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PubMed1994

Parametric analysis of rank transformed data for statistical assessment of genotoxicity data with examples from cultured mammalian cells.

The utility of rank transformation followed by parametric analysis of the ranks has been assessed for determination of the statistical significance of genotoxicity data. Both nonparametric and parametric analytical methods have defects when used to assess the significance of results from routine regulatory tests. Superficially, the rank transformation method followed by parametric analysis of ranks appears to be an ideal solution. However, we considered that such a test might suffer a substantial loss of power when used to analyse normally distributed data with very low sample replication. To test this hypothesis we took 22 data sets from five 'borderline' positive compounds in mouse lymphoma treat-and-plate assays where treatment-related increases were between 1.5- and 3-fold the control and analysed these results by Dunnett's t-test using rank transformed data and weighted, untransformed data. In theory these mouse lymphoma data should show the rank transformation system at its worst in comparison with parametric methodology using weighted data. Surprisingly, the rank transformation methodology showed no loss of power and, overall, performed more consistently than the weighted data methodology. Based on this limited number of data sets, rank transformation followed by parametric analysis of ranks seems to be an approach very suitable for genotoxicity assays in general, particularly where distributions are non-normal or of uncertain form. It combines the general applicability of non-parametric methods with the power of parametric analyses. However, the methodology still requires to be further validated in use and by computer simulation.

Animals↗
PubMed1984

A method for measuring the non-random bias of a codon usage table.

We describe a new statistical method for measuring bias in the codon usage table of a gene. The test is based on the multinomial and Poisson distributions. The method is used to scan DNA sequences and measure the strength of codon preference. For E. Coli we show that the strength of codon preference is related to levels of gene expression. The method can also be used to compare base triplet frequencies with those expected from the base composition. This second type of codon bias test is useful for distinguishing coding from non-coding regions.

Base Sequence↗
PubMed2000

Primary renal vasculitis in Norfolk--increasing incidence or increasing recognition?

BACKGROUND: The incidence of renal vasculitis has previously been estimated using histological definitions or only a single clinical diagnosis, e.g. Wegener's Granulomatosis (WG). Our hospital is the single referral centre for the former Norwich Health Authority (NHA) which encompasses a stable, homogeneous, well-defined and studied population. We estimated the overall incidence of primary renal vasculitis and the incidence within individual clinical disease classifications. METHODS: All cases of primary renal vasculitis diagnosed within the NHA over 66 months (1992-1997) were identified by review of renal biopsies, the Norfolk Vasculitis Register, hospital discharge summaries and plasmapheresis records. Patients were classified using the 1990 American College of Rheumatology criteria for Polyarteritis Nodosa (PAN), Churg Strauss Syndrome (CSS) and Henoch-Schonlein Purpura; the Chapel Hill Consensus Conference Definitions for Microscopic Polyangiitis (mPA) and the Lanham criteria for CSS. Incidence figures were calculated using the NHA adult population of 413747 (1994). Ninety-five per cent confidence intervals (C.I.) were calculated using the poisson distribution. RESULTS: The overall annual incidence for primary renal vasculitis was 18/million (C.I. 12.9-24.4). The annual incidence of renal involvement of individual diseases was as follows: WG 7.9/million (95% C.I. 4.7-12.5); mPA 7.5/million (95% C. I. 4.4-12.0); PAN 7.0/million (95% C.I. 4.0-11.4); HSP 3.1/million (95% C.I. 1.2-6.3); CSS 1.3/million (95% C.I. 0.3-3.9). CONCLUSIONS: The annual incidence for primary renal vasculitis overall and the individual subtypes in Norfolk is much higher than previous European estimates. This may reflect an increasing incidence in primary renal vasculitis with time or underestimation in previous studies. However the incidence of renal vasculitis in our population is markedly lower than reported in Kuwait. There may therefore be true variation in incidence between populations which could have implications for the aetiology of primary vasculitis.

