Grade-of-membership sibpair linkage analysis maps IDDM11 to chromosome 14q24.3-q31.

We demonstrate the use of Grade-of-membership (GoM) (Manton et al. 1994) for sibpair linkage analysis: GoM was used to map the IDDM11 locus to the region of chromosome 14q24.3 identified by Field et al. (1996). Haplotype groups were constructed from sib pair information on the number of shared alleles. The sample consisted of 578 sibling pairs found in 246 multiplex IDDM families. Both siblings were diabetic in 53% of the pairs (AA). Pair members could share 0, 1 or 2 alleles IBS at each of eight linked marker loci spanning IDDM11. Three model-based groups best represented the data on allele sharing: the groups corresponded to 'No', 'One' and 'Two' shared haplotypes for the region. Group 'Two' was larger (37% vs. 25%, p < 0.0001) and more homogeneous (p < 0.0001) than expected by chance consistent with the IDDM11 locus being a determinant of diabetes in multiplex families. Genetic linkage of IDDM to the region was demonstrated by a 19% increase in the proportion of AA pairs over the haplotype groups: 'No', 42%; 'One', 49%; 'Two', 61%, p = 0.0005, representing a 43% relative increase.

Density profiles of Alzheimer disease regional brain pathology for the huddinge brain bank: pattern recognition emulates and expands upon Braak staging.

Density profiles of Alzheimer's disease (AD) regional brain pathology were constructed for 249 subjects in the Huddinge Brain Bank. Counts per square millimeter for neurofibrillary tangles (NFT), diffuse plaques (DP), and neuritic plaques (NP) in 38 areas were investigated using a pattern recognition technique called GoM. The seven distributional profiles of AD neuropathology emulated and expanded upon Braak staging illustrating induction (Groups 1-3) and clinical progression (Groups 4-7). Normal aging represented limited AD changes, few NFT in the entorhinal cortex and hippocampal CA1 (Group 1). The threshold for possible AD was NFT in the subiculum (Group 2), found with DP in the neocortex. Temporal medial NFT was the threshold for probable AD (Group 4). The 'oldest-old', often demented without brain atrophy, had extensive entorhinal/CA1 NFT and cortical DP, but few cortical NFT or NP (Group 5). A second subtype 'disconnection' (Group 6) lacked AD pathology for a specific set of subcortical and cortical areas. Accumulation of NFT in first-affected areas continued through end-stage disease (Group 7), with apparent rapid transition of DP to NP in the cortex during clinical progression. The evolution of AD is a highly ordered sequential process. Pattern recognition approaches such as GoM may be useful in better defining the process.

Predicting 10-year care requirements for older people with suspected Alzheimer's disease.

OBJECTIVE: To describe the types and costs of care received for 10 years after the identification of an older person with suspected Alzheimer's disease (AD) by using data from 3254 patients with suspected AD who participated in the National Long Term Care Survey (NLTCS). METHODS: By using a Markov model derived using grade of membership techniques, the following were determined: survival probabilities at 10 years; years of survival during the 10 years; years in institutions; years with two or more impairments in basic activities of daily living; hours of paid and informal care while the older person lived in the community; and costs of paid community, institutional, and medical care. RESULTS: Greater degrees of cognitive impairment present when AD was identified were associated with reduced predicted probability of surviving 10 years, increased predicted number of years spent in institutions, increased hours of care required while affected individuals remained in the community, and increased costs of paid community, institutional, and medical care. Substantial differences between men and women were seen: severity-adjusted 10-year costs were almost two times higher for women with AD than for men ($75,000 compared with $44,000); according to sensitivity analysis, average 10-year costs might be as high as $109,000 for women and $67,000 for men. CONCLUSIONS: AD imposes a substantial burden on older persons. Interventions that slow the progression of the disease may therefore affect community survival as well as healthcare costs.

A mathematical typology analysis of DSM-III-R personality disorder classification: grade of membership technique.

