We use the additive risk model of Aalen (Aalen, 1980) as a model for the rate of a counting process. Rather than specifying the intensity, that is the instantaneous probability of an event conditional on the entire history of the relevant covariates and counting processes, we present a model for the rate function, i.e., the instantaneous probability of an event conditional on only a selected set of covariates. When the rate function for the counting process is of Aalen form we show that the usual Aalen estimator can be used and gives almost unbiased estimates. The usual martingale based variance estimator is incorrect and an alternative estimator should be used. We also consider the semi-parametric version of the Aalen model as a rate model (McKeague and Sasieni, 1994) and show that the standard errors that are computed based on an assumption of intensities are incorrect and give a different estimator. Finally, we introduce and implement a test-statistic for the hypothesis of a time-constant effect in both the non-parametric and semi-parametric model. A small simulation study was performed to evaluate the performance of the new estimator of the standard error.
Guidelines recommend treatment of latent tuberculosis in patients at increased risk for active tuberculosis. Studies investigating the association of therapy with serious adverse events have not included the entire treated population nor accounted for comorbidities or occurrence of similar events in the untreated general population. Our objective was to estimate the risk of adverse events requiring hospital admission that were associated with therapy for latent tuberculosis infection in the general population.
Using administrative health data from the province of Quebec, we created a historical cohort of all residents dispensed therapy for latent tuberculosis between 1998 and 2003. Each patient was matched on age, sex and postal region with two untreated residents. The observation period was 18 months (from 6 months before to 12 months after initiation of therapy). The primary outcome was hospital admission for therapy-associated adverse events.
During the period of observation, therapy for latent tuberculosis was dispensed to 9145 residents, of whom 95% started isoniazid and 5% started rifampin. Pretreatment comorbid illness was significantly more common among patients receiving such therapy compared with the matched untreated cohort. Of all patients dispensed therapy, 45 (0.5%) were admitted to hospital for a hepatic event compared with 15 (0.1%) of the untreated patients. For people over age 65 years, the odds of hospital admission for a hepatic event among patients treated for latent tuberculosis infection was significantly greater than among matched untreated people after adjustment for comorbidities (odds ratio [OR] 6.4, 95% CI 2.2-18.3). Excluding patients with comorbid illness, there were two excess admissions to hospital for hepatic events per 100 patients initiating therapy compared with the rate among untreated people over 65 years (95% CI 0.1-3.87).
The risk of adverse events requiring hospital admission increased significantly among patients over 65 years receiving treatment for latent tuberculosis infection. The decision to treat latent tuberculosis infection in elderly patients should be made after careful consideration of risks and benefits.
Cites: Chest. 2005 Jul;128(1):116-2316002924
Cites: JAMA. 1999 Mar 17;281(11):1014-810086436
Cites: Am J Respir Crit Care Med. 2006 Oct 15;174(8):935-5217021358
BACKGROUND: Although most epidemiological studies do not support a role for alcohol in the aetiology of pancreatic cancer, an increased risk among heavy drinkers cannot be excluded. METHODS: In a retrospective cohort based on the Swedish Inpatient Register, we analysed the risk of pancreatic cancer among patients admitted to hospital for alcoholism (n=178 688), alcoholic chronic pancreatitis (n=3500), non-alcoholic chronic pancreatitis (n=4952), alcoholic liver cirrhosis (n=13 553), or non-alcoholic liver cirrhosis (n=7057) from 1965 to 1994. Follow up through to 1995 was accomplished by linkage to nationwide registers. Standardised incidence ratios (SIRs) express the relative risks by taking the general Swedish population as reference. To minimise the possible influence of selection bias, we excluded the first year observations. RESULTS: Alcoholics had only a modest 40% excess risk of pancreatic cancer (SIR 1.4, 95% confidence interval (CI) 1.2-1.5). Overrepresented smokers among alcoholics might confound a true SIR of unity among alcoholics to approximately 1.4. SIR among alcoholic chronic pancreatitis patients (2.2, 95% CI 0.9-4.5) was considerably lower than that among non-alcoholic chronic pancreatitis patients (8.7, 95% CI 6.8-10.9), and decreased with increasing duration of follow up in both groups, indicating that most of the excess might be explained by reversed causation from undiagnosed cancers. Among patients with alcoholic liver cirrhosis, the increased risk of pancreatic cancer was also moderate (SIR 1.9, 95% CI 1.3-2.8) while no significant excess risk was found among non-alcoholic liver cirrhosis patients (SIR 1.2, 95% CI 0.6-2.2). CONCLUSIONS: The excess risk for pancreatic cancer among alcoholics is small and could conceivably be attributed to confounding by smoking.
