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A comparison of the case-control and case-crossover designs for estimating medical costs of nonfatal fall-related injuries among older Americans.

OBJECTIVES: Although the case-crossover design has been used widely in epidemiological and cost-offset studies as an alternative to the case-control design, it is rarely applied to cost-of-illness studies. In this study, costs for a series of hospitalized and nonhospitalized fall-related injuries were computed using the 2 approaches to allow for a direct comparison of the results. RESEARCH DESIGN: We used claims data from the Medicare fee-for-service 5% Standard Analytical Files. For the case-control design, those who sustained nonfatal fall-related injuries were tracked for 1 year after their first fall, and costs were compared, using regression analysis, to annual costs for a comparison sample of nonfallers. The case-crossover design used a modified regression approach that compared monthly costs of fallers before and after fall. RESULTS: We present unit costs for falls requiring (1) a hospitalization resulting in a live discharge, (2) an emergency department visit not resulting in an admission, and (3) falls requiring office-based or hospital outpatient visits only. Using the case-control design, these costs were $22,260, $3890, and $5040 respectively. Using the case-crossover design, these estimates were reduced to $20,920, $3230, and $4200. CONCLUSIONS: On average, estimates of the costs of fall injuries from the case-control design were between 6% and 17% greater than those from the case-crossover approach. These differences likely result from our inability to control for comorbidity differences between fallers and nonfallers in the case-control design. Under several scenarios, including unobserved heterogeneity between cases and controls, the case-crossover design, although computationally more intensive, produces more accurate results.

Accidental Falls↗

Crossover in diffusion equation: anomalous and normal behaviors.

Ubiquitous phenomena exist in nature where, as time goes on, a crossover is observed between different diffusion regimes (e.g., anomalous diffusion at early times which becomes normal diffusion at long times, or the other way around). In order to focus on such situations we have analyzed particular relevant cases of the generalized Fokker-Planck equation integral dgamma(')tau(gamma('))[ partial differential (gamma('))rho(x,t)]/ partial differential t(gamma('))= integral dmu(')dnu'D(mu('),nu('))[ partial differential (mu('))[rho(x,t)](nu('))]/ partial differential x(mu(')), where tau(gamma(')) and D(mu('),nu(')) are kernels to be chosen; the choice tau(gamma('))=delta(gamma(')-1) and D(mu('),nu('))=delta(mu(')-2)delta(nu(')-1) recovers the normal diffusion equation. We discuss in detail the following cases: (i) a mixture of the porous medium equation, which is connected with nonextensive statistical mechanics, with the normal diffusion equation; (ii) a mixture of the fractional time derivative and normal diffusion equations; (iii) a mixture of the fractional space derivative, which is related with Lévy flights, and normal diffusion equations. In all three cases a crossover is obtained between anomalous and normal diffusions. In cases (i) and (iii), the less diffusive regime occurs for short times, while at long times the more diffusive regime emerges. The opposite occurs in case (ii). The present results could be easily extended to more complex situations (e.g., crossover between two, or even more, different anomalous regimes), and are expected to be useful in the analysis of phenomena where nonlinear and fractional diffusion equations play an important role. Such appears to be the case for isolated long-ranged interaction Hamiltonians, which along time can exhibit a crossover from a longstanding metastable anomalous state to the usual Boltzmann-Gibbs equilibrium one. Another illustration of such crossover occurs in active intracellular transport.

Journal Article↗

Estimating the frequency distribution of crossovers during meiosis from recombination data.

Estimation of tetrad crossover frequency distributions from genetic recombination data is a classic problem dating back to Weinstein (1936, Genetics 21, 155-199). But a number of important issues, such as how to specify the maximum number of crossovers, how to construct confidence intervals for crossover probabilities, and how to obtain correct p-values for hypothesis tests, have never been adequately addressed. In this article, we obtain some properties of the maximum likelihood estimate (MLE) for crossover probabilities that imply guidelines for choosing the maximum number of crossovers. We give these results for both normal meiosis and meiosis with nondisjunction. We also develop an accelerated EM algorithm to find the MLE more efficiently. We propose bootstrap-based methods to find confidence intervals and p-values and conduct simulation studies to check the validity of the bootstrap approach.

Algorithms↗

Repeat median sternotomy after prior ante-aortic crossover right internal thoracic artery grafting.