Adult↗
PubMed1997

Cohort mortality study of rubber and plastics product makers in Italy.

A retrospective cohort mortality study was carried out in 20 industrial factories in the Local Health Unit Bologna Sud (Emilia Romagna, Italy), where different rubber and plastics products were manufactured. The cohort consisted of 925 subjects (578 males and 347 females) employed for at least six months continuously; follow-up was between the beginning of operation of each factory, ranging between mid fifties and mid seventies, and 31 December 1989. For those exposed more than one year cause specific Standardized Mortality Ratios (SMRs) were computed using regional rates for comparison, 90% confidence intervals (CI) were calculated assuming the Poisson distribution. Among the 748 subjects employed for more than one year (457 males and 291 females) there were no lost to follow-up, 54 individuals were dead (41 males and 13 females) and for three subjects the cause of death was unknown. The results showed that all causes mortality was above expectancy in the total cohort (SMR = 123; 54 Obs; 90% CI = 97-154), among males (SMR = 117; 41 Obs; 90% CI = 89-152) and females (SMR = 143; 13 Obs; 90% CI = 85-228). Increased mortality for all malignant tumours was observed in the total cohort (SMR = 150; 25 Obs; 90% CI = 104-209) and for both genders. All nine lung cancer cases were observed among males, the SMR was equal to 218 and was statistically significant; seven cases occurred at duration of exposure less than 10 years and six at latency up to 20 years. The interpretation in terms of causality of the present investigation is limited by the small number of observations and by exposure definition solely in terms of employment in the study factories; nonetheless the results are indicating the existence, in this group of rubber and plastics product makers, of an adverse health effect which deserve further investigation.

Adult↗
PubMed1984

Serologic evidence for widespread infection with La Crosse and St. Louis encephalitis viruses in the Indiana human population.

The vast under-reporting of La Crosse virus and St. Louis encephalitis virus infections in Indiana residents was evident when numerous inapparent infections were detected retrospectively using serum dilution neutralization analyses of serum obtained in November 1978-April 1979 from 10,208 persons (0.2% of the state's population). An antibody prevalence rate of 3.6% to St. Louis encephalitis virus was detected in the sample population as a whole, with rates as high as 13.2% for residents of individual counties. The estimated average annual rate of infection for the whole population was 0.32%. The antibody prevalence to La Crosse virus in the sample population as a whole was 2.3%, with rates ranging up to 12.5% for residents of individual counties. The estimated average annual rate of infection for the whole population was 0.29%. The epidemiologic behavior of the two viruses was quite different. Age-specific antibody prevalence for St. Louis encephalitis virus indicated a pattern of endemic infection existed in the population as a whole; antibody prevalence rose as the population aged. However, many other infections apparently occurred during the 1975 and earlier epidemics. Age-specific antibody prevalence for La Crosse virus indicated a typical pattern of endemic infection was present. The antibody prevalence to La Crosse virus was best described by the Poisson distribution and that of St. Louis encephalitis virus by the negative binomial distribution. These data support the hypothesis that St. Louis encephalitis virus primarily produces intermittent epidemics in the Midwest while La Crosse virus produces continuous seasonal endemic infections. However, evidence suggestive of a low level of interepidemic St. Louis encephalitis virus infection in the population was also obtained. Computer-drawn synagraphic mapping view "maps" of regional antibody prevalence rates demonstrated the existence of distinct foci of infection for each virus in the human population.

Adolescent↗
PubMed2002

Track counting and the blots.

Track detectors are very useful devices for alpha particle dosimetry. Alpha particle tracks are registered on the detector's surface. The registered track density is proportional to the dose. When the dose is low the greatest effect on the total error of dose assessment has a Poisson distribution (random error). When the dose is high, the greatest contribution to the total error is the effect of track overlapping (systemic error). This paper describes how to solve the problem of overlapping tracks when a computer aided image analyser is used. The formulae presented in this paper were proven in the international calibration programme run by NRPB and EU.