Centre for Digestive Diseases, Division of Hepatology, Karolinska University Hospital, Stockholm, Sweden; Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden. Electronic address: firstname.lastname@example.org.
High alcohol consumption is associated with an increased risk of severe liver disease. Current recommendations suggest it is safe for men to consume 30 grams of alcohol per day. We investigated the association between alcohol consumption early in life and later development of severe liver disease.
We used data on alcohol consumption at conscription to military service from 43,296 men (18-20?years) in Sweden between 1969 and 1970. Outcomes were defined as incident diagnoses of severe liver disease from systematic national registration of clinical events until the end of 2009. A Cox regression model adjusted for body mass index, smoking, use of narcotics, cognitive ability and cardiovascular capacity was applied.
During a mean follow-up of 37.8?years, 383 men developed severe liver disease. Alcohol consumption was associated with an increased risk of development of severe liver disease in a dose-response pattern (adjusted hazard ratio for every one gram/day increase 1.02; 95% CI 1.01-1.02). No evidence of a threshold effect was found. Importantly, a clear trend pointed towards an increased risk of severe liver disease in men who consumed less than 30 grams of alcohol per day.
Alcohol consumption in young men is associated with an increased risk of severe liver disease, up to 39?years later in life. The risk was dose-dependent, with no sign of a threshold effect. Current guidelines for safe alcohol intake in men might have to be revised.
We investigated more than 43,000 Swedish men in their late teens enlisted for conscription in 1969-1970. After almost 40?years of follow-up, we found that alcohol consumption was a significant risk factor for developing severe liver disease, independent of confounders. This risk was dose-dependent, and was most pronounced in men consuming two drinks per day or more.
To assess the alcohol drinking patterns in a cohort of primary sclerosing cholangitis (PSC) patients and the possible influence on the development of fibrosis.
Ninety-six patients with PSC were evaluated with a validated questionnaire about a patient's lifetime drinking habits: the lifetime drinking history (LDH) questionnaire. In addition, clinical status, transient elastography and biochemistry values were analysed and registered. Patients were defined as having either significant or non-significant fibrosis. Significant fibrosis was defined as either an elastography value of = 17.3 kPa or the presence of clinical signs of cirrhosis. Patients were divided into two groups depending on their alcohol consumption patterns; no/low alcohol consumption (one drink or unit/d) and moderate/high alcohol consumption (= 1 drink or unit/d). LDH data were calculated to estimate lifetime alcohol intake (LAI), current alcohol intake, drinks per year before and after diagnosis of PSC. We also calculated the number of episodes of binge-drinking (defined as consuming = 5 drinks per occasion) in total, before and after the diagnosis of PSC.
The mean LAI was 3882 units of alcohol, giving a mean intake after onset of alcohol consumption of 2.6 units per week. Only 9% of patients consumed alcohol equal to or more than one unit per day. Current alcohol intake in patients with significant fibrosis (n = 26) was less than in patients without significant fibrosis (n = 70), as shown by lower values of phosphatidylethanol (B-PEth) (0.1 ?mol/L vs 0.33 ?mol/L, respectively, P = 0.002) and carbohydrate-deficient transferrin (CDT) (0.88% vs 1.06%, respectively, P = 0.02). Self-reported LAI was similar between the two groups. Patients with significant fibrosis reduced their alcohol intake after diagnosis from 103 to 88 units per year whereas patients without fibrosis increased their alcohol intake after PSC diagnosis from 111 to 151 units/year. There were no correlations between elastography values and intake of alcohol (units/year) (r = -0.036).
