Population-based Reference Cohort Research Articles

Unraveling the link between CNVs, cognition and individual neuroimaging deviation scores from a population-based reference cohort

Unraveling the link between CNVs, cognition and individual neuroimaging deviation scores from a population-based reference cohort

P11.21.A LONG-TERM SURVIVAL WITH IDH WILDTYPE GLIOBLASTOMA: FIRST RESULTS FROM THE ETERNITY BRAIN TUMOR FUNDERS’ COLLABORATIVE CONSORTIUM (EORTC 1419)

Abstract BACKGROUND Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. METHODS European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and by the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumors, prognostic factors were analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. RESULTS At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterized) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumors with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% CI 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p<0.001) and had a high rate (48.8%) of MGMT promoter unmethylated tumors. CONCLUSION s Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.

Long-term survival with IDH wildtype glioblastoma: First results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419).

2016 Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and by the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumors, prognostic factors were analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the cut-off of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 not otherwise specified) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumors with O6-methylguanine DNA methyltransferase ( MGMT) promoter methylation. Median overall survival was 9.9 years (95% CI 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p<0.001) and had a high rate of MGMT promoter unmethylated tumors. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Never relapsing patients often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma. Clinical trial information: NCT03770468 .

Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419)

BackgroundMedian survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. MethodsEuropean Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. ResultsAt the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24–78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours. ConclusionsFreedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.

Socioeconomic outcomes beyond 30 years of age in a cohort born with very low birth weight.

As survival of infants born prematurely has increased dramatically, questions on long-term consequences have emerged. Our aim was to investigate long-term effects of very low birth weight on socioeconomic outcomes. One hundred and fifty very low birth weight infants (VLBW) born from 1980 to 1982 at Rigshospitalet, Denmark, who had previously been followed up at age 2, 4 and 18 years, were compared to cohorts of low birth weight, normal birth weight (NBW) and a national population-based reference cohort. From the Danish national registers we obtained data regarding educational level, financial independence and living arrangements. In addition, we used the previously published results from the three cohorts. The VLBW cohort had lower intelligence quotient and higher risk of significant school difficulties evaluated at age 4 and 18 years. When compared to the NBW cohort, at 30-36 years of age the VLBW cohort tended to have lower educational level, OR 1.7, 95% CI 0.8-3.9, were not financially independent OR 1.5, 95% CI 0.6-3.7, lived alone OR 2.0, 95% CI 1.0-3.8 and had higher rates of the combination of all three outcomes, OR 3.2, 95% CI 0.7-15.8. We found trends towards poor socioeconomic outcomes in young adults born with VLBW. The relative disadvantages appeared smaller than that in childhood.

Clinical assessment of blood pressure in 60 girls with Turner syndrome compared to 1888 healthy Danish girls.

Hypertension contributes to increased risk of cardiovascular disease in patients with Turner syndrome (TS). Our objective was to evaluate blood pressure (BP) in girls with TS followed longitudinally through childhood and adolescence compared to a newly established BP reference material. Cohort study with data collected from 1991 to 2019 consisting of a population-based reference cohort and a group of girls with TS followed at a single tertiary centre. Reference population of 1888 healthy girls with 4890 BP recordings and 60 girls with TS with 365 BP recordings. Difference in diastolic BP (DBP) and systolic BP (SBP), expressed in standard deviation scores (SDS), between girls with TS and the reference population, unadjusted and adjusted for BMI. Difference in BP (SDS) between TS subgroups (karyotype, oestrogen treatment, cardiac diagnosis). The girls with TS had significantly higher DBP (mean ± SD, 0.72 SDS ± 0.95; p < .001) and SBP (0.53 SDS ± 1.11; p = .001) than the reference population. Adjusted for BMI, girls with TS had significantly higher DBP (mean ± SE, 0.71 SDS ± 0.12; p < .001) but not SBP (0.17 SDS ± 0.16; p = .29). There was no significant difference in DBP (median, IQR: 0.97 SDS, 0.30-1.58 vs. 0.76 SDS, 0.10-1.20; p = .31) or SBP (0.51 SDS, 0.15-1.30 vs. 0.57 SDS, -0.30 to 1.05; p = .67) between individuals with or without a cardiac diagnosis. In the TS population, 55% (31/56) had at least one BP recording above the hypertension threshold. Our findings indicate that standardised longitudinal routine monitoring of BP in girls with TS already in childhood is of utmost importance.