This study employed grade of membership (GoM) analysis in a clinical setting to determine if the DSM-III-R personality disorder (PD) diagnostic criteria cluster into recognizable disorders resembling the official axis II nosology. The GoM model, based on fuzzy-set theoretic concepts, explicitly examines medical diagnostic systems by quantitatively identifying and characterizing subpatterns of illness within a broad class. A semistructured assessment of 110 outpatients was performed for 12 PDs and their 112 diagnostic criteria. GoM analysis was performed using internal variables of the 112 PD criteria rated as present or absent. Demographic variables, axis I and II diagnosis (structured clinical Interview for DSM [SCID]), and treatment response (Global Adjustment Scale [GAS]) information were used as external validators. Four pure types (PT) provided the most satisfactory solution to the data. PT-I is characterized by marked maladaptive personality pathology, which is manipulative, egocentric, impulsive, and alloplastic. PT-II consists primarily of exaggerated socially anxious and detached traits. PT-III is sociably dependent and autoplastic. PT-IV is essentially asymptomatic. GoM provides a more parsimonious handling of the PD criteria than provided by classifying according to DSM categories. The analysis fails to confirm the natural occurrence of any single specific axis II PD or cluster.

The prevalence and 3-year incidence of dementia in older Black and White community residents.

OBJECTIVE: To determine the prevalence and 3-year incidence of dementia in Blacks and Whites age 65 and older in a five-county Piedmont area of North Carolina. DESIGN: Stratified random sample of members of the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE) (baseline n = 4,136; 55% Black; weighted n = 28,000). Prevalence study members were differentially selected on the basis of score on the Short Portable Mental Status Questionnaire at the second in-person Duke EPESE wave. Incidence study members included all persons with obvious cognitive decline over a 3-year period, and a 10% sample of the remainder. MEASUREMENTS: Self- and informant report on health history, functional status, and memory. Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychology Battery administered to all subjects, and CERAD Clinical Battery to those with impaired memory. Clinical consensus to determine presence and type of dementia. RESULTS: Prevalence of dementia for persons > or =68 years old was 0.070 (95% confidence interval = 0.021-0.119) for Blacks and 0.072 (0.022-0.122) for Whites. Rates for Black men (0.078, 0.001-0.155) exceeded those for Black women (0.066, 0.003-0.129), but gender rates for Whites were reversed (men: 0.044, 0.000-0.103), (women: 0.087, 0.015-0.160). Neither race nor gender differences were significant. Prevalence of dementia increased through age 84 and tapered off thereafter. Three-year incidence of dementia was 0.058 (0.026-0.090) for Blacks and 0.062 (0.027-0.097) for Whites. Neither race nor gender differences were significant. Incidence increased through age 84, but moderated thereafter for all but Black men. The proportional representation of different types of dementia varied little by race. CONCLUSION: Prevalence, 3-year incidence, and types of dementia are comparable in Black and White elderly in the Piedmont area of North Carolina.

The construction of tridimensional representation of body and external reality in man. The greatest achievement of evolution to date implications for virtual reality.

Our 3-D Body Representation constructed during development by our Central Nervous System under the direction of our DNA, consists of a holographic representation arising from sensory input in the cerebellum and projected extraneurally in the brain ventricular fluid which has the chemical structure of liquid crystal. The structure of 3-D holographic Body Representation is then extrapolated by such cognitive instruments as boundarization, geometrization and gestalt organization upon the external environment which is perceived consequently as three dimensional. When the Body Representation collapses as in psychotic panic states. patients become terrified as they suddenly lose the perception of themselves and the world around them as three dimensional, solid in a reliably solid environment but feel suddenly that they are no longer a person but a disorganized blob. In our clinical practice we found serendipitously that the structure of three dimensionality can be restored even without medication by techniques involving stimulation of the body sensory system in the presence of a benevolent psychotherapist. Implications for Virtual Reality will be discussed.

Modern cosmology and the origin of our three dimensionality.

