Mammographic mass-screening and future breast cancer burden in Finland

A population-based early detection program for breast cancer has been in progress in Finland since 1987. According to regulations during the study period 1987-2001, free of charge mammography screening was offered every second year to women aged 50-59 years. Recently, the screening service was decided to be extended to age group 50-69. However, the scope of the program is still frequently discussed in public and information about potential impacts of mass-screening practice changes on future breast cancer burden is required. The aim of this doctoral thesis is to present methodologies for taking into account the mass-screening invitation information in breast cancer burden predictions, and to present alternative breast cancer incidence and mortality predictions up to 2012 based on scenarios of the future screening policy. The focus of this work is not on assessing the absolute efficacy but the effectiveness of mass-screening, and, by utilizing the data on invitations, on showing the estimated impacts of changes in an existing screening program on the short-term predictions. The breast cancer mortality predictions are calculated using a model that combines incidence, cause-specific and other cause survival on individual level. The screening invitation data are incorporated into modeling of breast cancer incidence and survival by dividing the program into separate components (first and subsequent rounds and years within them, breaks, and post screening period) and defining a variable that gives the component of the screening program. The incidence is modeled using a Poisson regression approach and the breast cancer survival by applying a parametric mixture cure model, where the patient population is allowed to be a combination of cured and uncured patients. The patients risk to die from other causes than breast cancer is allowed to differ from that of a corresponding general population group and to depend on age and follow-up time. As a result, the effects of separate components of the screening program on incidence, proportion of cured and the survival of the uncured are quantified. According to the predictions, the impacts of policy changes, like extending the program from age group 50-59 to 50-69, are clearly visible on incidence while the effects on mortality in age group 40-74 are minor. Extending the screening service would increase the incidence of localized breast cancers but decrease the rates of non-localized breast cancer. There were no major differences between mortality predictions yielded by alternative future scenarios of the screening policy: Any policy change would have at the most a 3.0% reduction on overall breast cancer mortality compared to continuing the current practice in the near future.

Genetic Heterogeneity in Autism Spectrum Disorders in a Population Isolate

Positional cloning has enabled hypothesis-free, genome-wide scans for genetic factors contributing to disorders or traits. Traditionally linkage analysis has been used to identify regions of interest, followed by meticulous fine mapping and candidate gene screening using association methods and finally sequencing of regions of interest. More recently, genome-wide association analysis has enabled a more direct approach to identify specific genetic variants explaining a part of the variance of the phenotype of interest. Autism spectrum disorders (ASDs) are a group of childhood onset neuropsychiatric disorders with shared core symptoms but varying severity. Although a strong genetic component has been established in ASDs, genetic susceptibility factors have largely eluded characterization. Here, we have utilized modern molecular genetic methods combined with the advantages provided by the special population structure in Finland to identify genetic risk factors for ASDs. The results of this study show that numerous genetic risk factors exist for ASDs even within a population isolate. Stratification based on clinical phenotype resulted in encouraging results, as previously identified linkage to 3p14-p24 was replicated in an independent family set of families with Asperger syndrome, but no other ASDs. Fine-mapping of the previously identified linkage peak for ASDs at 3q25-q27 revealed association between autism and a subunit of the 5-hydroxytryptamine receptor 3C (HTR3C). We also used dense, genome-wide single nucleotide polymorphism (SNP) data to characterize the population structure of Finns. We observed significant population substructure which correlates with the known history of multiple consecutive bottle-necks experienced by the Finnish population. We used this information to ascertain a genetically homogenous subset of autism families to identify possible rare, enriched risk variants using genome-wide SNP data. No rare enriched genetic risk factors were identified in this dataset, although a subset of families could be genealogically linked to form two extended pedigrees. The lack of founder mutations in this isolated population suggests that the majority of genetic risk factors are rare, de novo mutations unique to individual nuclear families. The results of this study are consistent with others in the field. The underlying genetic architecture for this group of disorders appears highly heterogeneous, with common variants accounting for only a subset of genetic risk. The majority of identified risk factors have turned out to be exceedingly rare, and only explain a subset of the genetic risk in the general population in spite of their high penetrance within individual families. The results of this study, together with other results obtained in this field, indicate that family specific linkage, homozygosity mapping and resequencing efforts are needed to identify these rare genetic risk factors.

