the Swedish Multi-Generation Register and the Swedish Twin Register from which 264,796 full-brother pairs, 1,736 monozygotic (MZ) and 1,961 dizygotic (DZ) twin pairs were identified. The twin pairs were analysed to identify the most parsimonious model for the genetic and environmental contribution to BMI variance. The full-brother pairs were subsequently divided into subgroups by year of birth to investigate trends in the genetic variance of BMI.
Results
The twin analysis showed that BMI variation could be explained by additive genetic and environmental factors not shared by co-twins. On the basis of the analyses of the full-siblings, the additive genetic variance of BMI increased from 4.3 [95% CI 4.04–4.53] to 7.9 [95% CI 7.28–8.54] within the study period, as did the unique environmental variance, which increased from 1.4 [95% CI 1.32–1.48] to 2.0 [95% CI 1.89–2.22]. The BMI heritability increased from 75% to 78.8%.
Conclusion
The results confirm the hypothesis that the additive genetic variance of BMI has increased strongly during the obesity epidemic. This suggests that the obesogenic environment has enhanced the influence of adiposity related genes.
doi:10.1371/journal.pone.0027135
PMCID: PMC3210134  PMID: 22087252
25.  Body Mass Index and Attempted Suicide: Cohort Study of 1,133,019 Swedish Men 
American Journal of Epidemiology  2010;172(8):890-899.
Associations between body mass index (BMI) and attempted (nonfatal) suicide have recently been reported. However, the few existing studies are relatively small in scale, the majority cross-sectional, and results contradictory. The authors have explored BMI–attempted suicide associations in a large cohort of 1,133,019 Swedish men born between 1950 and 1976, with BMI measured in early adulthood. During a mean follow-up of 23.9 years, a total of 18,277 (1.6%) men had at least 1 hospital admission for attempted suicide. After adjustment for confounding factors, there was a stepwise, linear decrease in attempted suicide with increasing BMI across the full BMI range (per standard deviation increase in BMI, hazard ratio = 0.93, 95% confidence interval: 0.91, 0.94). Analyses excluding men with depression at baseline were essentially identical to those based on the complete cohort. In men free from depression at baseline, controlling for subsequent depression slightly attenuated the raised risk of attempted suicide, particularly in lower weight men. This study suggests that lower weight men have an increased risk of attempted suicide and that associations may extend into the “normal” BMI range.
doi:10.1093/aje/kwq274
PMCID: PMC2984250  PMID: 20829269
body mass index; cohort studies; depression; social class; suicide, attempted

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