Assessment of practical applicability and clinical relevance of a commonly used LDL-C polygenic score in patients with severe hypercholesterolemia

Background and aimsLow-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype. MethodsFirst, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data. ResultsThe mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10–0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk. ConclusionsThis 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD.

Cardiometabolic Profiles in Women with a History of Hypertensive and Normotensive Fetal Growth Restriction.

Background: The majority of evidence on associations between pregnancy complications and future maternal disease focuses on hypertensive (Ht) complications. We hypothesize that impaired cardiometabolic health after pregnancies complicated by severe fetal growth restriction (FGR) is independent of the co-occurrence of hypertension. Materials and Methods: In a prospective cohort of women with a pregnancy complicated by early FGR (delivery <34 weeks gestation), with or without concomitant hypertension, cardiometabolic risk factors were assessed after delivery. A population-based reference cohort was used for comparison, and analyses were adjusted for age, current body mass index (BMI), smoking habits, and hormonal contraceptive use. Results: Median time from delivery to assessment was 4 months in both the Ht (N = 115) and normotensive (Nt) (N = 42) FGR groups. Compared with the reference group (N = 380), in both FGR groups lipid profile and glucose homeostasis at assessment were unfavorable. Women with Ht-FGR had the least favorable cardiometabolic profile, with higher prevalence ratios (PRs) for diastolic blood pressure >85 mmHg (PR 4.0, 95% confidence interval [CI] 2.1-6.7), fasting glucose levels >5.6 mmol/L (PR 2.9, 95% CI 1.4-5.6), and total cholesterol levels >6.21 mmol/L (PR 4.5, 95% CI 1.9-8.8), compared with the reference group. Women with Nt-FGR more often had a BMI >30 kg/m2 (PR 2.5, 95% CI 1.2-4.7) and high-density lipoprotein-cholesterol levels <1.29 mmol/L (PR 2.4, 95% CI 1.4-3.5), compared with the reference group. Conclusions: Women with a history of FGR showed unfavorable short-term cardiometabolic profiles in comparison with a reference group, independent of the co-occurrence of hypertension. Therefore, women with a history of FGR may benefit from cardiovascular risk factor assessment and subsequent risk reduction strategies.

Corrected QT Interval-Polygenic Risk Score and Its Contribution to Type 1, Type 2, and Type 3 Long-QT Syndrome in Probands and Genotype-Positive Family Members.

Long-QT syndrome (LQTS) is characterized by a prolonged heart rate-corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population. Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc-polygenic risk score (QTc-PRS). A weighted QTc-PRS (range, 0-154.8 ms) was calculated for each patient, and the FHS (Framingham Heart Study) population-based reference cohort (n=853). The average QTc-PRS in LQTS was 88.0±7.2 and explained only ≈2.0% of the QTc variability. The QTc-PRS in LQTS probands (n=137; 89.3±6.8) was significantly greater than both FHS controls (87.2±7.4, difference-in-means±SE: 2.1±0.7, P<0.002) and LQTS genotype-positive family members (87.5±7.4, difference-in-mean, 1.8±.7, P<0.009). There was no difference in QTc-PRS between symptomatic (n=156, 88.6±7.3) and asymptomatic patients (n=267; 87.7±7.2, difference-in-mean, 0.9±0.7, P=0.15). LQTS patients with a QTc≥480 ms (n=120) had a significantly higher QTc-PRS (89.3±6.7) than patients with a QTc<480 ms (n=303, 87.6±7.4, difference-in-mean, 1.7±0.8, P<0.05). There was no difference in QTc-PRS or QTc between genotypes. The QTc-PRS explained <2% of the QTc variability in our LQT1, LQT2, and LQT3 cohort, contributing 5× less to their QTc value than in the general population. This prototype QTc-PRS does not distinguish/predict the clinical outcomes of individuals with LQTS.

Cardiovascular and Metabolic Health of 74 Children From Women Previously Diagnosed With Polycystic Ovary Syndrome in Comparison With a Population-Based Reference Cohort.