We are three dimensional egocentric beings existing within a specific space/time continuum and dimensionality which we assume wrongly is the same for all times and places throughout the entire universe. Physicists name Omnipoint the origin of the universe at Dimension zero, which exploded as a Big Bang of energy proceeding at enormous speed along one dimension which eventually curled up into matter: particles, atoms, molecules and Galaxies which exist in two dimensional space. Finally from matter spread throughout the cosmos evolved life generating eventually the DNA molecules which control the construction of brains complex enough to construct our three dimensional Body Representation from which is extrapolated what we perceive as a 3-D universe. The whole interconnected structures which conjure up our three dimensionality are as fragile as Humpty Dumpty, capable of breaking apart with terrifying effects for the individual patient during a psychotic panic, revealing our three dimensionality to be but "maya", an illusion, which we psychiatrists work at putting back together.

Proxy response patterns among the aged: effects on estimates of health status and medical care utilization from the 1982-1984 long-term care surveys.

We examined the use of proxies in samples of persons aged 65 years and over from the 1982 and 1984 National Long-Term Care Surveys (NLTCS). The NLTCS are designed to describe the Medicare-enrolled elderly population, their health and functioning, hospital, home health, and institutional use. The NLTCS, being longitudinal, allows trends in functional and health status to be examined as well as the changing character of community-based and institutional services used by chronically disabled persons aged 65 years and older. In analyses of proxy responses there was little evidence of differences in accuracy between self- and proxy reports in persons with different health and functional characteristics. The amount and type of proxy reporting did depend on the health and functional characteristics of the sample person. The cognitively impaired, and the frail elderly, had high levels of proxy use as well as small differences in the accuracy of reporting service use and program enrollment. The results are consistent with methodological studies of proxy reporting in health surveys of other populations.

Sex differences in human mortality and aging at late ages: the effect of mortality selection and state dynamics.

Models of gender differences in human mortality and aging depend on assumptions about temporal rates of physiological change. Simple models like the Gompertz fail to describe the mortality of either males or females at late ages. This suggests a need for biologically more detailed models to represent the age dependency of human mortality as well as gender differences in that age dependence. By modeling the sex-specific interaction of time-varying covariates with multiple dimensions of mortality selection, one can more accurately describe the age dependence of mortality and more complex physiological aging patterns. The multivariate model of aging changes is used to describe gender differences using data from (a) a longitudinal study of physiological changes and mortality and (b) a nationally representative longitudinal survey of changes in function and mortality.

Nursing home residents: a multivariate analysis of their medical, behavioral, psychosocial, and service use characteristics.

BACKGROUND: Elderly residents of nursing homes often have multiple comorbidities and functional limitations. The status of 4,525 residents of complex and standard care units in 177 nursing homes where the nursing home was determined to provide adequate care, and from 14 specialized Alzheimer's units, was evaluated on 111 measures of medical condition, functional status, psychological well-being and cognitive performance in a demonstration study assessing quality of care in six states. Detailed measurements were also made of the types and amounts of services used (in minutes per day) by the residents. METHODS: Given the number of health measures, and the possibility of assessment error, a multivariate analytic procedure called Grade of Membership (GoM) was used. This procedure identified profiles of health and functioning measures to identify the characteristics of clinically distinct groups of nursing home residents. RESULTS: The analysis identified 11 profiles of health and functioning characteristics which described the 111 resident measurements. The 11 profiles predicted differentials in nursing home length of stay, and service use by various classes of caregivers. The GoM profiles described the data better than several other classification procedures applied to the same data. CONCLUSIONS: In nursing homes, elderly and oldest-old residents often have multiple comorbidities and disabilities. A multivariate procedure was able to identify the fundamental dimensions describing residents' variation on a number of health measures. These profiles predicted differences in service use so they had predictive validity. Thus, multivariate procedures may help identify clinically distinct groups in studies where complex measures are made.

Dementia praecox and manic-depressive insanity in 1908: a Grade of Membership analysis of the Kraepelinian dichotomy.

