Linear mixed models for estimating heritability and testing genetic association in family data

Coronary heart disease (CHD) is one of the leading causes of death worldwide. Linear mixed models (LMMs) are presented in this thesis and they are applied to family data from the European Multicenter Study on Familial Dyslipidemias in Patients with Premature Coronary Heart Disease (EUFAM) -project. The data contain 23 quantitative traits relating to risk of CHD and roughly 28 million genetic variants. The data consist of nearly 1600 individuals from around 150 families. Linear mixed models are used when the data contain clustering or repeated measurements. In other words, when the observations are dependent. In the EUFAM data the observations come from families. In this case, the linear mixed models take the relatedness of the individuals into account. Linear mixed models are applied for both heritability estimation and genome-wide association testing in this thesis. Both in simulations and in the analyses with the EUFAM-data the need for LMMs can be seen. The LMM has more statistical power than the standard linear model when heritability exists in the data. The standard linear model also has inflated type I error rate. Both of these occur because the standard linear model does not take the relatedness of the individuals into account. For example, in the genome-wide analysis done for the EUFAM-data the standard linear model gives a massive amount of false positives when compared to the linear mixed model. The thesis proves the usefulness of and need for linear mixed models when analyzing family data.Sydän- ja verisuonitaudit ovat maailmanlaajuisesti yksi yleisimpiä kuolinsyitä. Tutkielmassa esitellään lineaarinen sekamalli ja sitä sovelletaan European Multicenter Study on Familial Dyslipidemias in Patients with Premature Coronary Heart Disease (EUFAM) -projektin perheainestoon. Aineisto sisältää 23 jatkuvaa sydän- ja verisuonitauteihin liittyvää riskitekijää ja noin 28 miljoonaa geneettisiä varianttia. Aineisto koostuu lähes 1600 yksilöstä, jotka ovat peräisin noin 150 perheestä. Lineaarisia sekamalleja käytetään, kun aineisto sisältää ryhmittäytymistä tai toistuvia mittauksia. Toisin sanoen, kun havainnot ovat riippuvia toisistaan. EUFAM-aineistossa havainnot ovat peräisin perheistä, jolloin lineaarisella sekamallilla voidaan ottaa huomioon yksilöiden välinen sukulaisuus. Tutkielmassa sovelletaan lineaarisia sekamalleja periytyvyyden estimointiin ja genominlaajuiseen assosiaatiotutkimukseen. Sekä simulaatioissa että EUFAM-aineiston analyyseissä havaitsemme lineaarisen sekamallin tarpeellisuuden. Sekamallilla on enemmän tilastollista voimaa kuin tavallisella lineaarimallilla, kun selitettävään muuttujaan vaikuttaa periytyvyys. Tavallinen lineaarimalli myös aliarvioi tyypin I virheet. Nämä ovat seurausta siitä, ettei tavallinen lineaarimalli ota huomioon yksilöiden välisiä sukulaisuuksia. Esimerkiksi EUFAM-aineistolle tehdyssä genominlaajuisessa assosiaatiotutkimuksessa tavallinen lineaarimalli antaa huomattavan määrään vääriä assosiaatioita verrattaessa lineaariseen sekamalliin. Tutkielma osoittaa lineaarisen sekamallin hyödyllisyyden ja tarpeellisuuden analysoitaessa perheaineistoja

Why do infants need out-of-hospital emergency medical services? A retrospective, population-based study

BackgroundThe challenges encountered in emergency medical services (EMS) contacts with children are likely most pronounced in infants, but little is known about their out-of-hospital care. Our primary aim was to describe the characteristics of EMS contacts with infants. The secondary aims were to examine the symptom-based dispatch system for nonverbal infants, and to observe the association of unfavorable patient outcomes with patient and EMS mission characteristics.MethodsIn a population-based 5-year retrospective cohort of all 1712 EMS responses for infants (agePeer reviewe

Outcomes in children evaluated but not transported by ambulance personnel: Retrospective cohort study

Peer reviewe

Ability of prehospital NEWS to predict 1-day and 7-day mortality is reduced in older adult patients

Background National Early Warning Score (NEWS) does not include age as a parameter despite age is a significant independent risk factor of death. The aim of this study was to examine whether age has an effect on predictive performance of short-term mortality of NEWS in a prehospital setting. We also evaluated whether adding age as an additional parameter to NEWS improved its short-term mortality prediction. Methods We calculated NEWS scores from retrospective prehospital electronic patient record data for patients 18 years or older with sufficient prehospital data to calculate NEWS. We used area under receiver operating characteristic (AUROC) to analyse the predictive performance of NEWS for 1 and 7 day mortalities with increasing age in three different age groups: = 80 years. We also explored the ORs for mortality of different NEWS parameters in these age groups. We added age to NEWS as an additional parameter and evaluated its effect on predictive performance. Results We analysed data from 35 800 ambulance calls. Predictive performance for 7-day mortality of NEWS decreased with increasing age: AUROC (95% CI) for 1-day mortality was 0.876 (0.848 to 0.904), 0.824 (0.794 to 0.854) and 0.820 (0.788 to 0.852) for first, second and third age groups, respectively. AUROC for 7-day mortality had a similar trend. Addition of age as an additional parameter to NEWS improved its ability to predict short-term mortality when assessed with continuous Net Reclassification Improvement. Conclusions Age should be considered as an additional parameter to NEWS, as it improved its performance in predicting short-term mortality in this prehospital cohort.Peer reviewe

