Left, right and interval bivariate censored data: Evaluating screening mammography in the presence of lead -time bias, length bias and over-detection

Of the large clinical trials evaluating screening mammography efficacy, none included women ages 75 and older. Recommendations on an upper age limit at which to discontinue screening are based on indirect evidence and are not consistent. Screening mammography is evaluated using observational data from the SEER-Medicare linked database. Measuring the benefit of screening mammography is difficult due to the impact of lead-time bias, length bias and over-detection. The underlying conceptual model divides the disease into two stages: pre-clinical (T0) and symptomatic (T1) breast cancer. Treating the time in these phases as a pair of dependent bivariate observations, (t0,t1), estimates are derived to describe the distribution of this random vector. To quantify the effect of screening mammography, statistical inference is made about the mammography parameters that correspond to the marginal distribution of the symptomatic phase duration (T1). This shows the hazard ratio of death from breast cancer comparing women with screen-detected tumors to those detected at their symptom onset is 0.36 (0.30, 0.42), indicating a benefit among the screen-detected cases. ^

Data from PhD thesis

The ocean quahog, Arctica islandica is the longest-lived non-colonial animal known to science. A maximum individual age of this bivalve of 405 years has been found in a population off the north western coast of Iceland. Conspicuously shorter maximum lifespan potentials (MLSPs) were recorded from other populations of A. islandica in European waters (e.g. Kiel Bay: 30 years, German Bight: 150 years) which experience wider temperature and salinity fluctuations than the clams from Iceland. The aim of my thesis was to identify possible life-prolonging physiological strategies in A. islandica and to examine the modulating effects of extrinsic factors (e.g. seawater temperature, food availability) and intrinsic factors (e.g. species-specific behavior) on these strategies. Burrowing behavior and metabolic rate depression (MRD), tissue-specific antioxidant and anaerobic capacities as well as cell-turnover (= apoptosis and proliferation) rates were investigated in A. islandica from Iceland and the German Bight. An inter-species comparison of the quahog with the epibenthic scallop Aequipecten opercularis (MLSP = 8-10 years) was carried out in order to determine whether bivalves with short lifespans and different lifestyles also feature a different pattern in cellular maintenance and repair. The combined effects of a low-metabolic lifestyle, low oxidative damage accumulation, and constant investment into cellular protection and tissue maintenance, appear to slow-down the process of physiological aging in A. islandica and to afford the extraordinarily long MLSP in this species. Standard metabolic rates were lower in A. islandica when compared to the shorter-lived A. opercularis. Furthermore, A. islandica regulate mantle cavity water PO2 to mean values < 5 kPa, a PO2 at which the formation of reactive oxygen species (ROS) in isolated gill tissues of the clams was found to be 10 times lower than at normoxic conditions (21 kPa). Burrowing and metabolic rate depression (MRD) in Icelandic specimens were more pronounced in winter, possibly supported by low seawater temperature and food availability, and seem to be key energy-saving and life-prolonging parameters in A. islandica. The signaling molecule nitric oxide (NO) may play an important role during the onset of MRD in the ocean quahog by directly inhibiting cytochome-c-oxidase at low internal oxygenation upon shell closure. In laboratory experiments, respiration of isolated A. islandica gills was completely inhibited by chemically produced NO at low experimental PO2 <= 10 kPa. During shell closure, mantle cavity water PO2 decreased to 0 kPa for longer than 24 h, a state in which ROS production is supposed to subside. Compared to other mollusk species, onset of anaerobic metabolism is late in A. islandica in the metabolically reduced state. Increased accumulation of the anaerobic metabolite succinate was initially detected in the adductor muscle of the clams after 3.5 days under anoxic incubation or in burrowed specimens. A ROS-burst was absent in isolated gill tissue of the clams following hypoxia (5 kPa)-reoxygenation (21 kPa). Accordingly, neither the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), nor the specific content of the ROS-scavenger glutathione (GSH) was enhanced in different tissues of the ocean quahog after 3.5 days of self-induced or forced hypoxia/anoxia to prepare for an oxidative burst. While reduced ROS formation compared to routine levels lowers oxidative stress during MRD and also during surfacing, the general preservation of high cellular defense and the efficient removal and replacement of damaged cells over lifetime seem to be of crucial importance in decelerating the senescent decline in tissues of A. islandica. Along with stable antioxidant protection over 200 years of age, proliferation rates and apoptosis intensities in most investigated tissues of the ocean quahog were low, but constant over 140 years of age. Accordingly, age-dependent accumulations of protein and lipid oxidation products are lower in A. islandica tissues when compared to the shorter-lived bivalve A. opercularis. The short-lived swimming scallop is a model bivalve species representing the opposite life and aging strategy to A. islandica. In this species permanently high energy throughput, reduced investment into antioxidant defense with age, and higher accumulation of oxidation products are met by higher cell turnover rates than in the ocean quahog. The only symptoms of physiological change over age ever found in A. islandica were decreasing cell turnover rates in the heart muscle over a lifetime of 140 years. This may either indicate higher damage levels and possibly ongoing loss of functioning in the heart of aging clams, or, the opposite, lower rates of cell damage and a reduced need for cell renewal in the heart tissue of A. islandica over lifetime. Basic physiological capacities of different A. islandica populations, measured at controlled laboratory conditions, could not explain considerable discrepancies in population specific MLSPs. For example, levels of tissue-specific antioxidant capacities and cell turnover rates were similarly high in individuals from the German Bight and from Iceland. Rather than genetic differences, the local impacts of environmental conditions on behavioral and physiological traits in the ocean quahog seem to be responsible for differences in population-specific MLSPs.