Calibration↗
PubMed2006

Dose dependences of radiation induced yield in mixed radiation fields.

A theoretical model that describes dose dependences of trap filling (radiation yield) in mixed radiation fields consisting of two components is proposed. The model consists of one type of electron traps and one type of hole traps and assumes as an initial step the creation of two types of tracks, each represented by some volume with a uniform electron-hole pair density, different for each track. The relaxation process that follows comprises interband recombination, trapping of electrons and holes, and recombination of electrons with trapped holes and of holes with trapped electrons. These processes result in filled traps in amounts depending on the absorbed dose in the track and the number and types of tracks created in a given region of irradiated matter. The summation over the matter with areas of different degrees of overlapping (assuming poisson distribution of the created tracks), gives expressions for the dependences of trap filling as a function of doses for separated and simultaneous irradiation. It is shown that the key parameters determining the behaviour of the dose dependences are the ratios between the doses in the separated tracks and the average doses delivered on the irradiated matter by the separated components of the mixed field. If the ratios of the average dose to the track dose are low, the dose dependences will be linear. In the opposite limiting case the dose dependencies go to saturation. The linear and additive approximations of dose dependences in a mixed field are valid at low doses only.

Computer Simulation↗
PubMed2006

A comparative review of charged particle microbeam facilities.

At the low doses (and low dose rates) relevant to environmental and occupational radiation exposure (0-50 mSv), which are of practical concern for radiation protection, very few cells in the human organism experience more than one traversal by densely ionising particles in their lifetime, the intervals between the tracks, if any, typically being months or years. The biological effects of exactly one particle are not well known and cannot be simulated in vitro by conventional broad-beam exposures, due to the random Poisson distribution of tracks. Charged particle microbeam facilities are a unique tool that allows targeting of single cells and analysis of the induced damage on a cell-by-cell basis. In the past few years, many charged particle microbeam facilities for radiobiology have come into operation or are under development worldwide. Different experimental designs have been adopted at various laboratories regarding the achievement of micrometre (or sub-micrometre) ion beam size, by mechanical collimation or focusing, particle detection, and cell recognition and positioning systems. The different approaches are reviewed and discussed in this paper.

Cell Culture Techniques↗
PubMed1997

Germinal centre CD4+ T cells are an important site of HIV replication in vivo.

OBJECTIVE: CD4+ T cells are the main target for HIV. However, the highest HIV antigen concentration in infected subjects accumulates on the cell surface of follicular dendritic cells in the germinal centres of the lymphoid tissue. Germinal centres contain a T-helper cell subset which expresses CD57 molecules. Here we analysed virus replication and viral load in CD57+CD4+ germinal centre T cells and in the CD4+ T cells found mostly outside germinal centres (CD57-CD4+). METHODS: Peripheral blood mononuclear cells and lymph-node cells were prepared, stained for CD4 and CD57 and purified by FACS. Defined cell numbers of CD4+CD57+ cells and CD4+CD57- cells were sorted directly into polymerase chain reaction (PCR) tubes by FACS, equipped with an automated cell deposition unit and analysed by PCR to detect proviral DNA. Based on Poisson distribution, the expected level of infection was calculated. Viral replication was determined by amplifying double-spliced, single-spliced, and full-length transcripts of HIV using serially diluted cDNA of the FACS-sorted cells. RESULTS: An up to 10-fold higher frequency of infected cells was found in the CD57+CD4+ germinal centre T cells compared with CD57-CD4+ T cells. Furthermore, active viral replication was detected almost exclusively in the CD57+CD4+ T cells. CONCLUSIONS: The CD57+CD4+ germinal centre T cells are one of the sites of HIV infection and replication that may play a pivotal role in the pathogenesis of HIV infection.

Base Sequence↗
PubMed2000

Discontinuing or withholding primary prophylaxis against Mycobacterium avium in patients on successful antiretroviral combination therapy. The Swiss HIV Cohort Study.

