Biomedical subjects

T R Holford

Publications and source records attributed to T R Holford.

At least 19 recordsLinked to original sources

PubMed1992

Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer.

This study examined risk factors for development of a contralateral breast cancer among 4,660 US women diagnosed with a first primary breast cancer between 1980 and 1982. The authors believe it to be the first prospective cohort study on this topic that has employed direct patient interviews. All subjects were interviewed within 6 months of the diagnosis of their initial tumor as part of the multi-center, population-based, case-control Cancer and Steroid Hormone Study, and they were followed until the end of 1986 through the Surveillance, Epidemiology, and End Results program. Exclusive of those diagnosed during the initial 6 months after diagnosis of a first primary, 136 second primary breast cancers were identified. Proportional hazards models were used to assess the independent effects of multiple predictors. Specific risk factors evaluated included: age at diagnosis of first primary, exposure to exogenous hormones, menstrual and reproductive histories, tumor characteristics, demographic variables, and treatment modalities. The age-specific incidence rates of second primary breast cancer were higher in all age categories than are the incidence rates of breast cancer in the general population, yet the age at diagnosis of first primary breast cancer was not an important predictor of contralateral breast cancer. The risk of contralateral breast cancer was increased among cohort members who reported a personal history of benign breast biopsy (multivariable-adjusted rate ratio (RR) = 1.69, 95% confidence interval (CI) 1.13-2.53) and in those with an initial tumor that was classified as lobular carcinoma (multivariable-adjusted RR = 1.96, 95% CI 1.17-3.27). Treatment with chemotherapy for the first primary was associated with a lower risk of development of a second breast cancer (multivariable-adjusted RR = 0.56, 95% CI 0.33-0.96), while radiation therapy had little effect on the risk (multivariable-adjusted RR = 1.19, 95% CI 0.78-1.80).

Adult↗

PubMed1992

The genetic epidemiology of second primary breast cancer.

It is well established that women with a family history of breast cancer run a higher risk of breast cancer than do women without a family history. The evidence, however, is less clear regarding a possible association between a family history of breast cancer and risk of second primaries. The purpose of this prospective study was to estimate the risk for second primary breast cancer associated with having a family history of breast, endometrial, and ovarian cancers. A cohort of 4,660 women with a first primary breast cancer diagnosed between 1980 and 1982 were interviewed as part of the Cancer and Steroid Hormone Study, a multi-center population-based case-control study, and followed through eight Surveillance, Epidemiology, and End Results (SEER) program registries for 4 to 6 years. Of these women, 136 developed a second primary breast cancer in the contralateral breast at least 6 months after diagnosis of the first primary. Cox proportional hazards modeling techniques were used to model the time to onset of second primary breast cancer while adjusting for multiple predictors. The risk of contralateral breast cancer was elevated among cohort members who reported a history of breast cancer in a first-degree relative (multivariable-adjusted rate ratio (RR) = 1.91, 95% confidence interval (CI) = 1.22-2.99). Early age at onset (< 46 years) in the relative further increased the risk of developing contralateral breast cancer (sister: multivariable-adjusted RR = 3.36, 95% CI 1.62-6.98; mother: multivariable-adjusted RR = 2.35, 95% CI 1.02-5.43). Bilateral breast cancer in mothers was also associated with more than a two and a half-fold increase in risk (multivariable-adjusted RR = 2.55, 95% CI 1.02-6.35). The association between family history of breast cancer and risk of contralateral breast cancer did not vary substantially according to age at onset of the first primary breast cancer. The age-adjusted rate ratio for development of a second primary breast cancer among women with a first-degree relative with endometrial cancer was 2.13 (95% CI 1.04-4.35), while the corresponding rate ratio among women with a family history of ovarian cancer was 1.69 (95% CI 0.42-6.83). There was little evidence that age at onset among the relatives with endometrial or ovarian cancer affected the risk. Some of these findings have not been previously reported and need replication in future studies.

Adult↗

PubMed1992

Time trends of non-Hodgkin's lymphoma: are they real? What do they mean?

