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PubMed1999

Principles of medical decision making.

The consequences of medical decisions are inherently uncertain at the decisive moment. Using clinical examples related to the diagnosis and management of low back pain, the authors review some principles that can help physicians deal with this uncertainty. This article addresses the following: the use of probability as a useful representation of uncertainty, the use of Bayes' theorem to update probability estimates when new information is obtained, the measurement of a diagnostic test's accuracy, the use of the threshold model for choosing a diagnostic test, the principles of expected-value decision making, the use of utility assessment as a way of attaching value to outcomes, and the use of quality-adjusted life years as a measure of value. These principles can aid physicians in approaching complex and uncertain decisions with their patients. As the use of computers becomes more integrated into the process of care, the opportunity exists to move formal decision models from the policy level to the patient care level.

Cost-Benefit Analysis↗

PubMed2006

Common and specific genetic influences on aggressive and nonaggressive conduct disorder domains.

OBJECTIVE: To explore the genetic and environmental influences on DSM-IV conduct disorder (CD) aggressive and nonaggressive subscales, taking into account age and sex differences. METHOD: A community sample of 1,100 twin pairs (ages 11-18) was interviewed using the Diagnostic Interview Schedule for Children. Bivariate analyses, using variable threshold models accounting for age and sex differences, were used to determine the extent to which the genetic and environmental influences on aggressive and nonaggressive CD domains are shared or unique. RESULTS: The phenotypic correlation between aggressive and nonaggressive CD domains was 0.32. The most parsimonious bivariate model included additive genetic effects and nonshared environmental effects only (AE model). CONCLUSIONS: The results of behavior genetic model fitting suggest that the DSM-IV CD domains are influenced by unique genetic and environmental factors, but also share some common genetic and environmental influences. A large percentage of the covariation (61%) is caused by genetic factors. These results are consistent with a previous report on the bivariate heritability of aggressive and nonaggressive antisocial behavior, but extend the findings to DSM-IV domains.

Adolescent↗

PubMed2005

The mediation proportion: a structural equation approach for estimating the proportion of exposure effect on outcome explained by an intermediate variable.

It is often of interest to assess how much of the effect of an exposure on a response is mediated through an intermediate variable. However, systematic approaches are lacking, other than assessment of a surrogate marker for the endpoint of a clinical trial. We review a measure of "proportion explained" in the context of observational epidemiologic studies. The measure has been much debated; we show how several of the drawbacks are alleviated when exposures, mediators, and responses are continuous and are embedded in a structural equation framework. These conditions also allow for consideration of several intermediate variables. Binary or categorical variables can be included directly through threshold models. We call this measure the mediation proportion, that is, the part of an exposure effect on outcome explained by a third, intermediate variable. Two examples illustrate the approach. The first example is a randomized clinical trial of the effects of interferon-alpha on visual acuity in patients with age-related macular degeneration. In this example, the exposure, mediator and response are all binary. The second example is a common problem in social epidemiology-to find the proportion of a social class effect on a health outcome that is mediated by psychologic variables. Both the mediator and the response are composed of several ordered categorical variables, with confounders present. Finally, we extend the example to more than one mediator.

Adult↗

PubMed2001

Bill morphology reflects female independence from male parental help.

The study of territorial polygyny in birds has been influential in the development of the theory of social mating systems. Alternative female mating options have been studied within the framework of the polygyny-threshold model and later as the outcome of conflicts of interest between individuals. However, little attention has been given to variations between individual females, and how this affects their mating behaviour. Here, we test the hypothesis that some females are better adapted to raise nestlings without male assistance, and thus to mate polygynously. Specifically, we investigate whether intraspecific variation in female bill morphology is related to mating behaviour. This hypothesis is derived from earlier studies showing that, in both intra- and interspecific comparisons, uniparental care by females is correlated with the catching of larger prey items than when both parents provision the young. Using the polygynous dusky warbler (Phylloscopus fuscatus) as a model species, we found that, in accordance with our prediction, females with deep bills were more likely to mate as a secondary female. Moreover, regardless of mating status, females with deep bills settled in territories with more food and they received less male assistance in feeding their offspring. We argue that females with stronger bills are better adapted to exploit the abundance of large food items in rich territories and thus to raise young on their own. Our results demonstrate the importance of studying variations between individual females, and provide evidence for an extended version of the 'constrained-female hypothesis'. As bill depth is a highly heritable trait, our study strongly suggests that variation in female mating behaviour is not only related to ecological factors and female condition (as shown elsewhere) but also to heritable morphological traits.