OBJECTIVE: To assess the safety of discontinuing or withholding primary prophylaxis against disseminated Mycobacterium avium infection (MAC) in HIV infected patients on successful antiretroviral combination therapy. SETTING: National prospective multicentre cohort study. DESIGN: HIV-infected patients were eligible for the analysis if: (i) they had a history of at least two CD4 cell counts < 50 x 10(6)/l; (ii) they had never had MAC; (iii) they had discontinued or never begun primary prophylaxis against MAC; (iv) they received antiretroviral therapy and demonstrated an increase in CD4 cell counts to > or = 100 x 10(6)/l that was sustained for at least 12 weeks. From this time point until last follow-up, incidence of disseminated MAC disease was measured, and 99% confidence intervals were calculated assuming a Poisson distribution of events. RESULTS: Two-hundred and fifty-three patients (22.5% female; median age, 37 years, 30% injecting drug users) were eligible for analysis. Sixty-six per cent were in Centers for Disease Control and Prevention (CDC) stage C, and 28% were in CDC stage B. Their median nadir CD4 cell count was 10 x 10(6)/l, the median duration of CD4 cell count < 50 x 10(6)/l was 12 months. During a total follow-up of 364.3 patient-years there was no case of disseminated MAC. The one-sided 99% confidence limit for incidence density of MAC was 1.3 per 100 person-years. CONCLUSION: Discontinuing or withholding primary prophylaxis against MAC is safe in patients who have a sustained increase in their CD4 cell count to > or = 100 x 10(6)/l.

AIDS-Related Opportunistic Infections↗
PubMed2001

Use of a stochastic model to develop understanding of the impact of different patterns of antiretroviral drug use on resistance development.

OBJECTIVE: To use a stochastic model to gain insights into the consequence for resistance development of different drug use patterns. METHODS: We consider use of three drugs (A, B and C) where for each drug one and only one viral mutation is associated with ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. For drug A mutation is a, etc. We define eight populations of short-lived infected cells that live 1 day: Vo with no mutations a, b, c; Va with mutation a only, Vab with mutations a and b, etc. A random number generator was used to determine whether mutations occur in any one round of replication and to sample from a Poisson distribution to determine for each cell the number of cells of the same population created in the next generation, using the R operative at that time. Values of R depended on drug exposure, cost of resistance and availability of target cells. RESULTS: Treatment strategies and the resulting percentage (over 100 runs) developing full "resistance" in 1500 days (Vabc not equal 0) were: (i) ABC 1500 days 0%; (ii) A 300 days, AB 300 days, ABC 900 days 100%; (iii) AB 300 days, ABC 1200 days 33%; (iv) ABC 2/3 1500 days 15%; (v) ABC 1/2 1500 days 100%; (vi) ABC 50 days, no drugs 50 days, for 1500 days 1%, where ABC 2/3 means on-drug for 2 days in every 3, ABC 1/2 represents on-drug for 1 day in every 2, and represents suboptimal adherence. CONCLUSIONS: This model helps to develop understanding of key principles concerning development of resistance under different patterns of treatment use.

Anti-HIV Agents↗
PubMed1999

Confidence intervals for low-level, paired counting.

Neyman-Pearson principles are briefly discussed and 95% confidence intervals of the form [0, ##.##] are presented. Use is made of the fact that the probability of the difference of two random variables, each with a Poisson distribution, can be expressed in terms of modified Bessel functions of integral order and elementary functions. The validity of the values is discussed.

Confidence Intervals↗
PubMedDate not supplied

Intracoronary thallium-201 assessment of thrombolysis in acute myocardial infarction. Validation of the method of imaging before and after therapy.