Auxiliary material and basic geochemical and benthic foraminiferal stable isotope data for the interval bracketing Eocene Thermal Maximum 2 (ETM2) at DSDP Sites 401 and 550 in the northeastern Atlantic Ocean

Ever since its discovery, Eocene Thermal Maximum 2 (ETM2; ~53.7 Ma) has been considered as one of the "little brothers" of the Paleocene-Eocene Thermal Maximum (PETM; ~56 Ma) as it displays similar characteristics including abrupt warming, ocean acidification, and biotic shifts. One of the remaining key questions is what effect these lesser climate perturbations had on ocean circulation and ventilation and, ultimately, biotic disruptions. Here we characterize ETM2 sections of the NE Atlantic (Deep Sea Drilling Project Sites 401 and 550) using multispecies benthic foraminiferal stable isotopes, grain size analysis, XRF core scanning, and carbonate content. The magnitude of the carbon isotope excursion (0.85-1.10 per mil) and bottom water warming (2-2.5°C) during ETM2 seems slightly smaller than in South Atlantic records. The comparison of the lateral d13C gradient between the North and South Atlantic reveals that a transient circulation switch took place during ETM2, a similar pattern as observed for the PETM. New grain size and published faunal data support this hypothesis by indicating a reduction in deepwater current velocity. Following ETM2, we record a distinct intensification of bottom water currents influencing Atlantic carbonate accumulation and biotic communities, while a dramatic and persistent clay reduction hints at a weakening of the regional hydrological cycle. Our findings highlight the similarities and differences between the PETM and ETM2. Moreover, the heterogeneity of hyperthermal expression emphasizes the need to specifically characterize each hyperthermal event and its background conditions to minimalize artifacts in global climate and carbonate burial models for the early Paleogene.

Palaeolake Rehwiese, NE-Germany, Younger Dryas varved data set RW09

The first 1400-year floating varve chronology for north-eastern Germany covering the late Allerød to the early Holocene has been established by microscopic varve counts from the Rehwiese palaeolake sediment record. The Laacher See Tephra (LST), at the base of the studied interval, forms the tephrochronological anchor point. The fine laminations were examined using a combination of micro-facies and ?-XRF analyses and are typical of calcite varves, which in this case provide mainly a warm season signal. Two varve types with different sub-layer structures have been distinguished: (I) complex varves consisting of up to four seasonal sub-layers formed during the Allerød and early Holocene periods, and, (II) simple two sub-layer type varves only occurring during the Younger Dryas. The precision of the chronology has been improved by varve-to-varve comparison of two independently analyzed sediment profiles based on well-defined micro-marker layers. This has enabled both (1) the precise location of single missing varves in one of the sediment profiles, and, (2) the verification of varve interpolation in disturbed varve intervals in the parallel core. Inter-annual and decadal-scale variability in sediment deposition processes were traced by multi-proxy data series including seasonal layer thickness, high-resolution element scans and total organic and inorganic carbon data at a five-varve resolution. These data support the idea of a two-phase Younger Dryas, with the first interval (12,675 - 12,275 varve years BP) characterised by a still significant but gradually decreasing warm-season calcite precipitation and a second phase (12,275 - 11,640 varve years BP) with only weak calcite precipitation. Detailed correlation of these two phases with the Meerfelder Maar record based on the LST isochrone and independent varve counts provides clues about regional differences and seasonal aspects of YD climate change along a transect from a location proximal to the North Atlantic in the west to a more continental site in the east.