Animals↗

PubMed2004

Age and size at maturity: sex, environmental variability and developmental thresholds.

In most organisms, transitions between different life-history stages occur later and at smaller sizes as growth conditions deteriorate. Day and Rowe recently proposed that this pattern could be explained by the existence of developmental thresholds (minimum sizes or levels of condition below which transitions are unable to proceed). The developmental-threshold model predicts that the reaction norm of age and size at maturity will rotate in an anticlockwise manner from positive to a shallow negative slope if: (i) initial body size or condition is reduced; and/or (ii) some individuals encounter poor growth conditions at increasingly early developmental stages. We tested these predictions by rearing replicated populations of soil mites Sancassania berlesei (Michael) under different growth conditions. High-food environments produced a vertical relationship between age and size at maturity. The slope became increasingly shallow as food was reduced. By contrast, high food in the maternal environment reduced the slope of the reaction norm of age and size at maturity, whereas low food increased it. Overall, the reaction norm of age and size at maturity in S. berlesei was significantly nonlinear and differed for males and females. We describe how growth conditions, mother's environment and sex determine age and size at maturity in S. berlesei.

Acaridae↗

PubMed2025

Tulp3 quantitative alleles titrate requirements for viability, brain development, and kidney homeostasis but do not suppress Zfp423 mutations in mice.

Tubby-like protein 3 (TULP3) regulates receptor trafficking in primary cilia and antagonizes SHH signaling. Tulp3 knockout mice are embryonic lethal with developmental abnormalities in multiple organs, while tissue-specific knockouts and viable missense alleles cause polycystic kidney disease. Human patients with TULP3 mutations present with variable, but often multi-organ fibrotic disease. We previously showed that mouse and human Tulp3 expression is negatively regulated by ZNF423, which is required for SHH sensitivity in some progenitor cell models. The level of TULP3 function required to prevent mutant phenotypes has not been known. Here we report a Tulp3 quantitative allelic series, designed by targeting the polypyrimidine tract 5' to the splice acceptor of a critical exon, that shows distinct dose-response effects on viability, brain overgrowth, weight gain, and cystic kidney disease. We find limited evidence for genetic interaction with Zfp423 null or hypomorphic mutations. Together, these results establish an approach to developing quantitative allelic series by exon exclusion, rank-order dose-sensitivity of Tulp3 phenotypes, and model thresholds for TULP3 function to prevent severe outcomes.

Journal Article↗

PubMed2003

Optimal noise-aided signal transmission through populations of neurons.

Metabolic considerations and neurophysiological measurements indicate that biological neural systems prefer information transmission via many parallel low intensity channels, compared to few high intensity ones [S. B. Laughlin et al., Nature Neurosci. 1, 36 (1998)]. Furthermore, cortical neurons are exposed to a considerable amount of synaptic background activity, which increases the neurons' conductance and leads to a fluctuating membrane potential that, on average, is close to the threshold [A. Destexhe and D. Paré, J. Neurophysiol. 81, 1531 (1999)]. Recent studies have shown that noise can improve the transmission of subthreshold signals in populations of neurons, e.g., if their response is pooled. In general, the optimal noise level depends on the stimulus distribution and on the number of neurons in the population. In this contribution we show that for a large enough number of neurons the latter dependency becomes weak, such that the optimal noise level becomes almost independent of the number of neurons in the population. First we investigate a binary threshold model of neurons. We derive an analytic expression for the optimal noise level at each single neuron, which-for a large enough population size-depends only on quantities that are locally available to a single neuron. Using numerical simulations, we then verify the weak dependence of the optimal noise level on population size in a more realistic framework using leaky integrate-and-fire as well as Hodgkin-Huxley-type model neurons. Next we construct a cost function, where quality of information transmission is traded against its metabolic costs. Again we find that-for subthreshold signals-there is an optimal noise level which maximizes this cost. This noise level, however, is almost independent of the number of neurons, even for small population sizes, as numerical simulations using the Hodgkin-Huxley model show. Since the dependence of the optimal noise level on population size is weak for large enough populations, local neural adaptation is sufficient to adjust the level of noise to its optimal value.