Factors that need to be considered in the analysis of time trends in disease incidence are age, year of diagnosis, and birth cohort. When these are included in a log-linear model, a nonidentifiability problem arises from the linear dependence among these three time factors so that only specified functions of the parameters can be unambiguously determined. One of these invariant functions is the drift or the sum of the period and cohort trend. Non-Hodgkin's lymphoma incidence rates from Connecticut for the period 1935-1989 were analyzed for males and females. In addition to an age effect, both period and cohort significantly improved the fit of the model. The estimated drift shows that there has been a 10.3% increase in risk every 5 years since 1965 for females and 9.2% for males. It is unlikely that a trend of this magnitude can be attributed entirely to data artifact.

Adult↗

PubMed1992

Epidemiology of non-Hodgkin lymphoma in Connecticut. 1935-1988.

BACKGROUND: During the past decades, there have been reports of increases in the incidence and mortality rates due to non-Hodgkin lymphoma (NHL) in many parts of the world. The risk factors responsible for the increasing incidence are largely unknown. This study provided an overview of the incidence pattern of NHL in Connecticut and generated hypotheses for additional investigation. METHODS: This study was based on all the NHL cases reported to the Connecticut Tumor Registry (CTR) between 1935 and 1988. Crude, age-adjusted, and age-specific incidence rates of NHL were calculated for each sex. Age-adjusted incidence rates were calculated by the direct method standardized to the 1970 United States standard million population. The data are presented by calendar year and cohort year of birth to examine the secular trends and birth cohort effects. Racial information was not coded before 1957 and is of uncertain validity until the early 1970s; therefore, racial analysis was restricted to 1970-1988. Analyses by histologic subtypes and by anatomic sites were restricted to the last 3 decades (1960-1988) because more accurate classification systems were used during this time. RESULTS: A total of 11,326 newly diagnosed cases of NHL were included in the study. Of them, 5866 (52%) were diagnosed in men and 5460 (48%) were diagnosed in women. The study results indicated that the incidence rate of NHL has been increasing during the past decades for men and women, whites and blacks, nodular NHL and diffuse NHL, disease originating from lymph nodes and disease originating from other sites, and in all age groups, especially the older age groups. Birth cohort examination did not show any indication of a decline or levelling off in incidence rates among recent birth cohorts. Age-specific incidence rates in both sexes suggested that the rates increase with age, with a sharp increase beginning at 50 years of age and peaking at 80 years of age. Men had a 30% higher incidence rate than women, and whites had approximately 1.5 times the age-adjusted incidence rate of blacks. CONCLUSIONS: The results indicated that the incidence rate of NHL has been increasing in Connecticut during the past decades and is likely to continue to rise in the coming years. Analytical epidemiologic studies are needed to examine the risk factors that might account for the increase in NHL.

Adult↗

PubMed1992

A model for estimating level and net severity of spinal cord injuries.

Objective and detailed neurological assessments are essential in studies of the treatment and the epidemiology of acute spinal cord injuries. In practice, investigators use the expanded score, found by taking the total of the individual determinations, but this summary obscures important detail as to the level and the overall severity of injury. To address this issue, we present a method for estimating level and net severity of injury that makes use of isotonic regression and the Spearman-Kärber estimator. We describe the method for both sensory and motor assessments of neurologic function. In the special case where one gives an identical weight to the response at each level, these estimators algebraically partition the expanded score into separate contributions due to level and net severity. We provide a numerical example using data from the first National Acute Spinal Cord Injury Study, and we present a summary of the distribution of these parameters for this population.

Evaluation Studies as Topic↗

PubMed1992

A reversal in the long-term increase in deaths attributable to malignant melanoma.

For a few years in the 1980s, United States mortality rates suggested a plateau in the long-term increase for malignant melanoma. However, temporary plateaus in the increase of the age-adjusted rate by year of death have occurred in previous decades, only to be followed by a continued upward increase, with a long-term rise of about 2% per year. To determine whether a cessation in the long-term increase might be in progress, death rates were analyzed by year of birth, age at death, and year of death: (1) the long-term patterns of change are best described by birth cohort rather than by time period of death, indicating that analyses by a year of birth are key to a better understanding of the long-term trends; (2) in both men and women, evidence for a change in slope begins among those born in the early 1930s; (3) the decline in the rates begins among women born since the early 1930s and among men born since the early 1950s: the slope for men is -0.2661 (95% confidence limits [CL] = -0.380 to -0.152), and, for women, the slope is -0.02354 (95% CL = -0.041 to -0.005); (4) long-term Connecticut and US mortality trends were similar in pattern and direction, and long-term Connecticut incidence rates showed a persistent increase through the 1955 to 1965 birth cohorts. These analyses suggest a persistent cessation in the long-term increase and a downward trend in death rates from this cancer.

