Considerations for the design, analysis and presentation of in vivo studies.

OBJECTIVE: To describe, explain and give practical suggestions regarding important principles and key methodological challenges in the study design, statistical analysis, and reporting of results from in vivo studies. CONCLUSIONS: Pre-specifying endpoints and analysis, recognizing the common underlying assumption of statistically independent observations, performing sample size calculations, and addressing multiplicity issues are important parts of an in vivo study. A clear reporting of results and informative graphical presentations of data are other important parts.

OARSI Clinical Trials Recommendations: Key analytic considerations in design, analysis, and reporting of randomized controlled trials in osteoarthritis.

To highlight methodologic challenges pertinent to design, analysis, and reporting of results of randomized clinical trials in OA and offer practical suggestions to overcome these challenges. The topics covered in this paper include subject selection, randomization, approaches to handling missing data, subgroup analysis, sample size, and issues related to changing design mid-way through the study. Special attention is given to standardizing the reporting of results and economic analyses. Key findings include the importance of blinding and concealment, the distinction between superiority and non-inferiority trials, the need to minimize missing data, and appropriate analysis and interpretation of subgroup effects. Investigators may use the findings and recommendations advanced in this paper to guide design and conduct of randomized controlled trials of interventions for osteoarthritis.

Why the P-value culture is bad and confidence intervals a better alternative.

In spite of frequent discussions of misuse and misunderstanding of probability values (P-values) they still appear in most scientific publications, and the disadvantages of erroneous and simplistic P-value interpretations grow with the number of scientific publications. Osteoarthritis and Cartilage prefer confidence intervals. This is a brief discussion of problems surrounding P-values and confidence intervals.

Can sulphonylurea addition to lifestyle changes help to delay diabetes development in subjects with impaired fasting glucose? The Nepi ANtidiabetes StudY (NANSY).

The Nepi ANtidiabetes StudY (NANSY) is a 5-year randomized, double-blind, placebo-controlled trial in Swedish primary care, examining whether the development of type 2 diabetes (T2D) and retinopathy (separately reported) would be delayed in 40- to 70-year-old subjects with impaired fasting glucose (IFG) who, in addition to lifestyle changes, were treated with either placebo or low-dosage sulphonylurea (SU) (1-mg glimepiride; Amaryl). Of 274 subjects (163 men, 111 women), 138 were allocated to placebo (46.0% men, 56.8% women) and 136 to glimepiride (54.0% men, 43.2% women). The primary endpoint was conversion to diabetes. Average follow-up time was 3.71 years; 96 subjects converted to diabetes, 55 allocated to placebo and 41 to glimepiride (absolute difference 9.8%; p = 0.072). In conclusion, the study failed to support the notion that low-dose SU added to lifestyle changes in IFG subjects would help to delay the conversion to diabetes.

Sampling uncertainty in medical research.

OBJECTIVE: Statistical analysis is ubiquitous in medical research, but fundamental statistical principles are not always well understood, which has negative effects for both authors and readers of scientific papers. The purpose of this brief review is to provide a methodological overview on populations, samples, analysis units and sampling uncertainty to facilitate an increased understanding of statistical concepts.

Prospective malignancy grading of invasive squamous carcinoma of the uterine cervix. Prognostic significance in a long-term follow-up.

A multifactorial grading score (MGS) for invasive squamous cell carcinoma of the uterine cervix has demonstrated its capacity to predict survival in a 5-10 year perspective and metastasis frequencies, and is a valuable tool for treatment schedules. In this study it was shown that the power of prognosis is valid even up to 20 years. In this material from 619 cervical carcinoma patients the MGS scores turned out to remain as strong as earlier proven. Earlier studies have shown that MGS is superior to other mono- and multifactorial grading systems, histological differentiation into cell types, age, clinical stage, irradiation and DNA-analysis. Treatment of cervical squamous cell carcinoma is more specific today to meet the patients' need for instance to preserve fertility or to minimize operation and eventually radiotherapy. The MGS score is a strong prognostic tool in patients with cervical carcinoma.

Increased long-term mortality in patients less than 55 years old who have undergone knee replacement for osteoarthritis: results from the Swedish Knee Arthroplasty Register.

Patients with osteoarthritis undergoing knee replacement have been reported to have an overall reduced mortality compared with that of the general population. This has been attributed to the selection of healthier patients for surgery. However, previous studies have had a maximum follow-up time of ten years. We have used information from the Swedish Knee Arthroplasty Register to study the mortality of a large national series of patients with total knee replacement for up to 28 years after surgery and compared their mortality with that of the normal population. In addition, for a subgroup of patients operated on between 1980 and 2002 we analysed their registered causes of death to determine if they differed from those expected. We found a reduced overall mortality during the first 12 post-operative years after which it increased and became significantly higher than that of the general population. Age-specific analysis indicated an inverse correlation between age and mortality, where the younger the patients were, the higher their mortality. The shift at 12 years was caused by a relative over-representation of younger patients with a longer follow-up. Analysis of specific causes of death showed a higher mortality for cardiovascular, gastrointestinal and urogenital diseases. The observation that early onset of osteoarthritis of the knee which has been treated by total knee replacement is linked to an increased mortality should be a reason for increased general awareness of health problems in these patients.

Head trauma and exposure to prolactin-elevating drugs as risk factors for male breast cancer.

On the basis of information obtained from a population-based cancer registry in Sweden, male patients with breast cancer (n = 95) were found to have experienced significantly more brain concussions and skull fractures than male patients with lung cancer (n = 383) or malignant lymphoma (n = 69). Other risk factors significantly associated with breast cancer among men were drug treatment associated with prolactin elevations, radiation treatment, family history of breast cancer among first-degree relatives, a history of gynecomastia, gonadal injury, and treatment for inguinal hernias. The results confirm some previously described risk factors for male breast cancer and suggest that events elevating plasma prolactin (e.g., drugs, brain concussions, and skull fractures) and events predisposing for inguinal hernias may be new risk factors for the disease. Using hospital charts is likely to underestimate exposure for different risk factors; therefore, the results need to be confirmed in studies that directly retrieve information. However, such studies are difficult or impossible to undertake in most countries because the disease is so rare.

Early oral contraceptive use and breast cancer among premenopausal women: final report from a study in southern Sweden.

In southern Sweden during the 1960s, women began to use oral contraceptives (OCs) extensively at a young age. This case-control study investigates the relationship between the use of OCs and breast cancer development in women in southern Sweden diagnosed in the early 1980s. The risk for breast cancer after OC use among premenopausal women was modeled, after adjustment was made for age, age at menarche, and age at first full-term pregnancy or parity. Both the duration of OC use before 25 years of age and commencement of OC use at a young age were associated with a significant increase in the risk of breast cancer as well as a significant trend. The duration of OC use before the first full-term pregnancy was associated with an increased risk of breast cancer, but it did not show a significant trend. The total duration of OC use was weakly, but not significantly, associated with breast cancer development. The odds ratio for women starting OC use before 20 years of age was 5.8 [95% confidence interval (CI), 2.6-12.8]; for women using OCs for greater than 5 years before age 25, it was 5.3 (95% CI, 2.1-13.2); and for women using OCs for greater than or equal to 8 years before first full-term pregnancy, it was 2.0 (95% CI, 0.8-4.7). In multivariate analyses including the different measurements of OC use, only starting age of OC use was significantly associated with breast cancer. The exposure-response relationship between duration of OC use and risk of breast cancer depended on the age at first use of OCs. Given a fixed duration of OC use, the risk increased with younger starting age of OC use. The findings point to the importance of the early reproductive years as risk determinants for breast cancer after OC use.