Women with polycystic ovary syndrome (PCOS) have compromised cardiovascular health profiles and an increased risk of pregnancy complications. In order to evaluate potential consequences, we aim to compare the cardiovascular and metabolic health of the children from women with PCOS with a population-based reference cohort. We included children from women with PCOS between the age of 2.5 to 4 years (n = 42) and 6 to 8 years (n = 32). The reference groups consisted of 168 (3-4 years old) and 130 children (7-8 years old). In an extensive cardiovascular screening program, we measured anthropometrics and blood pressure (all children), heart function and vascular rigidity (young children), metabolic laboratory assessment and carotid intima thickness (old age-group). Results showed that young PCOS offspring have a significantly lower diastolic blood pressure (β = 2.3 [95% confidence interval, CI: 0.5-4.0]) and higher aortic pulse pressure (β = -1.4 [95% CI: -2.5 to -0.2]), compared to the reference population. Furthermore, a higher left ventricle internal diameter but a lower tissue Doppler imaging of the right wall in systole compared to the reference group was found. Older offspring of women with PCOS presented with a significantly lower breast and abdominal circumference, but higher triglycerides (β = -0.1 [95% CI: -0.2 to -0.1]), LDL-cholesterol (β = -0.4 [95% CI: -0.6 to -0.1]), and higher carotid intima-media thickness (β = -31.7 [95% CI: -46.6 to -16.9]) compared to the reference group. In conclusion, we observe subtle but distinct cardiovascular and metabolic abnormalities already at an early age in PCOS offspring compared to a population-based reference group, despite a lower diastolic blood pressure, breast, and abdominal circumference. These preliminary findings require confirmation in independent data sets.

Nature-assisted rehabilitation for reactions to severe stress and/or depression in a rehabilitation garden: Long-term follow-up including comparisons with a matched population-based reference cohort

To determine the effect of a nature-assisted rehabilitation programme in a group of patients with reactions to severe stress and/or mild to moderate depression. Changes in sick-leave status and healthcare consumption in these patients were compared with those in a matched population-based reference cohort (treatment as usual). Retrospective cohort study with a matched reference group from the general population. A total of 118 participants referred to a nature-assisted rehabilitation programme, and 678 controls recruited from the Skåne Health Care Register. For both groups, information on sick leave was extracted from the National Social Insurance Register and on healthcare consumption data from the Skåne Health Care Register. The interventional rehabilitation programme was designed as a multimodal programme involving professionals from horticulture and medicine. The programme was conducted in a rehabilitation garden, designed especially for this purpose. A significant reduction in healthcare consumption was noted among participants in the programme compared with the reference population. The main changes were a reduction in outpatient visits to primary healthcare and a reduction in inpatient psychiatric care. No significant difference in sick-leave status was found. A structured, nature-based rehabilitation programme for patients with reactions to severe stress and/or depression could be beneficial, as reflected in reduced healthcare consumption.

Long-term mortality risk by cause of death in newly diagnosed patients with epilepsy in Finland: a nationwide register-based study

To estimate long-term mortality by cause of death in a nationwide, register-based cohort of newly diagnosed patients with epilepsy (PWE). All noninstitutionalized Finnish PWE aged 10-74 years (n = 10,818) eligible for reimbursement for antiepileptic medication for the first time between 1990 and 1994 were identified in the database of Social Insurance Institution of Finland. Mortality was compared against a population-based reference cohort (n = 43,894). Hazard ratios (HR) and their 95 % confidence intervals (95 % CI) during a follow-up of 18 years were estimated using proportional hazards modeling. Potential years of life lost (PYLL) and excess fraction of causes of death attributable to epilepsy were estimated. PWE contributed 137,610 person-years of observation and there were 3,558 deaths. Mortality remained elevated up to 18 years post-diagnosis (HR 3.21, 95 % CI 3.07-3.35). Ischemic heart disease mortality in PWE was two-fold (HR 2.31, 95 % CI 2.09-2.54), and remained constantly elevated during entire follow-up in both men and women. Most premature mortality in terms of PYLL was attributable to brain cancer (17 %), other cancers (15 %), ischemic heart disease (11 %), as well as cerebrovascular diseases (10 %). The percentage of deaths in PWE statistically attributable to epilepsy was 3.9 % for accidents, 3.4 % for alcohol-related diseases, and 1.6 % for suicides. PWE had substantial excess mortality from non-communicable diseases, which did not disappear by 18 years. Diseases of the circulatory system and cancers, especially brain cancer, were the most important causes of death almost regardless of the mortality indicator.

O14.3 Long-Term Efficacy of Human Papillomavirus Vaccination Against Cervical Cancer

Human papillomavirus (HPV) vaccination trials have shown high efficacy (VE) against high grade cervical intraepithelial neoplasia (CIN2/3). CIN2/3 is a surrogate marker of invasive cervical cancer (ICC). These lesions may...