Adolescent↗

PubMed1992

Time trend and age-period-cohort effects on incidence of esophageal cancer in Connecticut, 1935-89.

The purpose of this study was to examine the incidence pattern of esophageal cancer in Connecticut (USA) during the past decades, and to identify components of birth cohort, period, and and age as determinants of the observed time trends by regression modelling. This study is based on all of the esophageal cancer cases reported to the Connecticut Tumor Registry between 1935 and 1989. A total of 6,310 incident cases were included. Results indicate that among males, the overall age-adjusted incidence rate of esophageal cancer increased after 1935 and peaked between 1955 and 1959. Since then, incidence rates have been relatively stable. Among females, the overall esophageal cancer rate has not changed markedly since 1935. Analysis by histologic type indicates that the incidence rate of squamous cell carcinoma has been declining in this population; adenocarcinoma, however, showed a continuous increase. A fivefold increase among males and a threefold increase among females were observed for adenocarcinoma of the esophagus between 1970 and 1989. If cancers of the esophagus and gastric cardia are considered together, the incidence rate of adenocarcinoma exceeds that of squamous cell carcinoma among males during 1985-89. The observed increasing trend for adenocarcinoma of the esophagus is mainly from cancers arising in the lower third of the esophagus and primarily among Whites, especially White males. The results from regression modeling indicate that both period and birth cohort may have contributed to the observed increasing trend, and adenocarcinoma of the esophagus is likely to increase continuously in this population in the coming years.

Adenocarcinoma↗

PubMed1992

Cross-cultural association between dietary animal protein and hip fracture: a hypothesis.

Age-adjusted female hip fracture incidence has been noted to be higher in industrialized countries than in nonindustrialized countries. A possible explanation that has received little attention is that elevated metabolic acid production associated with a high animal protein diet might lead to chronic bone buffering and bone dissolution. In an attempt to examine this hypothesis, cross-cultural variations in animal protein consumption and hip fracture incidence were examined. When female fracture rates derived from 34 published studies in 16 countries were regressed against estimates of dietary animal protein, a strong, positive association was found. This association could not plausibly be explained by either dietary dietary calcium or total caloric intake. Recent studies suggest that the animal protein-hip fracture association could have a biologically tenable basis. We conclude that further study of the metabolic acid-osteoporosis hypothesis is warranted.

Acid-Base Equilibrium↗

PubMed1992

Analysing the temporal effects of age, period and cohort.

Longitudinal trends can be analysed in terms of the effect of age, birth cohort or year of diagnosis. All three temporal effects are thought to be useful by epidemiologists, but they are not identifiable when assessed simultaneously. Partitioning the effects in terms of linear and curvature components is one approach to understanding the problem and finding a reasonable summary of trends. Other solutions can be expressed in terms of these components, and they can also be used to understand both subgroup and temporal interactions. One approach that may offer a way of understanding the effect of risk factor trends on population based rates is to use models that incorporate an effect due to the risk factors. These methods are discussed using lung cancer incidence and mortality to illustrate the underlying concepts.

Adult↗

PubMed1992

Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the second National Acute Spinal Cord Injury Study.

The 1-year follow-up data of a multicenter randomized controlled trial of methylprednisolone (30 mg/kg bolus and 5.4 mg/kg/hr for 23 hours) or naloxone (5.4 mg/kg bolus and 4.0 mg/kg/hr for 23 hours) treatment for acute spinal cord injury are reported and compared with placebo results. In patients treated with methylprednisolone within 8 hours of injury, increased recovery of neurological function was seen at 6 weeks and at 6 months and continued to be observed 1 year after injury. For motor function, this difference was statistically significant (p = 0.030), and was found in patients with total sensory and motor loss in the emergency room (p = 0.019) and in those with some preservation of motor and sensory function (p = 0.024). Naloxone-treated patients did not show significantly greater recovery. Patients treated after 8 hours of injury recovered less motor function if receiving methylprednisolone (p = 0.08) or naloxone (p = 0.10) as compared with those given placebo. Complication and mortality rates were similar in either group of treated patients as compared with the placebo group. The authors conclude that treatment with the study dose of methylprednisolone is indicated for acute spinal cord trauma, but only if it can be started within 8 hours of injury.