In order to study acute changes in perfusion with intracoronary thrombolytic therapy, we have used ten times the pretherapy intracoronary thallium-201 dose for the posttherapy study. Because of the larger posttherapy dose, the posttherapy images had ten times as many counts as the pretherapy images. Since the change in image quality between the pretherapy and posttherapy studies might affect interpretation, we studied the effect of image statistics on interpretation of perfusion scintigraphy. The pretherapy and posttherapy images were scored on a four-point scale in five segments on each of three views. In 31 patients, Poisson-distributed pseudorandom noise was added to the posttherapy study in order to match the statistical accuracy of the pretherapy study. A blinded interpretation of the pretherapy and posttherapy noise-added images was performed in the same way as the initial unblinded interpretation. The mean difference between the unblinded pretherapy and posttherapy scores (the improvement in thallium distribution with therapy) was 2.5+/-0.8 (standard error) compared with the difference between the blinded pretherapy and posttherapy noise-added scores which was 2.6+/-1.0. The correlation between readings of similar pairs of data was higher than the correlation between pretherapy and posttherapy studies. Thus, the difference in statistic quality of the pretherapy and posttherapy studies did not affect the interpretation of these studies. Therefore, our evaluation of pretherapy and posttherapy studies using a ten-fold increase in thallium-201 dosage is valid.

Coronary Vessels↗
PubMed1996

Violent methods associated with high suicide mortality among the young.

OBJECTIVE: To present rates and trends in suicide methods, and associations between these, in male and female adolescents in the age groups 15 through 19 years and 20 through 24 years in Finland from 1947 through 1991. METHOD: Suicide rates were calculated on the basis of the mean same-age population, and suicide trends by each method were analyzed by using the Poisson regression model. For the rates and trends, 95% confidence intervals based on the Poisson distribution were calculated. RESULTS: The suicide rate revealed a sharp and significant increase between 1965 and 1975 for both male age groups. Firearms and hanging accounted for the majority of that increase. These figures, however, were not accompanied by similar changes in the availability of firearms during that period. Moreover, an increased total suicide rate as well as that by automobile exhaust fumes in young adults after 1982 coincided with a widely presented Finnish movie which featured this method of committing suicide. In young women, however, intake of solids and liquids remained the most common suicide method. CONCLUSION: Suicide rates increased, especially by violent methods, which contributed to the high suicide mortality rate among the young. These methods, except firearms, however, are often difficult to restrict. This fact underlines the importance of the integration of various preventive measures of cooperation between mental health professionals and other authorities and of the recognition and care of young people at high suicide risk.

Adolescent↗
PubMed1994

Suicide as an outcome for medical disorders.

The association between suicide and medical disorder has not received as much attention as the association between suicide and psychiatric disorder. We identified by statistical overview medical disorders with an altered suicide risk. We found reports on the mortality of 63 medical disorders (ICD9 001-289, 320-999) said to have an altered suicide risk. English-language reports were located on MEDLINE with the search terms "disease name with mortality and follow-up"; and from the reference lists of these reports. We abstracted 235 reports of mortality studies of medical disorders with 2 years or more of follow-up, less than 10% loss of subjects, observed numbers of suicides given, and either the expected number or the facts from which to derive this. The ratio of the sum of the observed to the sum of the expected suicides, for each disorder, tested by the Poisson distribution gave an assessment of altered risk of death from suicide. Increased risk (p < 0.05) was seen for HIV/AIDS, malignant neoplasms as a group, head and neck cancers, Huntington disease, multiple sclerosis, peptic ulcer, renal disease, spinal cord injury, and systemic lupus erythematosus. Inconclusive evidence for increased risk was observed for amputation, heart valve replacement and surgery, disorders of the intestine (Crohn disease, ileostomy, ulcerative colitis), hormone replacement therapy, alcoholic liver disease, neurofibromatosis, systemic sclerosis, and Parkinson disease. Pregnancy and the puerperium had decreased risks (p < 0.05). There was no evidence of either increased or decreased risk for any of the other disorders studied.

Disease↗
PubMed2005

The influence of partner type and risk status on the sexual behavior of young men who have sex with men living with HIV/AIDS.