BACKGROUND: In situ bilateral internal thoracic artery (ITA), with ante-aortic crossover right ITA (RITA) is gaining popularity. However, the retrosternal position of the crossover RITA has raised concerns with regard to its compromise during subsequent resternotomy. METHODS: Ten patients underwent repeat median sternotomy after prior ante-aortic crossover RITA grafting. Specific RITA routing and fixation had been performed in the initial operation. Preoperative imaging, including computed tomography (CT) angiography, was performed to confirm RITA position in relation to the sternum and assess feasibility. RESULTS: Resternotomy was performed 4-48 months after the initial operation (median, 22 months). Nine crossover RITA grafts were functioning at the time of resternotomy. CT angiography was performed in four patients in whom the premarked RITA could not be localized on the plain chest radiograph. The feasibility of conducting a nonmodified resternotomy was determined based on preoperative imaging. All RITA grafts resumed their original position and none was injured during reentry. There was no early mortality, perioperative stroke, or reexploration for bleeding. One patient sustained myocardial infarction, however, not in a RITA-related distribution. CT angiography was predictive in confirming a free retrosternal space. CONCLUSIONS: Resternotomy after prior ante-aortic crossover RITA grafting can be performed at acceptable risk. Confirmation of a free retrosternal space by preoperative imaging may contribute to the safety of the procedure. Maneuvers performed during the first operation are useful in preventing RITA adherence to the sternum.

Aged↗

The Arabidopsis ROCK-N-ROLLERS gene encodes a homolog of the yeast ATP-dependent DNA helicase MER3 and is required for normal meiotic crossover formation.

Recent studies in Saccharomyces cerevisiae have unveiled that meiotic recombination crossovers are formed by two genetically distinct pathways: a major interference-sensitive pathway and a minor interference-insensitive pathway. Several proteins, including the MSH4/MSH5 heterodimer and the MER3 DNA helicase, are indispensable for the interference-sensitive pathway. MSH4 homologs have been identified in mice and Arabidopsis and shown to be required for normal levels of crossovers, suggesting that the function of MSH4 may be conserved among major eukaryotic kingdoms. However, it is not known whether an MER3-like function is also required for meiosis in animals and plants. We have identified an Arabidopsis gene that encodes a putative MER3 homolog and is preferentially expressed in meiocytes. T-DNA insertional mutants of this gene exhibit defects in fertility and meiosis. Detailed cytological studies indicate that the mutants are defective in homolog synapsis and crossover formation, resulting in a reduction of bivalents and in the formation of univalents at late prophase I. We have named this gene ROCK-N-ROLLERS (RCK) to reflect the mutant phenotype of chromosomes undergoing the meiotic 'dance' either in pairs or individually. Our results demonstrate that an MER3-like function is required for meiotic crossover in plants and provide further support for the idea that Arabidopsis, like the budding yeast, possesses both interference-sensitive and insensitive pathways for crossover formation.

Alleles↗

Individual and crossover effects of stress on adjustment in medical student marriages.

High-stress individuals may benefit from social support, although their support providers may be adversely affected via stress crossover effects. Individual and crossover effects of perceived stress within medical student marriages (n = 30) were investigated. Perceived spousal support was positively associated with individuals' own marital and emotional adjustment, attenuating stress effects. With regard to crossover effects, medical students' perceived stress was significantly associated with their spouses' emotional adjustment. Further, medical students' own emotional adjustment fully mediated this crossover effect. Results suggest that the contagion of negative affect may serve as a key mechanism through which stress crossover effects operate in marriage.

Adaptation, Psychological↗

Method of simulated screen sensitometry for asymmetric, low crossover medical x-ray films.

Recognition of the importance of performing simulated screen-light sensitometry of medical x-ray films for the purpose of processor quality control has increased over the past several years. As a result there is a greater need to provide new techniques for performing simulated screen-light sensitometry. Medical films with reduced intensifying screen-light crossover intended to achieve reduced blur and higher spatial resolution pose particular problems in doing simulated screen-light sensitometry if care is not taken to choose a proper simulated light sensitometer with the capability of simultaneous double-sided exposures. Misleading and incorrect sensitometric data can be obtained for film contrast evaluation if a single side exposure is used. Asymmetric, near-zero crossover films pose even greater problems as proper orientation of the film and proper degree of light output asymmetry need be achieved in order to obtain correct sensitometry. The films used in this study were three double emulsion films varying in crossover from 3% to 24%. Of the two very-low-crossover films, one had symmetric emulsion layers while the second featured emulsion layers which were asymmetric in terms of contrast and speed. Sensitometric data show several curve shapes with significant distortions, depending on orientation, for the asymmetric, low-crossover film when exposed using a single-sided exposure. Only by using a double-sided exposure and an appropriate neutral density filter to simulate the degree of screen-light asymmetry in this system could one achieve a characteristic curve comparable to that achieved by inverse square sensitometry.