Migraine with aura and migraine without aura are not distinct entities: further evidence from a large Dutch population study

It is often debated whether migraine with aura (MA) and migraine without aura (MO) are etiologically distinct disorders. A previous study using latent class analysis (LCA) in Australian twins showed no evidence for separate subtypes of MO and MA. The aim of the present study was to replicate these results in a population of Dutch twins and their parents, siblings and partners (N = 10,144). Latent class analysis of International Headache Society (IHS)-based migraine symptoms resulted in the identification of 4 classes: a class of unaffected subjects (class 0), a mild form of nonmigrainous headache (class 1), a moderately severe type of migraine (class 2), typically without neurological symptoms or aura (8% reporting aura symptoms), and a severe type of migraine (class 3), typically with neurological symptoms, and aura symptoms in approximately half of the cases. Given the overlap of neurological symptoms and nonmutual exclusivity of aura symptoms, these results do not support the MO and MA subtypes as being etiologically distinct. The heritability in female twins of migraine based on LCA classification was estimated at .50 (95% confidence intervals [CI] .27 - .59), similar to IHS-based migraine diagnosis (h2 = .49, 95% CI .19-.57). However, using a dichotomous classification (affected-unaffected) decreased heritability for the IHS-based classification (h2 = .33, 95% CI .00-.60), but not the LCA-based classification (h2 = .51, 95% CI .23-.61). Importantly, use of the LCA-based classification increased the number of subjects classified as affected. The heritability of the screening question was similar to more detailed LCA and IHS classifications, suggesting that the screening procedure is an important determining factor in genetic studies of migraine.

NEESTIMATOR v2: re-implementation of software for the estimation of contemporary effective population size (N-e) from genetic data

NeEstimator v2 is a completely revised and updated implementation of software that produces estimates of contemporary effective population size, using several different methods and a single input file. NeEstimator v2 includes three single-sample estimators (updated versions of the linkage disequilibrium and heterozygote-excess methods, and a new method based on molecular coancestry), as well as the two-sample (moment-based temporal) method. New features include the following: (i) an improved method for accounting for missing data; (ii) options for screening out rare alleles; (iii) confidence intervals for all methods; (iv) the ability to analyse data sets with large numbers of genetic markers (10000 or more); (v) options for batch processing large numbers of different data sets, which will facilitate cross-method comparisons using simulated data; and (vi) correction for temporal estimates when individuals sampled are not removed from the population (Plan I sampling). The user is given considerable control over input data and composition, and format of output files. The freely available software has a new JAVA interface and runs under MacOS, Linux and Windows.

Screening and breeding for genetic resistance to anthracnose in mango

Postharvest diseases remain a significant constraint to the transport, storage and marketing of mangoes. The two main ones are anthracnose and stem end rot. Anthracnose caused by Colletotrichum gloeosporioides is the more wide-spread of the two. Varieties within Mangifera indica are known to vary in their level of reactions to anthracnose; however, the best tolerance in current commercial cultivars is not sufficient to eliminate the need for pre- and postharvest fungicides treatments. A screening program was initiated in mango accessions in the Australian National Mango Genebank to look for any significant resistance to C. gloeosporioides in fruit as they ripened. Screening was conducted by rating reactions to natural infection of anthracnose and reactions to artificially inoculating fruit with virulent isolates of C. gloeosporioides. A range of reactions to the pathogen were identified, with strong resistance found in one accession of the species M. laurina. This accession was used as the pollen parent in a controlled crossing program with a M. indica hybrid from the Australian Mango Breeding Program (AMBP). Sixty successful hybrids between the species have been generated. The hybrid population will be screened for resistance to anthracnose and used for gene discovery investigations to identify markers for anthracnose resistance.

