Biomedical subjects
P K Andersen
Publications and source records attributed to P K Andersen.
Commentary: Secular trends in the context of competing risks.
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A prospective study showing long-term infection with human papillomavirus 16 before the development of cervical carcinoma in situ.
Human papillomavirus 16 (HPV16) is a predominant cause of cervical neoplasia. However, no population-based study with long-term follow-up has clarified the temporal relationship between HPV16 infection and occurrence of carcinoma in situ, or the importance of recurrent or persistent infection. This nested case-control study was carried out in a population-based cohort of women participating in cytological screening whose initial smear, taken in 1969-1995, was normal. During up to 26 years of follow-up, carcinoma in situ was diagnosed in 484 eligible women. Archival smears from these women were compared with smears from 619 individually matched controls. After DNA extraction, a highly sensitive PCR system was used to detect HPV16. Among case women, the prevalence of HPV16 positivity was 56% at the time of diagnosis. The relative risk of cervical carcinoma in situ increased from 3.6 (95% confidence interval, 1.2-11.0) 13 years before diagnosis to 11.1 (95% confidence interval, 5.5-22.2) 1 year before diagnosis. Having a positive smear at entry to the cohort increased risk >5-fold, whereas having persistent infection with HPV in two subsequent smears increased risk 30-fold. We estimated that among HPV16-positive women, the median incubation period from infection to carcinoma in situ was 7-12 years. We conclude that evidence of persistent and/or recurrent infection is associated with a drastically higher risk of cervical carcinoma in situ than occasional infection with HPV16.
Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study.
BACKGROUND: Infection with certain types of human papillomavirus (HPV), which is common among young women, increases the risk of cervical cancer. However, less than 1% of young women positive for oncogenic types of HPV develop cervical cancer. We investigated whether the amount of HPV DNA is a useful predictor of progression to cervical carcinoma in situ. METHODS: We estimated the amount of HPV 16 DNA by a PCR that uses the 5'-exonuclease (Taqman) method, in 478 women with cervical carcinoma in situ and 608 individually matched controls. To adjust for differences in the amount of genomic DNA between samples, we estimated the amount of a nuclear gene (beta-actin). We studied multiple smears (total 3835 archived samples) from each woman, taken over periods of up to 26 years, that covered normal cytology to development of cervical cancer. FINDINGS: The risk of cervical carcinoma in situ increased with the amount of HPV 16 DNA. Analysis of the first smear from each woman, collected a mean of 7.8 years before cancer diagnosis, showed that women with the 20% highest amount of HPV 16 DNA were at a 60-fold higher risk of developing cervical carcinoma in situ than women negative for HPV 16. The first smear samples were classified as normal by squamous-cell cytology. INTERPRETATION: Analysis of the amount of HPV DNA can predict cancer risk at a stage when current screening methods are uninformative. Testing for the amount of HPV 16 DNA during gynaecological health checks might strikingly improve our ability to distinguish between infections that have a high or low risk of progressing into cervical cancer.
Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study.
BACKGROUND: Persistent infection with certain types of human papillomavirus (HPV) is believed to be a prerequisite for the development of cervical neoplasia. Persistence may depend on certain characteristics, such as viral load, which has so far been given little attention. We investigated the association between HPV 16 viral load and cervical carcinoma in situ. METHODS: We did a nested case-control study of women participating in cytological screening in Sweden. We used a sensitive quantitative PCR assay to estimate HPV 16 load in multiple smears for each woman, taken during a period of up to 26 years before diagnosis. We calculated C, values, which decrease as the number of viral DNA copies increases. FINDINGS: 2081 smears from 478 cases and 1754 smears from 608 controls were tested. Among cases, we found a consistently increased load of HPV 16 already 13 years or more before diagnosis, and when many smears were still cytologically normal. Women with high HPV 16 viral loads were at least 30 times the relative risk of HPV-16-negative women more than a decade before diagnosis. The increase in relative risk was constant over time. About 25% of women (95% CI 0.12-0.32) infected with a high viral load before age 25 years developed cervical carcinoma in situ within 15 years. INTERPRETATION: Cervical carcinoma in situ associated with HPV 16 occurs mainly in HPV-16-positive women who have consistently high viral loads long term. Women at high risk could be identified by use of a quantitative HPV test in addition to cytological screening.