Effect of age adjustment on two triage methods

Background Most emergency departments rely on acuity assessment, triage, to recognize critically ill patients that need urgent treatment, and to allocate resources according to need. The accuracy of commonly used triage instruments such as the Emergency Severity Index (ESI) is lower for older adults compared to young patients. We aim to examine, whether adjusting the triage category by age leads to improvement in sensitivity without excessive increase in patient numbers in the higher triage categories. The primary outcome measure was 3-day mortality and secondary outcomes were 30-day mortality, hospital admission, and HDU/ICU admissions. Methods We gathered data of all adult patients who had an unscheduled visit to any of our three emergency departments within one month. The data was analysed for 3-day mortality, 30-day mortality, hospital admission, and high dependency unit or intensive care unit (HDU/ICU) admission. The analysis was run for both the standard ESI triage method and a local 3-level Helsinki University Hospital (HUH) method. A further analysis was run for both triage methods with age adjustment. Net reclassification improvement values were calculated to demonstrate the effect of age adjustment. Results Thirteen thousand seven hundred fifty-nine patients met the study criteria, median age was 57. 3-day mortality AUCs for unadjusted HUH and ESI triage were 0.77 (0.65-0.88) and 0.72 (0.57-0.87); 30-day mortality AUCs were 0.64 (0.59-0.69) and 0.69 (0.64-0.73); hospital admission AUCs were 0.60 (0.68-0.71) and 0.66 (0.65-0.68) and HDU/ICU admission AUCs were 0.67 (0.64-0.70) and 0.82 (0.79-0.86), respectively. Age adjustment improved accuracy for 30-day mortality and hospital admission. With the threshold age of 80, AUCs for 30-day mortality were 0.73 (0.68-0.77) and 0.77 (0.73-0.81) and for hospital admission, 0.66 (0.65-0.67) and 0.72 (0.71-0.73) for the HUH and ESI triage. The effect was similar with all cut off ages. Conclusion Moving older adults into a more urgent triage category based on age, improved the triage instruments' performance slightly in predicting 30-day mortality and hospital admission without excessive increase in patient numbers in the higher triage categories. Age adjustment did not improve HDU/ICU admission or 3-day mortality prediction.Peer reviewe

Validation of Score to Detect Intracranial Lesions in Unconscious Patients in Prehospital Setting

Objectives: Recognizing stroke and other intracranial pathologies in prehospital phase facilitates prompt recanalization and other specific care. Recognizing these can be difficult in patients with decreased level of consciousness. We previously derived a scoring system combining systolic blood pressure, age and heart rate to recognize patients with intracranial pathology. In this study we aimed to validate the score in a larger, separate population. Materials and methods: We conducted a register based retrospective study on patients >= 16 years old and Glasgow Coma ScorePeer reviewe

A potential method of identifying stroke and other intracranial lesions in a prehospital setting

Background Identifying stroke and other intracranial lesions in patients with a decreased level of consciousness may be challenging in prehospital settings. Our objective was to investigate whether the combination of systolic blood pressure, heart rate and age could be used to identify intracranial lesions. Methods We conducted a retrospective case-control study including patients with a decreased level of consciousness who had their airway secured during prehospital care. Patients with intracranial lesions were identified based on the final diagnoses at the end of hospitalization. We investigated the ability of systolic blood pressure, heart rate and age to identify intracranial lesions and derived a decision instrument. Results Of 425 patients, 127 had an intracranial lesion. Patients with a lesion were characterized by higher systolic blood pressure, lower heart rate and higher age (P = 140 mmHg had an odds ratio (OR) of 3.5 (95% confidence interval [CI] 1.7 to 7.0), and > 170 mmHg had an OR of 8.2 (95% CI 4.5-15.32) for an intracranial lesion (reference: = 100). Age 50-70 had an OR of 4.1 (95% CI 2.0 to 9.0), and > 70 years had an OR of 10.2 (95% CI 4.8 to 23.2), reference: <50. Logarithms of ORs were rounded to the nearest integer to create a score with 0-2 points for age and blood pressure and 0-1 for heart rate, with an increasing risk for an intracranial lesion with higher scores. The area under the receiver operating characteristics curve for the instrument was 0.810 (95% CI 0.850-0.890). Conclusions An instrument combining systolic blood pressure, heart rate and age may help identify stroke and other intracranial lesions in patients with a decreased level of consciousness in prehospital settings.Peer reviewe