(Appendix 1) Crustal helium-4 abundance and flux data for ODP Hole 130-806B

The mass accumulation rates (MARs) of aeolian dust in the ocean basins provide an important record of climate in the continental source regions of atmospheric dust and of the prevailing wind patterns responsible for dust transport in the geologic past. The incorporation of other terrigenous components such as volcanic ashes in seafloor sediments, however, often obscures the aeolian dust record. We describe a new approach which uses the delivery rate of crustal 4He to seafloor sediments as a proxy for the mass accumulation rate of old continental dust which is unaffected by the addition of other terrigenous components. We have determined the flux of crustal 4He delivered to the seafloor of the Ontong Java Plateau (OJP) in the western equatorial Pacific over the last 1.9 Myrs. Crustal 4He fluxes vary between 7.7 and 30 ncc/cm**2/kyr and show excellent correlation with global climate as recorded by oxygen isotopes, with high crustal 4He fluxes associated with glacial periods over the entire interval studied. Furthermore, the onset of strong 100 kyr glacial-interglacial climate cycling is clearly seen in the 4He flux record about 700 kyrs ago. These data record variations in the supply of Asian dust in response to climate driven changes in the aridity of the Asian dust sources, consistent with earlier work on Asian dust flux to the northern Pacific Ocean. However, in contrast to previous studies of sites in the central and eastern equatorial Pacific Ocean, there is no evidence that the Inter Tropical Convergence Zone (an effective rainfall barrier to the southward transport of northern hemisphere dust across the equator in the central and eastern Pacific) has influenced the delivery of Asian dust to the OJP. The most likely carrier phase for crustal helium in these sediments is zircon, which can reasonably account for all the 4He observed in the samples. As a first order estimate, these results suggest that the mass accumulation rate of Asian dust on the OJP over the last 1.9 Myrs varied from about 4 to 15 mg/ cm**2/kyr. In contrast, previous studies show that over the same interval the total MAR of terrigenous dust (i.e. Asian dust plus local volcanics) on OJP varied between about 34 and 90 mg/ cm**2/kyr.

Directional imbalance of freight rates : evidence from Japanese inter-prefectural data

By analyzing a comprehensive dataset on transport transactions in Japan, we describe a directional imbalance in freight rates by transport mode and examine its potential sources, such as economies of density and directionally imbalanced transport flow. There are certain numbers of observed links which show asymmetric transport costs. Instrumental variable analysis is used to show that economies of density account for deviation from symmetric freight rates between prefectures. Our results show that a 10% increase in outbound transport flow relative to inbound transport flow leads to a 2.1% decrease in outbound freight rate relative to inbound freight rate.

Evaluation of selected recurrence measures in discriminating pre-ictal and inter-ictal periods from epileptic EEG data

7 pages, 4 figures Acknowledgement We are grateful to M. Riedl and G. Ansmann for fruitful discussions and critical comments on earlier versions of the manuscript. This work was supported by the Volkswagen Foundation (Grant Nos. 88461, 88462, 88463, 85390, 85391 and 85392).

Preliminary comilation of data for retrospective world interval July 26-August 14, 1972,

Mode of access: Internet.

Inter-site and inter-scanner diffusion MRI data harmonization.

We propose a novel method to harmonize diffusion MRI data acquired from multiple sites and scanners, which is imperative for joint analysis of the data to significantly increase sample size and statistical power of neuroimaging studies. Our method incorporates the following main novelties: i) we take into account the scanner-dependent spatial variability of the diffusion signal in different parts of the brain; ii) our method is independent of compartmental modeling of diffusion (e.g., tensor, and intra/extra cellular compartments) and the acquired signal itself is corrected for scanner related differences; and iii) inter-subject variability as measured by the coefficient of variation is maintained at each site. We represent the signal in a basis of spherical harmonics and compute several rotation invariant spherical harmonic features to estimate a region and tissue specific linear mapping between the signal from different sites (and scanners). We validate our method on diffusion data acquired from seven different sites (including two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. Since the extracted rotation invariant spherical harmonic features depend on the accuracy of the brain parcellation provided by Freesurfer, we propose a feature based refinement of the original parcellation such that it better characterizes the anatomy and provides robust linear mappings to harmonize the dMRI data. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across multiple sites before and after data harmonization. We also show results using tract-based spatial statistics before and after harmonization for independent validation of the proposed methodology. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences can be accurately removed using the proposed method.