[Should all younger patients with breast cancer be offered adjuvant cytotoxic chemotherapy?].
The aim of the study was to investigate whether young age at diagnosis is a negative prognostic factor in primary breast cancer and how stage of disease at diagnosis and treatment may influence such an association. It was conducted as a retrospective cohort study based on a population-based data-base of breast cancer diagnosis with detailed information on tumour characteristics, treatment regimens, and vital status and included 10,356 patients with primary breast cancer less than 50 years of age at diagnosis. The main outcome measures were relative risk of dying within the first ten years after diagnosis according to age at diagnosis, adjusted for effect of known prognostic factors and expected mortality. Overall, young patients with low risk disease who did not receive adjuvant treatment had a significantly increasing risk of dying with decreasing age at diagnosis (adjusted relative risk: 45-49 years: 1 (reference); 40-44 years: 1.12 (0.89-1.40); 35-39 years: 1.40 (1.10-1.78); < 35 years: 2.18 (1.64-2.89). However, a similar trend was not seen in young patients who received adjuvant cytotoxic therapy. We found the same difference as above when comparing women receiving no treatment with those receiving adjuvant cytotoxic therapy within strata of node negative patients and patients with the same tumour size. In conclusion, the negative prognostic effect of young age is almost exclusively seen in women diagnosed with low risk disease not receiving adjuvant cytotoxic therapy, whereas young women who receive adjuvant cytotoxic therapy have the same prognosis as middle-aged women. These results suggest that young women with breast cancer, on the basis of age alone, should be regarded as high risk patients and be given adjuvant cytotoxic therapy.
Multi-state models for bleeding episodes and mortality in liver cirrhosis.
Data from a controlled clinical trial in liver cirrhosis are used to illustrate that multi-state models may be a useful tool in the analysis of data where survival is the ultimate outcome of interest but where intermediate, transient states are identified. We compare models for the marginal survival time distribution with models including transient states, both with respect to their clinical interpretation and with respect to the precision of survival probability estimates obtained from the various models.
Factors influencing the effect of age on prognosis in breast cancer: population based study.
OBJECTIVE: To investigate whether young age at diagnosis is a negative prognostic factor in primary breast cancer and how stage of disease at diagnosis and treatment influences such an association. DESIGN: Retrospective cohort study based on a population based database of patients with breast cancer containing detailed information on tumour characteristics, treatment regimens, and survival. SETTING: Denmark. SUBJECTS: 10 356 women with primary breast cancer who were less than 50 years old at diagnosis. MAIN OUTCOME MEASURES: Relative risk of dying within the first 10 years after diagnosis according to age at diagnosis after adjustment for known prognostic factors and expected mortality. RESULTS: Overall, young women with low risk disease who did not receive adjuvant treatment had a significantly increased risk of dying; risk increased with decreasing age at diagnosis (adjusted relative risk: 45-49 years (reference): 1; 40-44 years: 1.12 (95% confidence interval 0.89 to 1.40); 35-39 years: 1.40 (1.10 to 1.78); <35 years: 2.18 (1.64 to 2.89). However, no similar trend was seen in patients who received adjuvant cytotoxic treatment. The increased risk in younger women who did not receive adjuvant treatment compared with those who did remained when women were grouped according to presence of node negative disease and by tumour size. CONCLUSION: The negative prognostic effect of young age is almost exclusively seen in women diagnosed with low risk disease who did not receive adjuvant cytotoxic treatment. These results suggest that young women with breast cancer, on the basis of age alone, should be regarded as high risk patients and be given adjuvant cytotoxic treatment.