Grade of Membership (GoM) analysis, a multivariate classification technique based on fuzzy-set mathematics, was applied to the demographic, history, and mental-state data on 53 dementia praecox cases and 134 manic-depressive insanity cases admitted to Kraepelin's University Psychiatric Clinic in Munich in 1908. The original data recorded by Kraepelin and his collaborators on special Zählkarten (counting cards) were rated and coded in terms of the Present State Examination (PSE) Syndrome Check List. The statistical analysis resulted in a high degree of replication of Kraepelin's clinical entities. However, the dichotomy of dementia praecox and manic-depressive insanity was not fully supported. The catatonic syndrome tended to occupy an intermediate position between the two major psychoses. The possibility is discussed that catatonia in Kraepelin's time shared certain clinical features with the later diagnostic groupings of schizoaffective disorder, cycloid psychoses, and other "atypical" forms of psychotic illnesses.

The effects of health histories on stochastic process models of aging and mortality.

A model of human health history and aging, based on a multivariate stochastic process with both continuous diffusion and discrete jump components, is presented. Discrete changes generate non-Gaussian diffusion with time varying continuous state distributions. An approach to calculating transition rates in dynamically heterogeneous populations, which generalizes the conditional averaging of hazard rates done in "fixed frailty" population models, is presented to describe health processes with multiple jumps. Conditional semi-invariants are used to approximate the conditional p.d.f. of the unobserved health history components. This is useful in analyzing the age dependence of mortality and health changes at advanced age (e.g., 95+) where homeostatic controls weaken, and physiological dynamics and survival manifest nonlinear behavior.

Time-varying covariates in models of human mortality and aging: multidimensional generalizations of the Gompertz.

Models of mortality and aging depend on assumptions about physiological change even if they are not made explicit. Standard models, like the Gompertz, often fail to describe mortality at extreme ages, suggesting a need for biologically more detailed and flexible models. One solution is to model the interaction of time-varying covariates with mortality to better describe the age dependence of mortality, test hypotheses about the relation of physiological change and mortality, and use longitudinal data to generalize assumptions about physiological change. This model is applied to (a) a 34-year follow-up of risk factors and mortality and (b) a 9.5-year follow-up of function and mortality from longitudinal surveys of the U.S. elderly population.

Classification of taste responses in brain stem: membership in fuzzy sets.

1. Classification methods in sensory systems in general, and gustation in particular, tend to place each of the relevant objects, such as stimuli or neurons, into one class each. Some of these methods are based on the responsiveness of neurons to various stimuli; in these, each group must contain a variety of nonidentical members because of the individuality of each neuron or stimulus. 2. The "fuzzy" set method is appropriate for more accurate classification in such heterogeneous populations. In this method each member is given graded membership in several sets rather than membership in only one set. In the present paper we subjected previously published data on the responses of individual taste neurons to a variety of stimuli to fuzzy set analysis. 3. We found that the amounts of response of 46 neurons in the solitary nucleus of the rat to NaCl, HCl, sucrose, quinine HCl, and KCl could accurately be accounted for by giving each a grade of membership in three sets; the same held in the parabrachial nucleus of the rat for the responses of 41 neurons to the first four of these stimuli. The response was calculated as the sum of the products of the stimulus times neuron ratings in each set. 4. Temporal patterns of response have often been related, but with only moderate success, to the identity of the stimulus or neuron. These patterns could be accurately accounted for with the present method. Each of the products of designated parts of the stimulus ratings times the neuron ratings gave the basis for accurate description of the temporal course of the response of each neuron to each stimulus. 5. This method appears to account for the varieties of amount and temporal pattern of response of taste neurons with a simple mathematical process of few parameters. This suggests that within the known complexities of receptor mechanisms and mechanisms of neural processing, the neural message is reduced to a rather simple form. 6. The fuzzy set approach, which is based on disclosing underlying sets rather than placement of heterogeneous members into one of several essentialistic groups, may be useful in disclosure of the underlying mechanisms producing the neural responses in taste.