Biophysical Phenomena↗

Gene conversion tracts associated with crossovers in Rhizobium etli.

Gene conversion has been defined as the nonreciprocal transfer of information between homologous sequences. Despite its broad interest for genome evolution, the occurrence of this mechanism in bacteria has been difficult to ascertain due to the possible occurrence of multiple crossover events that would mimic gene conversion. In this work, we employ a novel system, based on cointegrate formation, to isolate gene conversion events associated with crossovers in the nitrogen-fixing bacterium Rhizobium etli. In this system, selection is applied only for cointegrate formation, with gene conversions being detected as unselected events. This minimizes the likelihood of multiple crossovers. To track the extent and architecture of gene conversions, evenly spaced nucleotide changes were made in one of the nitrogenase structural genes (nifH), introducing unique sites for different restriction endonucleases. Our results show that (i) crossover events were almost invariably accompanied by a gene conversion event occurring nearby; (ii) gene conversion events ranged in size from 150 bp to 800 bp; (iii) gene conversion events displayed a strong bias, favoring the preservation of incoming sequences; (iv) even small amounts of sequence divergence had a strong effect on recombination frequency; and (v) the MutS mismatch repair system plays an important role in determining the length of gene conversion segments. A detailed analysis of the architecture of the conversion events suggests that multiple crossovers are an unlikely alternative for their generation. Our results are better explained as the product of true gene conversions occurring under the double-strand break repair model for recombination.

Bacterial Proteins↗

Sgs1 regulates gene conversion tract lengths and crossovers independently of its helicase activity.

RecQ helicases maintain genome stability and suppress tumors in higher eukaryotes through roles in replication and DNA repair. The yeast RecQ homolog Sgs1 interacts with Top3 topoisomerase and Rmi1. In vitro, Sgs1 binds to and branch migrates Holliday junctions (HJs) and the human RecQ homolog BLM, with Top3alpha, resolves synthetic double HJs in a noncrossover sense. Sgs1 suppresses crossovers during the homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Crossovers are associated with long gene conversion tracts, suggesting a model in which Sgs1 helicase catalyzes reverse branch migration and convergence of double HJs for noncrossover resolution by Top3. Consistent with this model, we show that allelic crossovers and gene conversion tract lengths are increased in sgs1Delta. However, crossover and tract length suppression was independent of Sgs1 helicase activity, which argues against helicase-dependent HJ convergence. HJs may converge passively by a "random walk," and Sgs1 may play a structural role in stimulating Top3-dependent resolution. In addition to the new helicase-independent functions for Sgs1 in crossover and tract length control, we define three new helicase-dependent functions, including the suppression of chromosome loss, chromosome missegregation, and synthetic lethality in srs2Delta. We propose that Sgs1 has helicase-dependent functions in replication and helicase-independent functions in DSB repair by HR.

Chromosome Segregation↗

Crossover invariant subsets of the search space for evolutionary algorithms.

This paper addresses the relationship between schemata and crossover operators. In Appendix A a general mathematical framework is developed which reveals an interesting correspondence between the families of reproduction transformations and the corresponding collections of invariant subsets of the search space. On the basis of this mathematical apparatus it is proved that the family of masked crossovers is, for all practical purposes, the largest family of transformations whose corresponding collection of invariant subsets is the family of Antonisse's schemata. In the process, a number of other interesting facts are shown. It is proved that the full dynastic span of a given subset of the search space under either one of the traditional families of crossover transformations (one-point crossovers or masked crossovers) is obtained after [log2n] iterations where n is the dimension of the search space. The generalized notion of invariance introduced in the current paper unifies Radcliffe's notions of "respect" and "gene transmission". Besides providing basic tools for the theoretical analysis carried out in the current paper, the general facts established in Appendix A provide a way to extend Radcliffe's notion of "genetic representation function" to compare various evolutionary computation techniques via their representation.