Thermodilution versus inert gas rebreathing for estimation of effective pulmonary blood flow.
OBJECTIVE: To compare measurements of the effective pulmonary blood flow (Qep, i.e., nonshunted fraction of cardiac output, Qt) by the inert gas rebreathing (RB) method and the thermodilution (TD) technique in critically ill patients. DESIGN: Prospective, comparative study of a noninvasive method and an established invasive technique. SETTING: An 11-bed general intensive care unit in a university hospital. PATIENTS: A total of 14 critically ill patients, all mechanically ventilated and monitored with systemic and pulmonary artery catheters. MEASUREMENTS AND MAIN RESULTS: Qep was determined in duplicate by RB using a mass spectrometer for gas analysis. For each determination, Qt was measured in triplicate by the cold water bolus TD technique and averaged. Simultaneously mixed venous and arterial blood samples were analyzed to calculate the intrapulmonary shunt fraction and thereby convert estimates of Qt to Qep. Mean difference between paired estimates (RB - TD) was 0.01 L/min, so for differences was 1.19 L/min, and 95% confidence interval for the bias was -0.45 to 0.47 L/min. Coefficients of variation for repeated Qep estimates were 8% (RB) and 12% (TD), respectively. Coefficients of variation for RB estimates of functional residual capacity and lung tissue volume were 6% and 17%, respectively. CONCLUSIONS: The RB method is a promising method for simultaneous noninvasive estimation of Qep and functional residual capacity in mechanically ventilated patients. However, further investigations are needed to evaluate potential problems of the method before it can be recommended for clinical purposes.
Reproductive history and stage of breast cancer.
A woman's reproductive history influences her risk of breast cancer. The authors hypothesized that reproductive history also influences stage of disease at the time of diagnosis. The authors analyzed a population-based cohort of 1.5 million Danish women born between 1935 and 1978 for whom individual information on births was available. Between 1978 and 1994, 10,790 incident cases of breast cancer in women under 60 years of age were identified. Nulliparous women compared with parous women and women with a late age at first birth compared with an early age were at significantly increased risk of being diagnosed with a large tumor and with cancer that had spread to regional lymph nodes. However, such an association was not seen for women diagnosed with a small tumor and women with cancer that had not spread to regional lymph nodes. Reproductive history did not appear to influence the time interval from first symptoms to first physician visit ("patient delay") or the time interval from first physician visit to surgery ("doctor delay"). The authors conclude that reproductive history is associated both with incidence of breast cancer and with stage of the disease at diagnosis, indicating possible influences on tumor progression and growth rate. Intensified awareness is warranted to achieve earlier diagnosis among nulliparous women and women with a late age at first childbirth, with the hope of improving their prognosis.
Calculating the number needed to treat for trials where the outcome is time to an event.
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Testing for centre effects in multi-centre survival studies: a Monte Carlo comparison of fixed and random effects tests.
The problem of testing for a centre effect in multi-centre studies following a proportional hazards regression analysis is considered. Two approaches to the problem can be used. One fits a proportional hazards model with a fixed covariate included for each centre (except one). The need for a centre specific adjustment is evaluated using either a score, Wald or likelihood ratio test of the hypothesis that all the centre specific effects are equal to zero. An alternative approach is to introduce a random effect or frailty for each centre into the model. Recently, Commenges and Andersen have proposed a score test for this random effects model. By a Monte Carlo study we compare the performance of these two approaches when either the fixed or random effects model holds true. The study shows that for moderate samples the fixed effects tests have nominal levels much higher than specified, but the random effect test performs as expected under the null hypothesis. Under the alternative hypothesis the random effect test has good power to detect relatively small fixed or random centre effects. Also, if the centre effect is ignored the estimator of the main treatment effect may be quite biased and is inconsistent. The tests are illustrated on a retrospective multi-centre study of recovery from bone marrow transplantation.
