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Using Multivariate Statistics

A report of two cases

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

https://journals.sagepub.com/doi/pdf/10.1016/j.icrp.2012.02.001

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

GUEST EDITORIAL PART I: ICRP STATEMENT ON TISSUE REACTIONS PART II: EARLY AND LATE EFFECTS OF RADIATION IN NORMAL TISSUES AND ORGANS - THRESHOLD DOSES FOR TISSUE REACTIONS IN A RADIATION PROTECTION CONTEXT ABSTRACT PREFACE EXECUTIVE SUMMARY GLOSSARY 1. INTRODUCTION 1.1. Purpose of report 1.2. Definition and nature of tissue reactions to ionising radiation 1.3. General principles of radiation effects in cells and tissues 1.4. References 2. RESPONSE OF TISSUES AND ORGANS TO RADIATION 2.1. Haematopoietic and immune systems 2.2. Digestive system 2.3. Reproductive system 2.4. Skin 2.5. Cardiovascular and cerebrovascular systems 2.6. Eye 2.7. Respiratory system 2.8. Urinary tract 2.9. Musculoskeletal system 2.10. Endocrine system 2.11. Nervous system 2.12. References 3. MODIFIERS OF NORMAL TISSUE RESPONSE 3.1. Terminology 3.2. Mechanisms of action 3.3. Influence of modifiers on radiation response in tissue 3.4. References 4. THRESHOLD DOSES IN RELATION TO RADIOSENSITIVITY OF ORGANS AND TISSUES 4.1. Introduction 4.2. Haematopoietic and immune systems 4.3. Digestive system 4.4. Reproductive system 4.5. Skin 4.6. Cardiovascular and cerebrovascular systems 4.7. Eye 4.8. Respiratory system 4.9. Urinary tract 4.10. Musculoskeletal system 4.11. Endocrine system 4.12. Nervous system 4.13. Conclusions 4.14. References ANNEX A. SUMMARY OF STUDIES OF EXPOSURE AND OPACITIES OR CATARACTS

ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs -- threshold doses for tissue reactions in a radiation protection context

Here are two books on a topic new to Technometrics: statistical and mathematical demography. The first author of Applied Mathematical Demography wrote the first two editions of this book alone. The second edition was published in 1985. Professor Keyfritz noted in the Preface (p. vii) that at age 90 he had no interest in doing another edition; however, the publisher encouraged him to find a coauthor. The result is an additional focus for the book in the world of biology that makes it much more relevant for the sciences. The book is now part of the publisher’s series on Statistics for Biology and Health. Much of it, of course, focuses on the many aspects of human populations. The new material focuses on mature population models, the particular focus of the new author (see, e.g., Caswell 2000). As one might expect from a book that was originally written in the 1970s, it does not include a lot of information on statistical computing. The new book by Alho and Spencer is focused on putting a better emphasis on statistics in the discipline of demography (Preface, p. vii). It is part of the publisher’s Series in Statistics. The authors are both statisticians, so the focus is on statistics as used for demographic problems. The authors are targeting human applications, so their perspective on science does not extend any further than epidemiology. The book actually strikes a good balance between statistical tools and demographic applications. The authors use the first two chapters to teach statisticians about the concepts of demography. The next four chapters are very similar to the statistics content found in introductory books on survival analysis, such as the recent book by Kleinbaum and Klein (2005), reported by Ziegel (2006). The next three chapters are focused on various aspects of forecasting demographic rates. The book concludes with chapters focusing on three areas of applications: errors in census numbers, financial applications, and small-area estimates.