Algorithms↗

Pieces of the true crossover effect in neglect.

A subject with left hemispatial neglect exhibited the crossover effect on bisecting lines of varying lengths. On long lines he misbisected to the right and on shorter lines he misbisected to the left. Rather than being an idiosyncrasy of this one task, the crossover effect also occurred on variations of Milner's Landmark task and Bisiach's Endpoint task. Performances across different bisection task variations were highly correlated. The crossover effect is not specific to the traditional line bisection task but is a pervasive aspect of this subject's performance. As the crossover effect is not explained by current theories of neglect, determining the bases for the crossover effect constitutes a challenge in understanding neglect.

Attention↗

The influence of ambient coarse particulate matter on asthma hospitalization in children: case-crossover and time-series analyses.

In this study, we used both case-crossover and time-series analyses to assess the associations between size-fractionated particulate matter and asthma hospitalization among children 6-12 years old living in Toronto between 1981 and 1993. Specifically, we used exposures averaged over periods varying from 1 to 7 days to assess the effects of particulate matter on asthma hospitalization. We calculated estimates of the relative risk of asthma hospitalization adjusted for daily weather conditions (maximum and minimum temperatures, and average relative humidity) for an incremental exposure corresponding to the interquartile range in particulate matter. Both bidirectional case-crossover and time-series analyses revealed that coarse particulate matter (PM10-2.5) averaged over 5-6 days was significantly associated with asthma hospitalization in both males and females. The magnitude of this effect appeared to increase with increasing number of days of exposure averaging for most models, with the relative risk estimates stabilizing at about 6 days. Using a bidirectional case-crossover analysis, the estimated relative risks were 1.14 [95% confidence interval (CI), 1.02, 1.28] for males and 1.18 (95% CI, 1.02, 1.36) for females, for an increment of 8.4 microg/m(3) in 6-day averages of PM10-2.5. The corresponding relative risk estimates were 1.10 and 1.18, respectively, when we used time-series analysis. The effect of PM10-2.5 remained positive after adjustment for the effects of the gaseous pollutants carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3). We did not find significant effects of fine particulate matter (PM2.5) or of thoracic particulate matter (PM10) on asthma hospitalizations using either of these two analytic approaches. For the most part, relative risk estimates from the unidirectional case-crossover analysis were more pronounced compared with both bidirectional case-crossover and time-series analyses.

Air Pollutants↗

Religious attendance and mortality: implications for the black-white mortality crossover.

This study investigates the relationships among religious attendance, mortality, and the black-white mortality crossover. We build on prior research by examining the link between attendance and mortality while testing whether religious involvement captures an important source of population heterogeneity that contributes to a crossover Using data from the Established Populations for Epidemiologic Studies of the Elderly, we find a strong negative association between attendance and mortality. Our results also show evidence of a racial crossover in mortality rates for both men and women. When religious attendance is modeled in terms of differential frailty, clear gender differences emerge. For women, the effect of attendance is race- and age-dependent, modifying the age at crossover by 10 years. For men, however; the effect of attendance is not related to race and does not alter the crossover pattern. When other health risks are modeled in terms of differential frailty, wefind neither race nor age-related effects. Overall, the results highlight the importance of considering religious attendance when examining racial and gender differences in age-specific mortality rates.

Black or African American↗

A link between meiotic prophase progression and crossover control.

During meiosis, most organisms ensure that homologous chromosomes undergo at least one exchange of DNA, or crossover, to link chromosomes together and accomplish proper segregation. How each chromosome receives a minimum of one crossover is unknown. During early meiosis in Caenorhabditis elegans and many other species, chromosomes adopt a polarized organization within the nucleus, which normally disappears upon completion of homolog synapsis. Mutations that impair synapsis even between a single pair of chromosomes in C. elegans delay this nuclear reorganization. We quantified this delay by developing a classification scheme for discrete stages of meiosis. Immunofluorescence localization of RAD-51 protein revealed that delayed meiotic cells also contained persistent recombination intermediates. Through genetic analysis, we found that this cytological delay in meiotic progression requires double-strand breaks and the function of the crossover-promoting heteroduplex HIM-14 (Msh4) and MSH-5. Failure of X chromosome synapsis also resulted in impaired crossover control on autosomes, which may result from greater numbers and persistence of recombination intermediates in the delayed nuclei. We conclude that maturation of recombination events on chromosomes promotes meiotic progression, and is coupled to the regulation of crossover number and placement. Our results have broad implications for the interpretation of meiotic mutants, as we have shown that asynapsis of a single chromosome pair can exert global effects on meiotic progression and recombination frequency.