Modelling covariate adjusted mortality relative to a standard population.
A study of long term survival of 1487 patients given an allogeneic bone marrow transplant for acute myelogenous leukaemia and 729 patients given a transplant for severe aplastic anaemia was conducted by the International Bone Marrow Transplant Registry. One aim of this study is to determine if the mortality rates of these patients return after some period of time to the same mortality rate as in the general population. To examine this question a model for the relative mortality of a bone marrow transplant patient relative to a matched individual in the general population is presented. This model allows for different relative mortality rates depending on the risk factors the patient may have. We discuss an estimation procedure for this model and construct a test that the mortality rate in the transplanted population is the same as in the reference population over a given time interval.
Multivariate competing risks.
Competing risks models can be used to compare the effect of risk factors for different causes of death or subtypes of a disease. However, sometimes more than one outcome classification is available and if two such classifications are correlated, one may speculate whether differences in the effect of a risk factor according to one classification simply may be an effect of differences according to the other correlated classification. We introduce in this paper the new concept of multivariate competing risks to test formally such a hypothesis.
Reproductive risk factors for breast cancer by receptor status, histology, laterality and location.
It is well established that a woman's reproductive history influences her risk of breast cancer. We examined whether the effect of reproductive history was similar for different sub-types of breast cancer. The study was based on a population-based cohort of 1.5 million Danish women born between 1935 and 1978, with individual information on births. Between 1978 and 1994, 10,790 incident cases of breast cancer were identified in a nationwide cancer registry, including detailed information on receptor status, histology, laterality and location of the tumour. Overall, the incidence of breast cancer was 13% lower in parous compared with nulliparous women. This reduction was significantly stronger for mucinous than for ductal carcinomas and for tumours located centrally than for those non-central in the breast. Overall, the incidence in parous women increased by 10% by each 5-year postponement of their first birth. For the incidence of lobular carcinomas this increase was significantly stronger, and for mucinous carcinomas it tended to be stronger than for ductal carcinomas. For the incidence of centrally located tumours the increase was stronger than for non-centrally located tumours. On average, there was a 10% decrease in breast-cancer risk by each additional birth. This decrease was seen in most sub-types, but not for lobular carcinomas of for centrally located tumours. According to our findings, lobular and mucinous carcinomas and centrally located tumours may have risk-factor profiles that differ from other types of breast cancer.
[The course of affective disorders--a registry study].
In recent years, studies of the risk of recurrence in affective disorder in relation to the number of prior episodes have given contradictory results. Survival analysis was used to calculate the rate of recurrence after successive episodes in a case register study including all hospital admissions with primary affective disorder in Denmark during 1971-1993. Totally, 20,350 first-admission patients were discharged with a diagnosis of affective disorder, depressive or manic/circular type. The rate of recurrence increased with the number of previous episodes in both unipolar and bipolar disorder. Initially, the two types of disorders followed markedly different courses, but later in the course of the illness the rate of recurrence was the same for the two disorders. The course of severe unipolar and bipolar disorder seems to be progressive in nature despite the effect of treatment.
Recurrence in affective disorder: analyses with frailty models.
The risk of recurrence in affective disorder is influenced by the number of prior episodes and by a person's tendency toward recurrence. Newly developed frailty models were used to estimate the effect of the number of episodes on the rate of recurrence, taking into account individual frailty toward recurrence. The study base was the Danish psychiatric case register of all hospital admissions for primary affective disorder in Denmark during 1971-1993. A total of 20,350 first-admission patients were discharged with a diagnosis of major affective disorder. For women with unipolar disorder and for all kinds of patients with bipolar disorder, the rate of recurrence was affected by the number of prior episodes even when the effect was adjusted for individual frailty toward recurrence. No effect of episodes but a large effect of the frailty parameter was found for unipolar men. The authors concluded that the risk of recurrence seems to increase with the number of episodes of bipolar affective disorder in general and for women with unipolar disorder.