OBJECTIVES: The influence of partner type and risk status on the unprotected sexual behavior of young men living with HIV (YMLH) who have sex with men is examined. METHODS: Sexual behavior and sexual partner characteristics of 217 YMLH recruited from adolescent care clinics in 4 AIDS epicenters (Los Angeles, San Francisco, New York, and Miami) were assessed. YMLH were categorized by sexual behavior pattern, and sexual partners were classified by type and risk status. Generalized linear modeling employing overdispersed Poisson distribution was used to analyze the effect of partner type and partner risk status on unprotected sex acts. RESULTS: Most YMLH (62%) reported multiple partners, 26% reported 1 sexual partner, and 12% reported abstinence in the past 3 months. Approximately 34% of polygamous and 28% of monogamous youth engaged in unprotected sex. Monogamous youth were most likely to have unprotected sex with HIV-positive partners. Polygamous youth were most likely to have unprotected sex with HIV-positive partners, irrespective of whether the partner was regular or casual. For polygamous YMLH, unprotected sex did not differ among single-time/new partners with different risk levels. CONCLUSIONS: Partner characteristics influence the condom use behavior of YMLH. YMLH make decisions regarding condom use based on perception of their partner's risk. Preventive interventions must include skills for acquiring accurate information about partner risk status and education regarding the health risks of unprotected sex with HIV seroconcordant partners.

Adolescent↗
PubMed2005

Analysis of case-crossover designs using longitudinal approaches: a simulation study.

BACKGROUND: Application of case-crossover designs provides an alternative to time-series analysis for analyzing the health-related effects of air pollution. Although some case-crossover studies can control for trend and seasonality by design, to date they have been analyzed as matched case-control studies. Such analyses may exhibit biases and a lower statistical efficiency than traditional time series analyzed with Poisson. METHODS: In this article, case-crossover studies are treated as cohort studies in which each subject is observed for a short period of time before and/or after the event, thus making possible analyzing with Andersen-Gill and generalized linear mixed models. We conducted a simulation study to compare the behavior of these models applied to case-crossover designs with time series analyzed with Poisson and with case-crossover analyzed by conditional logistic regression. To this end, we created a random variable that follows a Poisson distribution of low (2/day) and high mean events (22/day). This variable is a function of an unobserved confounding variable (that introduces trend and seasonality) and data on small particulate matter (PM10) from Barcelona. In addition, scenarios were created to assess the effect on exposure exerted by autocorrelation and the magnitude of the pollutant coefficient. RESULTS: The full semisymmetric design analyzed with generalized linear mixed models yields good coverage and a high statistical power for air-pollution effect magnitudes close to the real values but shows bias for high effect magnitudes. This bias seems to be attributable to autocorrelation in the exposure variable. CONCLUSIONS: Longitudinal approaches applied to case-crossover designs may prove useful for analyzing the acute effects of environmental exposures.

Air Pollutants↗
PubMed2000

Individual reproductive success and effective population size in the greater white-toothed shrew Crocidura russula.

In order to investigate the determinants of effective population size in the socially monogamous Crocidura russula, the reproductive output of 44 individuals was estimated through genetic assignment methods. The individual variance in breeding success turned out to be surprisingly high, mostly because the males were markedly less monogamous than expected from previous behavioural data. Males paired simultaneously with up to four females and polygynous males had significantly more offspring than monogamous ones. The variance in female reproductive success also exceeded that of a Poisson distribution (though to a lesser extent), partly because females paired with multiply mated males weaned significantly more offspring. Polyandry also occurred occasionally, but only sequentially (i.e. without multiple paternity of litters). Estimates of the effective to census size ratio were ca. 0.60, which excluded the mating system as a potential explanation for the high genetic variance found in this shrew's populations. Our data suggest that gene flow from the neighbourhood (up to one-third of the total recruitment) is the most likely cause of the high levels of genetic diversity observed in this shrew's subpopulations.

Animals↗