Acute Disease↗

PubMed1991

Trends in female breast cancer in Connecticut and the United States.

Trends for female breast cancer were examined by age, period and cohort for the years 1950-1984 in U.S. mortality. Connecticut mortality and Connecticut incidence. Birth cohort patterns were evident for all three sets of data. The results confirm a continuing increase in invasive breast cancer by providing evidence of a strong birth cohort pattern, over a time series of 90 years of birth cohorts. This trend appears to be real for the most part because of the cohort patterns and because there is minimal underdetection in data obtained by autopsy and blind biopsy. Secondly, when cohort modeling is applied to breast cancer mortality, there is an indication of a modest decline in recent breast cancer mortality (in the face of an apparent long-term increase), which suggests that control of breast cancer mortality may have developed in recent decades, perhaps through earlier detection and improved treatment. Finally, in contrast with a prior report, there is little evidence for a clinically important difference in time trend between pre- and postmenopausal breast cancer.

Age Factors↗

PubMed1991

Understanding the effects of age, period, and cohort on incidence and mortality rates.

Time trends for population-based disease rates often are summarized by using direct adjustment by period of diagnosis or death. Similarly, the effect of age often is presented graphically as age-specific rates for a given period of diagnosis. These approaches may be necessary if there is an absence of long-term data, as they provide a natural way for annually updating information when monitoring trends, or they may be a convenient way of summarizing a large amount of data (7, 10, 11, 39, 45). However, these summaries only can adjust for the effect of age in a given period; they implicitly ignore the cohort effect. The effect of cohort is an important factor in understanding time trends for many diseases. Thus, it is not advisable to use data analytic strategies that routinely ignore it. Another alternative to modeling is to give a graphical presentation of the age-specific rates themselves. As I noted in the introduction, some of the first analyses to identify the effect of cohort on diseases, such as tuberculosis and lung cancer, relied entirely on a graphical analysis. Although graphs certainly are an important part of the interpretation of time trends, it would be a mistake to limit your analysis to impressions of points on a graph. For example, such a perusal would not give an objective indication of the statistical significance of a particular pattern. Regression analysis forces us to recognize a fundamental problem with interpreting time trends in disease rates--a problem that you should remember, even when trying to understand a graphical display of time trends in age-specific rates.

Adult↗

PubMed1990

A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study.

Studies in animals indicate that methylprednisolone and naloxone are both potentially beneficial in acute spinal-cord injury, but whether any treatment is clinically effective remains uncertain. We evaluated the efficacy and safety of methylprednisolone and naloxone in a multicenter randomized, double-blind, placebo-controlled trial in patients with acute spinal-cord injury, 95 percent of whom were treated within 14 hours of injury. Methylprednisolone was given to 162 patients as a bolus of 30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogram per hour for 23 hours. Naloxone was given to 154 patients as a bolus of 5.4 mg per kilogram, followed by infusion at 4.0 mg per kilogram per hour for 23 hours. Placebos were given to 171 patients by bolus and infusion. Motor and sensory functions were assessed by systematic neurological examination on admission and six weeks and six months after injury. After six months the patients who were treated with methylprednisolone within eight hours of their injury had significant improvement as compared with those given placebo in motor function (neurologic change scores of 16.0 and 11.2, respectively; P = 0.03) and sensation to pinprick (change scores of 11.4 and 6.6; P = 0.02) and touch (change scores, 8.9 and 4.3; P = 0.03). Benefit from methylprednisolone was seen in patients whose injuries were initially evaluated as neurologically complete, as well as in those believed to have incomplete lesions. The patients treated with naloxone, or with methylprednisolone more than eight hours after their injury, did not differ in their neurologic outcomes from those given placebo. Mortality and major morbidity were similar in all three groups. We conclude that in patients with acute spinal-cord injury, treatment with methylprednisolone in the dose used in this study improves neurologic recovery when the medication is given in the first eight hours. We also conclude that treatment with naloxone in the dose used in this study does not improve neurologic recovery after acute spinal-cord injury.

Acute Disease↗

PubMed1990

Conception delay after oral contraceptive use: the effect of estrogen dose.