Assessment of neuroleptic-induced movement disorders in a naturalistic schizophrenia population

The prevalence and assessment of neuroleptic-induced movement disorders (NIMDs) in a naturalistic schizophrenia population that uses conventional neuroleptics were studied. We recruited 99 chronic schizophrenic institutionalized adult patients from a state nursing home in central Estonia. The total prevalence of NIMDs according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) was 61.6%, and 22.2% had more than one NIMD. We explored the reliability and validity of different instruments for measuring these disorders. First, we compared DSM-IV with the established observer rating scales of Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS) (for neuroleptic-induced parkinsonism, NIP) and Abnormal Involuntary Movement Scale (AIMS) (for tardive dyskinesia), all three of which have been used for diagnosing NIMD. We found a good overlap of cases for neuroleptic-induced akathisia (NIA) and tardive dyskinesia (TD) but somewhat poorer overlap for NIP, for which we suggest raising the commonly used threshold value of 0.3 to 0.65. Second, we compared the established observer rating scales with an objective motor measurement, namely controlled rest lower limb activity measured by actometry. Actometry supported the validity of BARS and SAS, but it could not be used alone in this naturalistic population with several co-existing NIMDs. It could not differentiate the disorders from each other. Quantitative actometry may be useful in measuring changes in NIA and NIP severity, in situations where the diagnosis has been made using another method. Third, after the relative failure of quantitative actometry to show diagnostic power in a naturalistic population, we explored descriptive ways of analysing actometric data, and demonstrated diagnostic power pooled NIA and pseudoakathisia (PsA) in our population. A subjective question concerning movement problems was able to discriminate NIA patients from all other subjects. Answers to this question were not selective for other NIMDs. Chronic schizophrenia populations are common worldwide, NIMD affected two-thirds of our study population. Prevention, diagnosis and treatment of NIMDs warrant more attention, especially in countries where typical antipsychotics are frequently used. Our study supported the validity and reliability of DSM-IV diagnostic criteria for NIMD in comparison with established rating scales and actometry. SAS can be used with minor modifications for screening purposes. Controlled rest lower limb actometry was not diagnostically specific in our naturalistic population with several co-morbid NIMDs, but it may be sensitive in measuring changes in NIMDs.

Reduced visual function and its association with physical functioning in the Finnish adult population : Prevalence, causes, and need for eye care services

The purpose of this study was to estimate the prevalence and distribution of reduced visual acuity, major chronic eye diseases, and subsequent need for eye care services in the Finnish adult population comprising persons aged 30 years and older. In addition, we analyzed the effect of decreased vision on functioning and need for assistance using the World Health Organization’s (WHO) International Classification of Functioning, Disability, and Health (ICF) as a framework. The study was based on the Health 2000 health examination survey, a nationally representative population-based comprehensive survey of health and functional capacity carried out in 2000 to 2001 in Finland. The study sample representing the Finnish population aged 30 years and older was drawn by a two-stage stratified cluster sampling. The Health 2000 survey included a home interview and a comprehensive health examination conducted at a nearby screening center. If the invited participants did not attend, an abridged examination was conducted at home or in an institution. Based on our finding in participants, the great majority (96%) of Finnish adults had at least moderate visual acuity (VA ≥ 0.5) with current refraction correction, if any. However, in the age group 75–84 years the prevalence decreased to 81%, and after 85 years to 46%. In the population aged 30 years and older, the prevalence of habitual visual impairment (VA ≤ 0.25) was 1.6%, and 0.5% were blind (VA < 0.1). The prevalence of visual impairment increased significantly with age (p < 0.001), and after the age of 65 years the increase was sharp. Visual impairment was equally common for both sexes (OR 1.20, 95% CI 0.82 – 1.74). Based on self-reported and/or register-based data, the estimated total prevalences of cataract, glaucoma, age-related maculopathy (ARM), and diabetic retinopathy (DR) in the study population were 10%, 5%, 4%, and 1%, respectively. The prevalence of all of these chronic eye diseases increased with age (p < 0.001). Cataract and glaucoma were more common in women than in men (OR 1.55, 95% CI 1.26 – 1.91 and OR 1.57, 95% CI 1.24 – 1.98, respectively). The most prevalent eye diseases in people with visual impairment (VA ≤ 0.25) were ARM (37%), unoperated cataract (27%), glaucoma (22%), and DR (7%). One-half (58%) of visually impaired people had had a vision examination during the past five years, and 79% had received some vision rehabilitation services, mainly in the form of spectacles (70%). Only one-third (31%) had received formal low vision rehabilitation (i.e., fitting of low vision aids, receiving patient education, training for orientation and mobility, training for activities of daily living (ADL), or consultation with a social worker). People with low vision (VA 0.1 – 0.25) were less likely to have received formal low vision rehabilitation, magnifying glasses, or other low vision aids than blind people (VA < 0.1). Furthermore, low cognitive capacity and living in an institution were associated with limited use of vision rehabilitation services. Of the visually impaired living in the community, 71% reported a need for assistance and 24% had an unmet need for assistance in everyday activities. Prevalence of ADL, instrumental activities of daily living (IADL), and mobility increased with decreasing VA (p < 0.001). Visually impaired persons (VA ≤ 0.25) were four times more likely to have ADL disabilities than those with good VA (VA ≥ 0.8) after adjustment for sociodemographic and behavioral factors and chronic conditions (OR 4.36, 95% CI 2.44 – 7.78). Limitations in IADL and measured mobility were five times as likely (OR 4.82, 95% CI 2.38 – 9.76 and OR 5.37, 95% CI 2.44 – 7.78, respectively) and self-reported mobility limitations were three times as likely (OR 3.07, 95% CI 1.67 – 9.63) as in persons with good VA. The high prevalence of age-related eye diseases and subsequent visual impairment in the fastest growing segment of the population will result in a substantial increase in the demand for eye care services in the future. Many of the visually impaired, especially older persons with decreased cognitive capacity or living in an institution, have not had a recent vision examination and lack adequate low vision rehabilitation. This highlights the need for regular evaluation of visual function in the elderly and an active dissemination of information about rehabilitation services. Decreased VA is strongly associated with functional limitations, and even a slight decrease in VA was found to be associated with limited functioning. Thus, continuous efforts are needed to identify and treat eye diseases to maintain patients’ quality of life and to alleviate the social and economic burden of serious eye diseases.