Animals↗

Chromosome-wide regulation of meiotic crossover formation in Caenorhabditis elegans requires properly assembled chromosome axes.

Most sexually reproducing organisms depend on the regulated formation of crossovers, and the consequent chiasmata, to accomplish successful segregation of homologous chromosomes at the meiosis I division. A robust, chromosome-wide crossover control system limits chromosome pairs to one crossover in most meioses in the nematode Caenorhabditis elegans; this system has been proposed to rely on structural integrity of meiotic chromosome axes. Here, we test this hypothesis using a mutant, him-3(me80), that assembles reduced levels of meiosis-specific axis component HIM-3 along cohesin-containing chromosome axes. Whereas pairing, synapsis, and crossing over are eliminated when HIM-3 is absent, the him-3(me80) mutant supports assembly of synaptonemal complex protein SYP-1 along some paired chromosomes, resulting in partial competence for chiasma formation. We present both genetic and cytological evidence indicating that the him-3(me80) mutation leads to an increased incidence of meiotic products with two crossovers. These results indicate that limiting the amount of a major axis component results in a reduced capacity to communicate the presence of a (nascent) crossover and/or to discourage others in response.

Animals↗

Trans events associated with crossovers are revealed in the absence of mismatch repair genes in Saccharomyces cerevisiae.

Genetic analysis of recombination in Saccharomyces cerevisiae has revealed products with structures not predicted by the double-strand break repair model of meiotic recombination. A particular type of recombinant containing trans heteroduplex DNA has been observed at two loci. Trans events were originally identified only in tetrads in which the non-Mendelian segregations were not associated with a crossover. Because of this, these events were proposed to have arisen from the unwinding of double Holliday junctions. Previous studies used palindromes, refractory to mismatch repair, as genetic markers whereas we have used a complementary approach of deleting mismatch repair proteins to identify heteroduplex DNA. We found that the markers occurred in trans and were associated with crossovers. In both mlh1Delta and msh2Delta strains, the frequency of trans events associated with a crossover exceeded that predicted from the random association of crossovers with noncrossover trans events. We propose two different models to account for trans events associated with crossovers and discuss the relevance to wild-type DSB repair.

Alcohol Oxidoreductases↗

The use of the case-crossover design in studying illicit drug use.

The case-crossover design was developed to study time-varying exposures that cause transient excess risk of acute health events. It is a variant of case-control and subject-as-own-control research designs, involving use of information about exposure history of each case to estimate the transient effect. This kind of self-control design can help to reduce sampling bias otherwise introduced in the selection of controls, as well as confounding bias that might be derived from enduring individual characteristics, especially personality traits and other long-standing inherited or acquired vulnerabilities. When the subject is used as his or her own control, these personal vulnerabilities are matched. In this paper we discuss strengths and weaknesses of the case-crossover design and suggest applications of the case-crossover design in epidemiologic studies on suspected hazards of illicit drug use, and in studies of drug use and co-occurring psychiatric disturbances. We conclude that the case-crossover design can play a useful role, but it discloses a need to secure fine-grained measurements in epidemiologic research on psychiatric comorbidity. As explained in the paper, we also believe the case-crossover method may be of use to criminologists who study the drugs-crime nexus, to services researchers and clinicians who seek to understand treatment entry and compliance behavior, and to etiologists interested in polydrug use.

Case-Control Studies↗

The two-period crossover design in medical research.

The crossover design has enjoyed popularity with many clinical researchers, but has been criticized by biostatisticians. The central problem is the inability to derive an unbiased estimate of the treatment effect when differences occur because of the different sequences in which treatments are applied. This problem can be traced to a deficiency of the logic of the crossover arrangement itself. Factors that can invalidate the findings of a crossover trial include nonuniform pharmacologic and psychologic carry-over effects, failure to return patients to their baseline state before the crossover, nonuniform changes in the patients over time, and the use of time-dependent response measures. When these problems can be anticipated, a parallel-groups design should be used instead of a crossover trial.

Clinical Trials as Topic↗