Univariate Discrete Distributions

Purpose Based on the experience of biodosimetry laboratories during the COVID-19 pandemic, the purpose of this paper is to describe the challenges of providing biodosimetry service in the event of a major radiation incident during a pandemic. This includes describing some of the preparations and planning made by biodosimetry laboratories and special challenges in maintaining a state of readiness while adhering to safety protocols and balancing the need to assist with the COVID-19 response where possible. Experiences of several biodosimetry laboratories will be described and lessons learned will be outlined that could be applied to any large population-scale emergencies. Conclusions There are many challenges that arise when maintaining capacity and capabilities for biodosimetry when faced with a global pandemic such as COVID-19. The key is to be prepared for anything within reason. This includes, but is not limited to, maintaining flexibility, shifting and reorganizing deployment of staff between pandemic response and biodosimetry needs, strengthening networks to be able to provide assistance to other laboratories, managing staff in the face of possible infections and preparing protocols for the handling of potentially infected biological samples according to regulatory requirements. By implementing these recommendations, international biodosimetry networks can be prepared to address large-scale radiological incidents within the context of a pandemic and ensure the safety of biodosimetry personnel as well as victims in such dual emergencies.

What if a major radiation incident happened during a pandemic? - Considerations of the impact on biodosimetry.

The Running the European Network of biological and retrospective dosimetry (RENEB) network of laboratories has a range of biological and physical dosimetry assays that can be deployed in the event of a radiation incident to provide exposure assessment. To maintain operational capability and provide training, RENEB runs regular inter-laboratory comparison (ILC) exercises. The RENEB ILC2021 was carried out with all the biological and physical dosimetry assays employed in the network. The focus of this paper is to evaluate the results from 6 laboratories that took part using the gamma-H2AX radiation-induced foci assay. For two laboratories this was their first RENEB ILC. Blood samples were homogenously exposed to 240 kVp X rays (1 Gy/min) to provide calibration data, (0–4 Gy), and a few weeks later three blind coded test samples, (0, 1.2 and 3.5 Gy) were prepared. All samples were allowed a 2 h repair time at 37°C before being transported, on ice packs, to the participating laboratories. On arrival, the samples were processed, scored either manually or automatically for gamma-H2AX foci and dose estimates for the 3 blind coded samples sent to the organizing laboratory. The temperature of samples during transit and the time taken to report the dose estimates were recorded. Subsequent examination of the data from each laboratory used the doses estimates to assign triage categories to the samples. After receipt of the samples, the quickest report of dose estimates was 4.6 h. Analysis of variance revealed that the laboratory carrying out the assay had a significant effect on the foci yield (P < 0.001) for the calibration data, but not on the dose estimates of the blind coded samples (P = 0.101). All laboratories correctly identified the unirradiated and irradiated samples, although the dose estimates for the latter tended to under-estimate the dose. Two participants seriously under-estimated the dose for the highly exposed sample, which resulted in the sample being placed in the lowest triage category not the highest. However, this under-estimation resulted from the samples not remaining cold during shipment, due to a delay in transit and was not related to the experience of the participating laboratory. Overall, the RENEB network laboratories have demonstrated it is possible to quickly identify a recent whole-body acute exposure using the gamma-H2AX assay within the conditions of the ILC. In addition, an ILC provides a useful training and harmonization exercise for laboratories.

RENEB Inter-Laboratory Comparison 2021: The Gamma-H2AX Foci Assay

tumourigenesis in Apc min/+ mice

The application of random effect models to different radiation biomarkers, including cytogenetic, protein-based, and gene-expression based biomarkers, is discussed. Explicit case studies are provided for the latter two scenarios, in which random effect models appear especially attractive as they can cope well with the large inter-individual variation which is typical for these biomarkers.

On the use of random effect models for radiation biodosimetry.

Telomeres are specialised structures at the ends of mammalian chromosomes with many unique properties. Recombinational events at telomeres are more frequent than in the remainder of the genome by seve

Elizabeth A. Ainsbury

Papers

What if a major radiation incident happened during a pandemic? - Considerations of the impact on biodosimetry.

RENEB Inter-Laboratory Comparison 2021: The Gamma-H2AX Foci Assay

tumourigenesis in Apc min/+ mice

On the use of random effect models for radiation biodosimetry.

A possible role for telomerase RNA and telomere length in global mitotic recombination.