Understanding long‐term protection of human papillomavirus vaccination against cervical carcinoma: Cancer registry‐based follow‐up

Phase III clinical trials of human papilloma virus (HPV) vaccination have shown ≥95% efficacy against HPV16/18 associated cervical intraepithelial neoplasia (CIN) Grade 2/3. Long-term surveillance is, however, needed to determine the overall vaccine efficacy (VE) against CIN3 and invasive cervical carcinoma (ICC). During population-based recruitment between September 2002 and March 2003, 1,749 16- to 17-year old Finns participated in a multi-national randomized Phase III HPV6/11/16/18 vaccine (FUTURE II) trial for the determination of VE against HPV16/18 positive CIN2/3. The passive follow-up started at the country-wide, population-based Finnish Cancer Registry (FCR) six months after the active follow-up and voluntary cross-vaccination in April 2007. A cluster randomized, population-based reference cohort of 15,744 unvaccinated, originally 18-19 year old Finns was established in two phases in 2003 and 2005 after the FUTURE II recruitment. We linked these cohorts with the FCR in 2007-2011 (HPV vaccine and placebo cohorts) and 2006-2010 and 2008-2012 (unvaccinated reference cohorts 1 and 2) to compare their incidences of CIN3 and ICC. The four years passive follow-up resulted in 3,464, 3,444 and 62,876 person years for the HPV6/11/16/18, original placebo and reference cohorts, after excluding cases discovered during the clinical follow-up and individuals not at risk. The numbers of CIN3 and ICC cases identified were 0 and 0, 3 and 0, 59 and 3 for the HPV6/11/16/18, placebo and the unvaccinated reference cohorts. The corresponding CIN3 incidence rates were 0/100,000 (95% confidence interval 0.0-106.5), 87.1/100,000 (95% CI 17.9-254.5) and 93.8/100,000 (95% CI 71.4-121), respectively. Long-term surveillance up to 8 years (and longer) post vaccination of the HPV6/11/16/18 vaccine and placebo cohorts, and the unvaccinated reference cohort (not exposed to interventions) for the most stringent efficacy end-points by passive cancer registry-based follow-up is feasible.

Mortality by clinical characteristics in a tertiary care cohort of adult patients with chronic epilepsy

The authors evaluated the contribution of various clinical characteristics to mortality risk and underlying causes of death among all adult patients with epilepsy seen at the Department of Neurology, Oulu University Hospital in Finland during 1996 and 1997. Hazard ratios (HRs) for mortality in 1998-2006 relative to a population-based reference cohort were estimated using Cox modeling, with adjustment for age and gender. The HR for total mortality was 2.66 (95% confidence interval [CI] 2.09-3.39). Infectious etiology of epilepsy (HR 5.77, 95% CI 2.52-13.2) and a seizure frequency of ≥1 per month (HR 4.42, 95% CI 3.00-6.52) related to high risks of death. Cancer (21%), ischemic heart disease (15%), and accidents (12%) caused most of the potential years of life lost. Despite recent advances in treatment of epilepsy and improved seizure control, chronic epilepsy still carries a substantially increased risk of death.

Birth rate among patients with epilepsy: a nationwide population-based cohort study in Finland.

Few reports on population-based studies of birth rate among epilepsy patients have been published. In most previous studies, fertility has been lower among epilepsy patients than in the rest of the population. However, conflicting results have also been reported. Because of small samples and selective material, the generalizability of these results is also limited. The authors conducted a population-based cohort study of birth rate (1985-2001) in a nationwide Finnish cohort of patients with newly diagnosed epilepsy and a population-based reference cohort. All patients (n = 14,077) approved as eligible for reimbursement for antiepileptic medication from the Social Insurance Institution of Finland (KELA) for the first time between 1985 and 1994 were identified from the KELA database. A reference cohort (n = 29,828) was identified from the Finnish Population Register Center, with frequency-matching on age. Information on follow-up status and livebirths were also obtained from the Finnish Population Register Center. The birth rate was lower in patients with epilepsy than in the reference cohort among both men (hazard ratio = 0.58, 95% confidence interval: 0.54, 0.62) and women (hazard ratio = 0.88, 95% confidence interval: 0.83, 0.93). There were a clear decreasing trend by age at observation in men with epilepsy and a moderate decreasing trend by age at start of follow-up in women with epilepsy.