Accuracy of Emergency Severity Index in older adults

Background and importance Emergency Severity Index is a five-level triage tool in the emergency department that predicts the need for emergency department resources and the degree of emergency. However, it is unknown whether this is valid in patients aged greater than or equal to 65 years. Objective The aim of the study was to compare the accuracy of the Emergency Severity Index triage system between emergency department patients aged 18-64 and greater than or equal to 65 years. Design, settings, and participants This was a retrospective observational cohort study of adults who presented to a Finnish emergency department between 1 February 2018 and 28 February 2018. All data were collected from electronic health records. Outcome measures and analysis The primary outcome was 3-day mortality. The secondary outcomes were 30-day mortality, hospital admission, high dependency unit or ICU admission, and emergency department length of stay. The area under the receiver operating characteristic curve and cutoff performances were used to investigate significant associations between triage categories and outcomes. The results of the two age groups were compared. Main results There were 3141 emergency department patients aged 18-64 years and 2370 patients aged greater than or equal to 65 years. The 3-day mortality area under the curve in patients aged greater than or equal to 65 years was greater than that in patients aged 18-64 years. The Emergency Severity Index was associated with high dependency unit/ICU admissions in both groups, with moderate sensitivity [18-64 years: 61.8% (50.9-71.9%); greater than or equal to 65 years: 73.3% (63.5-81.6%)] and high specificity [18-64 years: 93.0% (92.0-93.8%); greater than or equal to 65 years: 90.9% (90.0-92.1%)]. The sensitivity was high and specificity was low for 30-day mortality and hospital admission in both age groups. The emergency department length of stay was the longest in Emergency Severity Index category 3 for both age groups. There was no significant difference in accuracy between age groups for any outcome. Conclusion Emergency Severity Index performed well in predicting high dependency unit/ICU admission rates for both 18-64 years and greater than or equal to 65-year-old patients. It predicted the 3-day mortality for patients aged greater than or equal to 65 years with high accuracy. It was inaccurate in predicting 30-day mortality and hospital admission for both age groups.Peer reviewe

A potential method of identifying stroke and other intracranial lesions in a prehospital setting

Background Identifying stroke and other intracranial lesions in patients with a decreased level of consciousness may be challenging in prehospital settings. Our objective was to investigate whether the combination of systolic blood pressure, heart rate and age could be used to identify intracranial lesions. Methods We conducted a retrospective case-control study including patients with a decreased level of consciousness who had their airway secured during prehospital care. Patients with intracranial lesions were identified based on the final diagnoses at the end of hospitalization. We investigated the ability of systolic blood pressure, heart rate and age to identify intracranial lesions and derived a decision instrument. Results Of 425 patients, 127 had an intracranial lesion. Patients with a lesion were characterized by higher systolic blood pressure, lower heart rate and higher age (P = 140 mmHg had an odds ratio (OR) of 3.5 (95% confidence interval [CI] 1.7 to 7.0), and > 170 mmHg had an OR of 8.2 (95% CI 4.5-15.32) for an intracranial lesion (reference: = 100). Age 50-70 had an OR of 4.1 (95% CI 2.0 to 9.0), and > 70 years had an OR of 10.2 (95% CI 4.8 to 23.2), reference: <50. Logarithms of ORs were rounded to the nearest integer to create a score with 0-2 points for age and blood pressure and 0-1 for heart rate, with an increasing risk for an intracranial lesion with higher scores. The area under the receiver operating characteristics curve for the instrument was 0.810 (95% CI 0.850-0.890). Conclusions An instrument combining systolic blood pressure, heart rate and age may help identify stroke and other intracranial lesions in patients with a decreased level of consciousness in prehospital settings.Peer reviewe

Maternal Thyroid Disease and the Risk of Childhood Cancer in the Offspring

Maternal thyroid disease, especially hypothyroidism, affects pregnancy and its outcome. In-utero exposure to autoimmune thyroid disease has been reported to associate with childhood ALL in the offspring. We evaluated the risk of childhood cancer in the offspring following exposure to maternal thyroid disease in a case-control setting using registry data. All patients with their first cancer diagnosis below the age of 20 years were identified from the Finnish Cancer Registry (n = 2037) and matched for sex and birth year at a 1:5 ratio to population controls identified from the Medical Birth Registry (n = 10,185). We collected national information on maternal thyroid disease from the Medical Birth Registry, Care Register for Health Care, Register for Reimbursed Drug Purchases and Register of Special Reimbursements. We used conditional logistic regression to analyze childhood cancer risk in the offspring. The adjusted OR for any childhood cancer was 1.41 (95%, CI 1.00–2.00) comparing the offspring of mothers with hypothyroidism and those with normal thyroid function. The risk of lymphomas was increased (adjusted OR for maternal hypothyroidism 3.66, 95%, CI 1.29–10.38). The results remained stable when mothers with cancer history were excluded from the analyses. Maternal hypothyroidism appears to be associated with an increased risk for childhood lymphoma in the offspring. The association exists even after excluding possible familial cancers