PSC patients have low alcohol consumption. The lack of correlation between fibrosis and alcohol intake indicates that a low alcohol intake is safe in these patients.
Alcoholic cirrhosis is associated with hyperactivation and dysregulation of the immune system. In addition to its ability to increase risk for infections, it also may increase the risk for autoimmune diseases. We studied the incidence of autoimmune diseases among patients with alcoholic cirrhosis vs controls in Denmark.
We collected data from nationwide health care registries to identify and follow up all citizens of Denmark diagnosed with alcoholic cirrhosis from 1977 through 2010. Each patient was matched with 5 random individuals from the population (controls) of the same sex and age. The incidence rates of various autoimmune diseases were compared between patients with cirrhosis and controls and adjusted for the number of hospitalizations in the previous year (a marker for the frequency of clinical examination).
Of the 24,679 patients diagnosed with alcoholic cirrhosis, 532 developed an autoimmune disease, yielding an overall increased adjusted incidence rate ratio (aIRR) of 1.36 (95% confidence interval [CI], 1.24-1.50). The strongest associations were with Addison's disease (aIRR, 2.47; 95% CI, 1.04-5.85), inflammatory bowel disease (aIRR, 1.56; 95% CI, 1.26-1.92), celiac disease (aIRR, 5.12; 95% CI, 2.58-10.16), pernicious anemia (aIRR, 2.35; 95% CI, 1.50-3.68), and psoriasis (aIRR, 4.06; 95% CI, 3.32-4.97). There was no increase in the incidence rate for rheumatoid arthritis (aIRR, 0.89; 95% CI, 0.69-1.15); the incidence rate for polymyalgia rheumatica decreased in patients with alcoholic cirrhosis compared with controls (aIRR, 0.47; 95% CI, 0.33-0.67).
Based on a nationwide cohort study of patients in Denmark, alcoholic cirrhosis is a risk factor for several autoimmune diseases.
The aim of this study was to determine the risk of developing primary liver cancer in patients with a diagnosis of alcoholism, liver cirrhosis, or both. Three population-based, mutually exclusive cohorts were defined on the basis of hospital discharge diagnosis between 1965 and 1983. Complete follow-up through 1984--excluding the first year of follow-up--showed that among 8,517 patients with a diagnosis of alcoholism, 13 cancers occurred, vs. 4.2 expected (standardized incidence ratio (SIR) = 3.1; 95% confidence interval (CI) = 1.6 to 5.3); among 3,589 patients with liver cirrhosis, 59 cancers occurred, vs. 1.7 expected (SIR = 35.1; 95% CI = 26.7 to 45.3), and among 836 patients with both diagnoses, 11 cancers occurred, vs. 0.3 expected (SIR = 34.3; 95% CI = 17.1 to 61.3). Thus, alcoholism alone entailed a moderately increased risk and alcoholism with liver cirrhosis did not increase the high relative risk for liver cancer more than cirrhosis alone. We conclude that alcohol intake may be a liver carcinogen only by being causally involved in the development of cirrhosis; and further, that the risk of developing liver cancer following cirrhosis in this population is similar to or higher than that after chronic hepatitis-B-virus infection in other Western countries.