Assessment of Risk for Type 1 Diabetes in Children of Affected Families and in the General Population : Role of Immunological and Metabolic Markers

Background and aims. Type 1 diabetes (T1D), an autoimmune disease in which the insulin producing beta cells are gradually destroyed, is preceded by a prodromal phase characterized by appearance of diabetes-associated autoantibodies in circulation. Both the timing of the appearance of autoantibodies and their quality have been used in the prediction of T1D among first-degree relatives of diabetic patients (FDRs). So far, no general strategies for identifying individuals at increased disease risk in the general population have been established, although the majority of new cases originate in this population. The current work aimed at assessing the predictive role of diabetes-associated immunologic and metabolic risk factors in the general population, and comparing these factors with data obtained from studies on FDRs. Subjects and methods. Study subjects in the current work were subcohorts of participants of the Childhood Diabetes in Finland Study (DiMe; n=755), the Cardiovascular Risk in Young Finns Study (LASERI; n=3475), and the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP) Study subjects (n=7410). These children were observed for signs of beta-cell autoimmunity and progression to T1D, and the results obtained were compared between the FDRs and the general population cohorts. --- Results and conclusions. By combining HLA and autoantibody screening, T1D risks similar to those reported for autoantibody-positive FDRs are observed in the pediatric general population. Progression rate to T1D is high in genetically susceptible children with persistent multipositivity. Measurement of IAA affinity failed in stratifying the risk assessment in young IAA-positive children with HLA-conferred disease susceptibility, among whom affinity of IAA did not increase during the prediabetic period. Young age at seroconversion, increased weight-for-height, decreased early insulin response, and increased IAA and IA-2A levels predict T1D in young children with genetic disease susceptibility and signs of advanced beta-cell autoimmunity. Since the incidence of T1D continues to increase, efforts aimed at preventing T1D are important, and reliable disease prediction is needed both for intervention trials and for effective and safe preventive therapies in the future. Our observations confirmed that combined HLA-based screening and regular autoantibody measurements reveal similar disease risks in pediatric general population as those seen in prediabetic FDRs, and that risk assessment can be stratified further by studying glucose metabolism of prediabetic subjects. As these screening efforts are feasible in practice, the knowledge now obtained can be exploited while designing intervention trials aimed at secondary prevention of T1D.

Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is a valid screening tool in chemotherapy outpatients

Purpose In the oncology population where malnutrition prevalence is high, more descriptive screening tools can provide further information to assist triaging and capture acute change. The Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF) is a component of a nutritional assessment tool which could be used for descriptive nutrition screening. The purpose of this study was to conduct a secondary analysis of nutrition screening and assessment data to identify the most relevant information contributing to the PG-SGA SF to identify malnutrition risk with high sensitivity and specificity. Methods This was an observational, cross-sectional study of 300 consecutive adult patients receiving ambulatory anti-cancer treatment at an Australian tertiary hospital. Anthropometric and patient descriptive data were collected. The scored PG-SGA generated a score for nutritional risk (PG-SGA SF) and a global rating for nutrition status. Receiver operating characteristic curves (ROC) were generated to determine optimal cut-off scores for combinations of the PG-SGA SF boxes with the greatest sensitivity and specificity for predicting malnutrition according to scored PG-SGA global rating. Results The additive scores of boxes 1–3 had the highest sensitivity (90.2 %) while maintaining satisfactory specificity (67.5 %) and demonstrating high diagnostic value (AUC = 0.85, 95 % CI = 0.81–0.89). The inclusion of box 4 (PG-SGA SF) did not add further value as a screening tool (AUC = 0.85, 95 % CI = 0.80–0.89; sensitivity 80.4 %; specificity 72.3 %). Conclusions The validity of the PG-SGA SF in chemotherapy outpatients was confirmed. The present study however demonstrated that the functional capacity question (box 4) does not improve the overall discriminatory value of the PG-SGA SF.

Neonatal screening for amino acidaemias in Karnataka, south India

Consanguineous marriages are strongly favoured among the peoples of South India. Because of the potential genetic risks resulting from inbreeding, a neonatal screening project was established in 1980 in the state of Karnataka for the identification of amino acidaemias. To date, blood samples obtained by toe-stab from 98,256 neonates have been tested by thin layer chromatography, with 46 single and 70 general amino acidaemias detected. The coefficients of inbreeding (F) for the two groups of neonates were 0.0336 and 0.0350, by comparison with a previously determined F value for the general, new-born population of 0.0298. The most common single abnormality detected was tyrosinaemia, with spontaneous resolution in the majority of cases.

An unusual distribution of glucose-6-phosphate dehydrogenase deficiency of south Indian newborn population.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is seen at a higher frequency in many national and ethnic groups in areas of current or former malaria endemicity. A screening programme undertaken to evaluate the gene frequencies for this deficiency in the highly inbred South Indian population of Karnataka revealed that of the 5140 neonates screened, 7.8% were G6PD deficient with no correlation between the reported level of inbreeding and enzyme deficiency. An interesting finding was the equal number of male (198) and female (207) individuals, with G6PD activity of less than 3 IU. The possible implications of this finding with regard to the expression of G6PD gene is discussed.

Nonequilibrium dynamics of photoexcited electrons in graphene: Collinear scattering, Auger processes, and the impact of screening

We present a combined analytical and numerical study of the early stages (sub-100-fs) of the nonequilibrium dynamics of photoexcited electrons in graphene. We employ the semiclassical Boltzmann equation with a collision integral that includes contributions from electron-electron (e-e) and electron-optical phonon interactions. Taking advantage of circular symmetry and employing the massless Dirac fermion (MDF) Hamiltonian, we are able to perform an essentially analytical study of the e-e contribution to the collision integral. This allows us to take particular care of subtle collinear scattering processes - processes in which incoming and outgoing momenta of the scattering particles lie on the same line - including carrier multiplication (CM) and Auger recombination (AR). These processes have a vanishing phase space for two-dimensional MDF bare bands. However, we argue that electron-lifetime effects, seen in experiments based on angle-resolved photoemission spectroscopy, provide a natural pathway to regularize this pathology, yielding a finite contribution due to CM and AR to the Coulomb collision integral. Finally, we discuss in detail the role of physics beyond the Fermi golden rule by including screening in the matrix element of the Coulomb interaction at the level of the random phase approximation (RPA), focusing in particular on the consequences of various approximations including static RPA screening, which maximizes the impact of CM and AR processes, and dynamical RPA screening, which completely suppresses them. © 2013 American Physical Society.