Symptom profiles of psychiatric disorders based on graded disease classes: an illustration using data from the WHO International Pilot Study of Schizophrenia.

The Grade of Membership (GoM) model is a classification procedure which allows a person to be a member of more than one diagnostic class. It simultaneously quantifies the degrees of membership in classes while generating the discrete symptom profiles or 'pure types' describing classes. The model was applied to the symptomatology, history, and follow-up of 1065 cases in the WHO International Pilot Study of Schizophrenia. The model produced an eight diagnostic class or 'pure type' solution, of which five were related to the diagnostic concepts of schizophrenia and paranoid disorder, two types were affective disorders, and one asymptomatic type. A subtype of paranoid schizophreniform disorder found primarily in developing countries was identified. There was a strong association between pure types and the original clinical and computer generated (CATEGO) diagnoses. A GoM based psychiatric classification might more clearly identify core disease processes than conventional classification models by filtering the confounding effects of individual heterogeneity from pure type definitions.

Home health and skilled nursing facility use: 1982-90.

In this article, analyses are made of home health and skilled nursing facility (SNF) use for the period 1982-90 using Medicare records linked to data on community and institutional residents from the National Long-Term Care Surveys (NLTCSs) of 1982, 1984, and 1989. The combined survey and administrative data analyses are performed to ascertain how the chronic health and functional characteristics of community and institutional residents using Medicare-reimbursed services changed during the period. During this period, changes had been made in the Medicare system that affected the use of services for persons with specific health and functional problems.

Use of Medicare services before and after introduction of the prospective payment system.

OBJECTIVE: The case mix-adjusted pattern of use of health care services, especially posthospital care, is compared before and after the introduction of Medicare's Prospective Payment System (PPS). DATA SOURCES: The 1982 and 1984 National Long Term Care Surveys (NLTCS) linked to Medicare administrative records 1982-1986 provide health and health service use data for 12-month periods before and after the introduction of PPS. STUDY DESIGN: Case-mix differences between pre- and post-periods are controlled by using the Grade of Membership model to identify health groups from the NLTCS data. Differences in timing (e.g., hospital length of stay) were controlled using life table models estimated for each health group, that is, service use patterns pre- and post-PPS are compared within groups. PRINCIPAL FINDINGS: Hospital LOS and admission rates declined post-PPS. Changes in the timing and location of death occurred but, overall, mortality did not increase. Changes in post-acute care service use by elderly, chronically disabled Medicare beneficiaries were observed: home health service use increased overall and among the unmarried disabled population. CONCLUSIONS: PPS did not adversely affect quality of care as reflected in mortality or in hospital readmissions. Moreover, the differential use of post-acute care, and changes in hospital LOS by health group, indicate that the system responded, specific to marital status and age, to the severity of needs of chronically disabled persons.

Neuropsychiatric development: two case reports about the use of dietary fish oils and/or choline supplementation in children.

Choline supplementation has been used with moderate success in subgroups of adult patients with neuropsychiatric and medical problems. The dietary fish oils have also been used in adults with hypercholesterolemia. We report on two young children with multiple neurodevelopmental delays, one who responded to choline and eicosapentaenoic acid, and the other to choline alone. A brief discussion about choline's metabolic pathways and benefits is included.

Genetic heterogeneity in Alzheimer's disease: a grade of membership analysis.

Grade of membership analysis (GoM) may have particular relevance for genetic epidemiology. The method can flexibly relate genetic markers, clinical features, and environmental exposures to possible subtypes of disease termed pure types even when population allele frequencies and penetrance functions are not known. Hence, GoM may complement existing strategies that sometimes fail in the presence of heterogeneity or when case definition is not well established. To illustrate the method, individuals in the Seattle data set were evaluated with respect to affection status, age at onset, pedigree, sex, and genetic markers on chromosomes 19 and 21. Seven pure types were found which we have designated as: Early Onset, Late Onset, Probable, and Unaffected 1 to Unaffected 4.