Animals↗

PubMed2006

tie-dyed1 Regulates carbohydrate accumulation in maize leaves.

Acquisition of cell identity requires communication among neighboring cells. To dissect the genetic pathways regulating cell signaling in later leaf development, a screen was performed to identify mutants with chloroplast pigmentation sectors that violate cell lineage boundaries in maize (Zea mays) leaves. We have characterized a recessive mutant, tie-dyed1 (tdy1), which develops stable, nonclonal variegated yellow and green leaf sectors. Sector formation requires high light, occurs during a limited developmental time, and is restricted to leaf blade tissue. Yellow tdy1 sectors accumulate excessive soluble sugars and starch, whereas green sectors appear unaffected. Significantly, starch accumulation precedes chlorosis in cells that will become a yellow sector. Retention of carbohydrates in tdy1 leaves is associated with a delay in reproductive maturity, decreased stature, and reduced yield. To explain the tdy1 sectoring pattern, we propose a threshold model that incorporates the light requirement and the hyperaccumulation of photoassimilates. A possible function consistent with this model is that TDY1 acts as a sugar sensor to regulate an inducible sugar export pathway as leaves develop under high light conditions.

Carbohydrate Metabolism↗

PubMed2004

The Arabidopsis FtsH metalloprotease gene family: interchangeability of subunits in chloroplast oligomeric complexes.

The Arabidopsis At filamentation temperature sensitive (FtsH) metalloprotease gene family comprises 12 members (AtFtsH1-AtFtsH12), including three pairs of closely related genes that are targeted to chloroplasts (AtFtsH2 and AtFtsH8; AtFtsH1 and AtFtsH5; and AtFtsH7 and AtFtsH9). Mutations in AtFtsH5 (var1) and AtFtsH2 (var2) give rise to variegated plants with green- and white-sectored leaves. Cells in the green sectors contain morphologically normal chloroplasts, whereas cells in the white sectors are blocked in chloroplast biogenesis. A major question is how chloroplasts arise in cells that have a mutant genotype. We have found by two-dimensional (2-D) green gel and gel filtration analyses that AtFtsH2/VAR2 forms oligomeric complexes. Two bands in the 2-D green gels that correspond to AtFtsH5/VAR1 + AtFtsH1 and AtFtsH2/VAR2 + AtFtsH8 have been identified, and these bands are coordinately reduced in amount in var1 and var2 thylakoids that lack AtFtsH5/VAR1 and AtFtsH2/VAR2, respectively. These reductions are not because of alterations in transcript abundance. Overexpression of AtFtsH8 in var2-4 (a putative null allele) normalizes the variegation phenotype of the mutant and restores the two bands to their wild-type levels. These results suggest that AtFtsH8 is interchangeable with AtFtsH2/VAR2 in AtFtsH-containing oligomers, and that the two proteins have redundant functions. Consistent with this hypothesis, AtFtsH2 and AtFtsH8 have similar expression patterns, as monitored by promoter-beta-glucuronidase (GUS) fusion and RT-PCR experiments. Based on our findings, we propose that AtFtsH1, AtFtsH2/VAR2, AtFtsH5/VAR1, and AtFtsH8 interact to form oligomeric structures, and that subunit stoichiometry is controlled post-transcriptionally in var1 and var2, perhaps by turnover. A threshold model is presented to explain the pattern of variegation in var2 in which AtFtsH8 provides a compensating activity in the green sectors of the mutant.

Arabidopsis↗

PubMed1981

Cleft palate: a genetic and epidemiologic investigation.

An examination of kindred histories of 561 Danish probands who have non-syndromic CP has indicated that neither a multifactorial-threshold model nor a single major locus model is completely compatible with the data. This suggests etiologic heterogeneity for CP, which was tested with kindred data. As recommended by Smith (1976), at attempt to define partially this heterogeneity within the CP phenotype was undertaken by grouping and comparing the kindred data. It is both reasonable and heuristic to propose that CP,, as defined in this investigation, is composed of three groups: (1) Syndromic CP; (2) Familial CP, which appears to have an autosomal dominant component to its etiology, and (3) Non-familial CP which, by demonstrating an increasing frequency of CP and a maternal age effect, appears to be related to environmental factors which may cause CP or other malformations.