The third subband population in modulation-doped InGaAs/InAlAs heterostructures

We have observed the population of the third (n=3) two-dimensional electron subband of InGaAs/ InAlAs modulation-doped structures with very dense sheet carrier density by means of Fourier transform photoluminescence (PL). Three well-resolved PL peaks centered at 0.737, 0.908, and 0.980 eV are observed, which are attributed to the recombination transitions from the lowest three electron subbands to the n=1 heavy-hole subband. The subband separations clearly exhibit the features of the stepped quantum well with triangle and square potential, consistent with numerical calculation. Thanks to the presence of the Fermi cutoff, the population ratio of these three subbands can be estimated. Temperature and excitation intensity dependence of the quantum well luminescence intensity is also analyzed. (C) 1997 American Institute of Physics.

Established cardiovascular disease and CVD risk factors in a primary care population of middle-aged Irish men and women

Contemporary Irish data on the prevalence of major cardiovascular disease (CVD) risk factors are sparse. The primary aims of this study were (1) to estimate the prevalence of major cardiovascular disease risk factors, including Type 2 Diabetes Mellitus, in the general population of men and women between the ages of 50 and 69 years; and (2) to estimate the proportion of individuals in this age group at high absolute risk of cardiovascular disease events on the basis of pre-existing cardiovascular disease or as defined by the Framingham equation. Participants were drawn from the practice lists of 17 general practices in Cork and Kerry using stratified random sampling. A total of 1018 people attended for screening (490 men, 48%) from 1473 who were invited, a response rate of 69.1%. Cardiovascular disease risk factors and glucose intolerance are common in the population of men and women aged between 50 and 69 years. Almost half the participants were overweight and a further quarter met current international criteria for obesity, one of the highest recorded prevalence rates for obesity in a European population sample. Forty per cent of the population reported minimal levels of physical activity and 19% were current cigarette smokers. Approximately half the sample had blood pressure readings consistent with international criteria for the diagnosis of hypertension, but only 38% of these individuals were known to be hypertensive. Eighty per cent of the population sample had a cholesterol concentration in excess of 5 mmol/l. Almost 4% of the population had Type 2 Diabetes Mellitus, of whom 30% were previously undiagnosed. A total of 137 participants (13.5%) had a history or ECG findings consistent with established cardiovascular disease. Of the remaining 881 individuals in the primary prevention population, a total of 20 high-risk individuals (19 male) had a risk of a coronary heart disease event 30% over ten years according to the Framingham risk equation, giving an overall population prevalence of 2.0% (95% CI 1.3 - 3.0). At a risk level 20% over ten years, an additional 91 individuals (8.9%) were identified. Thus a total of 24.4% of the population were at risk either through pre-existing CVD (13.5%) or an estimated 10-year risk exceeding 20% according to the Framingham risk equation (10.9%). Thus a substantial proportion of middle-aged men are at high risk of CVD. The findings emphasise the scale of the CVD epidemic in Ireland and the need for ongoing monitoring of risk factors at the population level and the need to develop preventive strategies at both the clinical and societal level.

An examination of the underlying trait structure of psychopathy: applications for screening and measurement

This thesis seeks to clarify the faceted organisation of psychopathy with a view to developing a comprehensive protocol for the assessment of core psychopathic personality traits. The framework developed will, as best as possible, be free of sample bias. The Self-and Informant-report Deviant Personality Screen (DPS) is introduced and a series of empirical studies are conducted to examine the psychometric properties and construct validity of these measures in general and offender populations. Findings from these studies provide strong support for the utility of the DPS scales for the appraisal of psychopathy across diverse population samples. In addition to this, the utility of cognitive based performance measures for the assessment of emotional deficits in psychopathy is evaluated. Results from this study suggest limited correspondence between these measurement techniques and self-report psychopathy measures. Finally, research conducted on offenders suggests that information obtained from DPS reports may be useful within a broad framework of risk assessment. Further empirical and theoretical implications of the research are discussed.