A significant delay was observed in conception among 248 former oral contraceptive (OC) users compared with women discontinuing other methods of contraception (n = 1,365). The mean time to conception was 5.88 cycles (95% confidence interval [CI] 5.38, 6.38) for former OC users and 3.64 cycles (95% CI 3.49, 3.79) after other contraceptives. Women discontinuing OCs with higher doses of estrogen (greater than or equal to 50 micrograms) had greater conception delays than those on lower estrogen doses who, in turn, had longer delays than other method users. Oral contraceptive use was associated with significant reductions in conception for each of the first six cycles after discontinuation. This study provides further evidence for a direct effect of oral contraception on delayed conception, suggests that the delay lasts longer than previously thought, and finds that the probability of conception after OC discontinuation depends on the estrogen dose of the OC.

Adolescent↗

PubMed1989

Age, period and cohort effects on the risk of major depression: results from five United States communities.

Rates of major depression are presented from the recently completed Epidemiologic Catchment Area (ECA) Study based on probability samples of over 18,000 adults, 18 years of age and older, living in five U.S. communities. These rates were analyzed to describe simultaneously the changes affecting successive birth cohorts and the changes associated with the period in which the onset of the disorder occurred, using age-period-cohort (APC) models. The non-identifiability problem inherent in all APC models was resolved by assuming that the linear period effect and linear cohort effect were non-negative. This assumption is consistent with our a priori substantive knowledge of the disease. Under this assumption, as the linear period effect varies from its minimum to its maximum values, a family of curves representing the possible effects of a factor was generated for each of the time factors--age, period and cohort. The results of the analysis showed a sharp increase in rates of major depression among both men and women in the birth cohort born during the years 1935-1945. The rates among females, however, seemed to have stabilized in the generations born since 1945, while the rates in males continued to rise sharply among the cohorts born in the following decade, after which, in 1955, they also levelled off. In contrast, the rates associated with period of onset of major depression continued to increase between the years 1960-1980 among both men and women of all ages studied. These findings are considered in light of the persistent concentration of depression in women and in biologically related members of families of affected individuals.

Adolescent↗

PubMed1989

Simultaneous interval estimates of the odds ratio in studies with two or more comparisons.

More than one odds ratio estimate will often arise from a single epidemiologic study. Examples of designs where this may occur include those where there is more than one case or control group, and investigations of several risk factors as part of the same study. Various methods for presenting multiple interval estimates are discussed, including: the naive method, the Bonferroni method, the Dunn method, the Scheffé method, and the Dunnett method. For rectangular regions the Dunnett method gives a region with the most appropriate confidence level, but this region contains a different set of odds ratio estimates than are implied by the usual significance tests. A confidence ellipse circumscribed by the Scheffé limits gives the best agreement with the significance tests. Each of these methods is illustrated with a numerical example.

Epidemiologic Methods↗

PubMed1989

Log-linear models for the analysis of matched cohort studies.

The application of conditional logistic regression to the analysis of matched case-control studies has now become quite customary. In addition, it is well known that software designed to fit linear logistic and log-linear models can be used in these analyses. The application of conditional logistic regression to cohort designs is described, and an approach is developed that adapts the linear logistic and log-linear models for the analysis of prospectively collected data. Specific situations discussed include matched pairs, 2:1 matching, and studies in which some subjects are pair matched and others matched 2:1. The methods are illustrated with numeric examples.

Case-Control Studies↗

PubMed1988

Patterns of invasive melanoma in the Connecticut Tumor Registry. Is the long-term increase real?

The decades-long increase in incidence rates for melanoma has been ascribed to artifactual changes in case ascertainment rather than to true changes in disease risk. In this study, population-based incidence data for invasive cutaneous malignant melanoma from the Connecticut Tumor Registry were categorized into seven age groups and four time periods to examine the pattern of change over four decades. Analyses of age, period, and cohort variables focused on the curvature components, which are estimable functions. Statistical modeling demonstrated the following: (1) incidence rates have increased by birth cohort in both sexes with no requirement for a period variable, regardless of whether data are examined by 10-year, 5-year, or 1-year intervals of diagnosis; (2) this pattern in incidence rates differed from the patterns of change in the two indices of case ascertainment, the proportion of cases confirmed microscopically and the proportion of cases in localized stage, both of which exhibited changes by period of diagnosis rather than by birth cohort; and (3) adjustment for these two indices caused a downward bend in the cohort curve for females but not for males. The results suggested that much of the observed increase for this tumor was real.

Adolescent↗