BACKGROUND: A number of studies have shown variations in the occurrence of alcoholism between different socioeconomic groups and occupations, but it has not been clear to what extent this is related to the average alcohol consumption in the same socioeconomic groups or occupations. METHODS: The relationship between socioeconomic group and occupation and hospital discharge 1981-1983 due to 'diagnoses related to alcoholism' (AD) (alcohol psychosis, alcoholism, and alcohol intoxication) and liver cirrhosis was studied in a cohort of 375,035 men and 140,139 women in 13 counties in Sweden who had reported the same occupation in the censuses of 1960 and 1970. Data on alcohol consumption in different socioeconomic groups and occupations were collected from a conscription investigation and from the Swedish twin registry with data from 1969/70 and 1973 respectively. RESULTS: Intermediate or higher non-manual employees had lower risk of AD as well as of liver cirrhosis compared to manual workers for both sexes. Among males several, mostly blue-collar, occupations had increased relative risks of AD. A high level of association was found between the relative risks of AD and liver cirrhosis in socioeconomic groups, and the relative risk of AD in occupations, and the average alcohol consumption in the same socioeconomic groups/occupations among males. Such an association was not evident among women. CONCLUSION: The study shows, contrary to previous Swedish evidence, that there is a strong relationship between the incidence of alcoholism in socioeconomic groups and occupations and the average alcohol consumption in these groups among men.
We studied the alpha-radiation risks in patients who received injections of Thorotrast, an X-ray contrast medium used in Europe, Japan, and the United States from 1930 to 1955. Thorotrast was composed of thorium dioxide (ThO2) and Th-232, a naturally occurring radionuclide. Because the physical half-life of ThO2 is 14 billion years and Thorotrast is hardly eliminated from the body, tissues in which it was deposited are irradiated by alpha-radiation for the entire lifetime of the subject. The dosimetry of Thorotrast patients is very complicated, but currently its reliability is quite high compared with other irradiated populations. The major causes of the death of Thorotrast patients are liver cancer, liver cirrhosis, leukemia, and other cancers. Three histologies of liver cancer are found: cholangiocarcinoma, hepatocellular carcinoma, and angiosarcoma. Although cholangiocarcinoma is the most frequent, angiosarcoma is characteristic of alpha-radiation. Among blood neoplasms with a higher incidence of increase than the general population, erythroleukemia and myelodysplastic syndrome were remarkable. Thorotrast patients exhaled a high concentration of radon (Rn-220), a progeny of Th-232, but no excesses of lung cancer in the patients of Japan, Germany, and Denmark were reported. Mutation analyses of p53 genes and loss of heterozygosity (LOH) studies at 17p locus were performed to characterize the genetic changes in Thorotrast-induced liver tumors. Interestingly, LOH, supposedly corresponding to large deletions was not frequent; most mutations were transitions, also seen in tumors of the general population, suggesting that genetic changes of Thorotrast-induced cancers are mainly delayed mutations, and not the result of the direct effects of radiation.
Despite advances in the treatment of hepatocellular carcinoma (HCC), a great proportion of patients are eligible only for palliative therapy for reasons of advanced-stage disease or poor hepatic reserve. The use of transarterial chemoembolization (TACE) in the palliation of non-resectable HCC has shown a survival benefit in European and Asian populations. The aim of this study was to assess the efficacy of TACE by analysing overall 5-year survival, interval changes of tumour size and serum alpha-fetoprotein (AFP) levels in a prospective North American cohort.
From September 2005 to December 2010, 46 candidates for TACE were enrolled in the study. Collectively, they underwent 102 TACE treatments. Data on tumour response, serum AFP and survival were prospectively collected.
In compensated cirrhotic patients, serial treatment with TACE had a stabilizing effect on tumour size and reduced serum AFP levels during the first 12 months. Overall survival rates at 1, 2 and 3 years were 69%, 58% and 20%, respectively. Younger individuals and patients with a lower body mass index, affected by early-stage HCC with involvement of a single lobe, had better survival in univariate analysis. After adjustment for risk factors, early tumour stage (T1 and T2 vs. T3 and T4) at diagnosis was the only statistically significant predictor for survival.
In compensated cirrhotic patients, TACE is an effective palliative intervention and HCC stage at diagnosis seems to be the most important predictor of longterm outcomes.
Cites: Ann Surg Oncol. 2000 Sep;7(8):593-60011005558