A simulation approach for power calculation in large cohort studies based on multistate models

Realistic power calculations for large cohort studies and nested case control studies are essential for successfully answering important and complex research questions in epidemiology and clinical medicine. For this, we provide a methodical framework for general realistic power calculations via simulations that we put into practice by means of an R‐based template. We consider staggered recruitment and individual hazard rates, competing risks, interaction effects, and the misclassification of covariates. The study cohort is assembled with respect to given age‐, gender‐, and community distributions. Nested case‐control analyses with a varying number of controls enable comparisons of power with a full cohort analysis. Time‐to‐event generation under competing risks, including delayed study‐entry times, is realized on the basis of a six‐state Markov model. Incidence rates, prevalence of risk factors and prefixed hazard ratios allow for the assignment of age‐dependent transition rates given in the form of Cox models. These provide the basis for a central simulation‐algorithm, which is used for the generation of sample paths of the underlying time‐inhomogeneous Markov processes. With the inclusion of frailty terms into the Cox models the Markov property is specifically biased. An “individual Markov process given frailty” creates some unobserved heterogeneity between individuals. Different left‐truncation‐ and right‐censoring patterns call for the use of Cox models for data analysis. p‐values are recorded over repeated simulation runs to allow for the desired power calculations. For illustration, we consider scenarios with a “testing” character as well as realistic scenarios. This enables the validation of a correct implementation of theoretical concepts and concrete sample size recommendations against an actual epidemiological background, here given with possible substudy designs within the German National Cohort.     

Effect of feeding boxes on the behavior of stereotyping amur tigers (Panthera tigris altaica) in the Zurich Zoo,Zurich, Switzerland

The stereotyped pacing shown by the two Amur tigers in the Zurich Zoo was hypothesized as being caused by permanently frustrated appetitive foraging behavior. Several electrically controlled feeding boxes were installed and access to each box was possible only twice a day for 15 min at semi‐random times. The boxes had to be opened actively by the tigers. Two trials were carried out: one with solitary confinement, and one with paired confinement. During box feeding, the female's stereotyped pacing was significantly reduced from 16% (solitary confinement, conventional feeding) and 7% (paired confinement, conventional feeding) to 1% (solitary confinement) and less than 0.01% (paired confinement) of the daily observed time. The female's sleeping increased significantly in both solitary and paired confinement. The male only showed a significant reduction in stereotyped pacing behavior when kept with the female (conventional feeding: 10%; box feeding: <0.01% of the daily observed time). On days with a box‐feeding regime in paired confinement, the male spent 25% (83 min) of the observed time with active behavior at the feeding boxes. The results support the hypothesis that permanently frustrated appetitive foraging behavior causes stereotyped pacing in adult tigers. Zoo Biol 21:573–584, 2002. © 2002 Wiley‐Liss, Inc.     

Solvent cage effects: the influence of radical mass and volume on the recombination dynamics of radical cage pairs generated by photolysis of [CpCH2CH2N(CH3)C(O)(CH2)nCH3Mo(CO)3]2 (n = 3, 8, 13, 18) (Cp = eta 5-C5H4) complexes

The photochemistry of the [(CpR)Mo(CO)(3)](2) molecules, where CpR = eta(5)-C(5)H(4)(CH(2))(2)C(O)NCH(3)(CH(2))(n)CH(3) (n = 3, 8, 13, and 18), was examined using femtosecond pump-probe transient absorption spectroscopy. The goal of this study was to investigate the importance of radical size and mass on the dynamics and efficiency of geminate radical-radical recombination. The femtosecond results demonstrated the lack of any size/mass dependence of the recombination efficiency. This finding contrasts with results from a prior study that did find a size/mass dependence using a steady-state photochemical technique. To explain these conflicting results, it is proposed that the femtosecond pump-probe results are a measurement of the efficiency of primary geminate recombination whereas the steady-state method results are a measurement of the sum of primary and secondary geminate recombination efficiencies. The size/mass dependence is evident in the latter because secondary geminate recombination is a slower diffusive recombination process and therefore depends on the steric properties of the radicals. Although the existence of primary and secondary recombination channels is often taken for granted, experimental differentiation of primary and secondary caging has proven to be difficult because it is not possible for a single experimental technique to span the entire timescale for recombination of a radical cage pair and adequately resolve these recombination pathways.     

Ciliary receptors associated with the mouth and pharynx of Acoela (Acoelomorpha): a comparative ultrastructural study

The ultrastructure and distribution of receptor cells near the mouth and (where present) the pharynx of Hofstenia miamia, Proporus bermudensis, Conaperta thela, and Convoluta convoluta (Acoela) were investigated by transmission electron microscopy and confocal laser scanning microscopy of specimens stained with a fluorescence marker for actin. Five types of monociliary receptors were identified: (1) non‐collared receptors with a single long and narrow ciliary rootlet; (2) non‐collared receptors with a wide main ciliary rootlet and a smaller posterior rootlet; (3) non‐collared receptors with a single wide and hollow ciliary rootlet with a granulated core; (4) Collar (?) receptors with obliquely radial filament bundles in the cell apex and with a single hollow ciliary rootlet composed of numerous strand‐like elements; and (5) Collar receptors lacking a striated rootlet but with a granular body (swallow's nest rootlet). While H. miamia bears the first two receptor types, P. bermudensis has receptors of type 1, 3 and 5, and Cona. thela and Conv. convoluta have receptors of type 3, 4 and 5. The density of receptors is generally highest at the anterior body tip, regardless of where the mouth is located. Most receptor types occur scattered over the whole body but type 2 receptors of H. miamia are restricted to the pharynx and mouth region. The lack of a common receptor type specific for the mouth and pharynx of the investigated species points to an independent origin of the pharynges in Hofsteniidae and in Proporidae and of the mouth tube in Convolutidae. Moreover, the homology of the so‐called collar receptors in Acoela with typical collar receptors in other invertebrates is questioned.     

Human λ light chain locus: Organization and DNA sequences of three genomicJ regions

Evidence for the genomic organization of human lambda light chain joining (J) region gene segments is presented. A mouse J probe was used in Southern hybridizations to localize joining region sequences in a cosmid clone containing the genomic cluster of six human lambda constant (C) region gene segments. The results of these hybridizations suggest the presence of at least one J gene segment upstream from each constant region gene segment. The DNA sequences indicate that the human JI, J2, and J3 gene segments have consensus nonamer and heptamer sequences, proposed to be involved in V-J joining, are capable of encoding the known amino acid sequences for the respective J peptides, and have a sequence which could give functional RNA splice site at the end of their coding regions. Our data show that a single functional J is located 1.3 or 1.6 kb upstream of each of the C gene segments known to encode the Mcg, Kern^– Oz^–, and Kern^–Oz⁺ isotypes. Therefore, the gene organization of this region of the human lambda locus is J1 CI -J2C2-J3C3. The DNA sequences ofJ 1,J 2, andJ 3 presented in this paper establish that a singleJ gene segment precedes each expressed C gene segment, and support a model for the evolution of the human JC clusters where JICI andJ2C2-J3C3. arose from different ancestral JC units.