Abnormalities, Multiple↗

PubMed1994

Inbreeding and congenital heart diseases in a north Indian population.

The study was performed in six mohallahs (colonies) of Aligarh City (North India). All six mohallahs are predominantly inhabited by Qureshi (meat sellers, a highly endogamous group) Muslims. A total of 1721 infants and children up to the age of 6 years were examined to determine the incidence of congenital heart diseases (CHD) in relation to the degree of consanguinity of the parents. Around 43% of the subjects were the offspring of consanguineous marriages including second-cousin, first-cousin-once-removed and first-cousin. A higher percentage of CHD was found in the offspring of consanguineous marriages: about 3.37% out of 741 children as compared to 1.22% in 980 offspring of non-consanguineous marriages, whereas in the first-cousin offspring, the percentage of CHD rose to 4.41%. The differences were found to be statistically significant. The present study suggests a genetic influence and also casts doubt on the applicability of a polygenic threshold model to all forms of cardiac malformation.

Chi-Square Distribution↗

PubMed1994

Etiological subgroups in non-syndromic isolated cleft palate. A genetic-epidemiological study of 52 Danish birth cohorts.

Isolated cleft palate (CP) is considered to be a heterogeneous trait with an important genetic contribution to the etiology. Multifactorial-threshold models of non-syndromic CP inheritance assume a female predominance. The present study of 52 Danish birth cohorts, using several ascertainment sources, identified 2301 CP cases. It was found that, although females tended to be more severely affected than males, the overall sex ratio was close to one. For the latter half of the study period (1962-87), which probably had the best ascertainment, the sex ratio for non-syndromic CP was 0.95 (95% C.I. 0.85-1.07). Marked difference in sex ratios for non-syndromic overt CP including the hard palate (CPH) and non-syndromic overt CP of the soft palate only (CPS) (0.69 vs 1.00, p < 1.00, p < 0.05) suggested that these two conditions may be etiologically distinct, a hypothesis which is embryologically plausible. In agreement with this hypothesis, Danish family data from surgically treated CP cases showed a strong tendency to segregate only one of the CP subtypes within families. Future studies are recommended to test the existence of a possible etiological difference between CPH and CPS.

Child↗

PubMed2005

Estimation of heritability for Tying-up syndrome in the Thoroughbred racehorse by Gibbs sampling.

Tying-up is a condition that primarily affects the muscles of horses. In this study, the heritability of the Tying-up syndrome in the Thoroughbred racehorse was estimated by Bayesian analysis with Gibbs sampling based on the threshold model for binary traits. The data used were the clinical data in racehorses diagnosed by veterinarians of the Racehorse Clinics of Japan Racing Association from 2000 to 2003. The health status of the Tying-up was treated as a binary trait. In the genetic analysis, the effect of changing the amount of the pedigree or inbreeding information on the estimation of heritability was investigated, too. The heritability estimates with non-zero probability in the posterior densities were approximately 0.16-0.18 in minimum, suggesting that the heritability of the Tying-up is not zero at least. The posterior density distributions of the heritability estimates were generally more pointed and sharp with using inbreeding coefficients than without using it, suggesting that more stable estimations were obtained when inbreeding coefficients were used. Among the different amounts of pedigree and inbreeding information, the heritabilities obtained with three or four generations of pedigree using inbreeding coefficients seems to be preferable, i.e. heritability of 0.42 or 0.43 for Tying-up.

Animals↗

PubMed2006

Genetic and environmental influences on extreme personality dispositions in adolescent female twins.

BACKGROUND: The objective was to determine whether the pattern of environmental and genetic influences on deviant personality scores differs from that observed for the normative range of personality, comparing results in adolescent and adult female twins. METHODS: A sample of 2,796 female adolescent twins ascertained from birth records provided Junior Eysenck Personality Questionnaire data. The average age of the sample was 17.0 years (S.D. 2.3). Genetic analyses of continuous and extreme personality scores were conducted. Results were compared for 3,178 adult female twins. RESULTS: Genetic analysis of continuous traits in adolescent female twins were similar to findings in adult female twins, with genetic influences accounting for between 37% and 44% of the variance in Extraversion (Ex), Neuroticism (N), and Social Non-Conformity (SNC), with significant evidence of shared environmental influences (19%) found only for SNC in the adult female twins. Analyses of extreme personality characteristics, defined categorically, in the adolescent data and replicated in the adult female data, yielded estimates for high N and high SNC that deviated substantially (p < .05) from those obtained in the continuous trait analyses, and provided suggestive evidence that shared family environment may play a more important role in determining personality deviance than has been previously found when personality is viewed continuously. However, multiple-threshold models that assumed the same genetic and environmental determinants of both normative range variation and extreme scores gave acceptable fits for each personality dimension. CONCLUSIONS: The hypothesis of differences in genetic or environmental factors responsible for N and SNC among female twins with scores in the extreme versus normative ranges was partially supported, but not for Ex.

Adolescent↗

PubMed1994

Early cognition, communication and language in children with focal brain injury.

The authors report a longitudinal study of the first stages of cognitive, communicative and linguistic development of six Italian-speaking infants with unilateral brain lesions acquired before the point at which language acquisition normally would begin. Substantial variability was observed in the language-cognition profiles displayed by these children. To unify these diverse profiles, the authors propose a 'cognitive infrastructure' or 'threshold' model of early language development, in which the appearance of speech depends on the presence of certain cognitive prerequisites; once those are in place, some degree of dissociation between linguistic and cognitive development can be observed. The contribution of neurological factors to these profiles appears to be complex, suggesting an interaction between lesion site, lesion size and the presence of seizure disorders and/or anticonvulsant drugs.

Age Factors↗

PubMedDate not supplied

Discordant microform cleft lip in a dizygotic female twin.

Details are given regarding a pair of dizygotic twins, discordant for microform cleft lip. The maternal history is reviewed, indicating three environmental factors as relevant to the origin of the cleft, using the multifactoral threshold model. Nurses are encouraged to survey and report cases concerning microform cleft lip.

Adult↗

PubMed2005

Genetic influences in irritable bowel syndrome: a twin study.

BACKGROUND: Aggregation of symptoms of abdominal pain or bowel disturbance has been described in the families of patients with irritable bowel syndrome (IBS). This may be due to environmental factors, including learned responses to abdominal symptoms or a genetic contribution to the etiology of IBS. OBJECTIVES: To determine the relative contribution of genetic factors to IBS by evaluating IBS symptoms in monozygotic (MZ) and dizygotic (DZ) twins. METHODS: A total of 4,480 unselected twin pairs identified from a national volunteer twin register were asked to complete a validated questionnaire. IBS was defined by the Rome II criteria. RESULTS: A total of 5,032 subjects replied (56% response rate). One thousand eight hundred seventy complete twin pairs were evaluable; 888 MZ pairs (82 male pairs, mean age 51, SD 13 (range 19-81) yr) and 982 DZ pairs (69 male pairs, age 52, SD 13 (20-82) yr). The prevalence of IBS was 17% in MZ and 16% in DZ twins. There was no significant difference in casewise concordance rates between the MZ and DZ twins (28%vs 27%, p=NS). Logistic regression analysis revealed that decreasing age and increasing psychosomatic score were independently associated with IBS. Multifactorial liability threshold modeling suggested that a combination of unique and shared environmental factors provided the best model for IBS. In contrast, somatization was shown to be moderately heritable. CONCLUSION: Genetic factors are of little or no influence on IBS where the predominant influences appear to be environmental.

Adult↗

PubMed1997

Heritability of epileptic seizures in the Belgian tervueren.

Survey data were collected on the incidence of epileptic seizures in 997 Belgian tervuerens. The heritability of this disorder was estimated as 0.77 (with a 95 per cent confidence interval spanning from 0.65 to 0.88) using a Bayesian analysis in an ordered categorical threshold model. Single locus models do not appear adequate as an explanation for this inherited seizure disorder. The high heritability estimate suggests that breeders can wage a successful battle against this disorder by breeding unaffected individuals, particularly those from families with no history of seizures.

Age Factors↗