P.Mean:  Answers to Chapter 6 exercises in Statistical Evidence (created 2008-09-29).

1. Review the following abstracts. Specify what the sample is and define what you think is a reasonable population that this research is trying to generalize to.

 The outcome of extubation failure in a community hospital intensive care unit: a cohort study. Seymour, C. W., Martinez, A., Christie, J.D., and Fuchs, B. D. Critical Care 2004, 8:R322–R327. Introduction: Extubation failure has been associated with poor intensive care unit (ICU) and hospital outcomes in tertiary care medical centers. Given the large proportion of critical care delivered in the community setting, our purpose was to determine the impact of extubation failure on patient outcomes in a community hospital ICU. Methods: A retrospective cohort study was performed using data gathered in a 16-bed medical/surgical ICU in a community hospital. During 30 months, all patients with acute respiratory failure admitted to the ICU were included in the source population if they were mechanically ventilated by endotracheal tube for more than 12 hours. Extubation failure was defined as reinstitution of mechanical ventilation within 72 hours (n ¼ 60), and the control cohort included patients who were successfully extubated at 72 hours (n ¼ 93). Results: The primary outcome was total ICU length of stay after the initial extubation. Secondary outcomes were total hospital length of stay after the initial extubation, ICU mortality, hospital mortality, and total hospital cost. Patient groups were similar in terms of age, sex, and severity of illness, as assessed using admission Acute Physiology and Chronic Health Evaluation II score (p > 0.05). Both ICU (1.0 vs. 10 days; p < 0.01) and hospital length of stay (6.0 vs. 17 days; p < 0.01) after initial extubation were significantly longer in re-intubated patients. ICU mortality was significantly higher in patients who failed extubation (odds ratio ¼ 12.2, 95% confidence interval [CI] ¼ 1.5–101; p < 0.05), but there was no significant difference in hospital mortality (odds ratio ¼ 2.1, 95% CI ¼ 0.8–5.4; p < 0.15). Total hospital costs (estimated from direct and indirect charges) were significantly increased by a mean of US$33,926 (95% CI ¼ US$22,573–45,280; p < 0.01). Conclusion: Extubation failure in a community hospital is univariately associated with prolonged inpatient care and significantly increased cost. Corroborating data from tertiary care centers, these adverse outcomes highlight the importance of accurate predictors of extubation outcome. This is an open source publication. The full free text is available at: ccforum.com/content/8/5/R322.

Effect of paracetamol (acetaminophen) and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690]. Dippel, D.W. J., vanBreda, E. J., vanderWorp, H. B., vanGemert, H. M. A., Meijer, R. J., Kappelle, L. J., Koudstaal, P. J., and the PISA-investigators. BMC Cardiovascular Disorders 2003, 3:2. Background: Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect. Methods: Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1,000 mg SIMON: Statistical Evidence in Medical Trials 06-simon-chap06 Revise Proof page 157 10.11.2005 11:18am What Do All These Numbers Mean? 157 acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter. Results: No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.38C larger reduction in body temperature from baseline than placebo treatment (95% CI, 0.0– 0.68C). Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period. Conclusions: Treatment with a daily dose of 6,000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further, large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome. This is an open source publication. The full free text is available at: www.biomedcentral.com/1471-2261/3/2.

2. Interpret the CIs reported in the same set of abstracts. Specify a range of clinical indifference as best you can and interpret these intervals with respect to that range.

Elevated white cell count in acute coronary syndromes: relationship to variants in inflammatory and thrombotic genes. Byrne, C. E., Fitzgerald, A., Cannon, C. P., Fitzgerald, D. J., and Shields, D.C. BMC Medical Genetics 2004, 5:13. Background: Elevated white blood cell counts (WBC) in acute coronary syndromes (ACS) increase the risk of recurrent events, but it is not known if this is exacerbated by pro-inflammatory factors. We sought to identify whether pro-inflammatory genetic variants contributed to alterations in WBC and C-reactive protein (CRP) in an ACS population. Methods: WBC and genotype of interleukin 6 (IL-6 G-174C) and of interleukin- 1 receptor antagonist (IL1RN intronic repeat polymorphism) were investigated in 732 Caucasian patients with ACS in the OPUS-TIMI-16 trial. Samples for measurement of WBC and inflammatory factors were taken at baseline, i.e. Within 72 hours of an acute myocardial infarction or an unstable angina event. Results: An increased white blood cell count (WBC) was associated with an increased C-reactive protein (r ¼ 0.23, p < 0.001) and there was also a positive correlation between levels of b-fibrinogen and C-reactive protein (r ¼ 0.42, p < 0.0001). IL1RN and IL6 genotypes had no significant impact upon WBC. The difference in median WBC between the two homozygote IL6 genotypes was 0.21/mm3 (95% CI, 0.41, 0.77), and 0.03/mm3 (95% CI, 0.55, 0.86) for IL1RN. Moreover, the composite endpoint was not significantly affected by an interaction between WBC and the IL1 (p ¼ 0.61) or IL6 (p ¼ 0.48) SIMON: Statistical Evidence in Medical Trials 06-simon-chap06 Revise Proof page 158 10.11.2005 11:18am 158 What Do All These Numbers Mean? genotype. Conclusions: Cytokine pro-inflammatory genetic variants do not influence the increased inflammatory profile of ACS patients. This is an open source publication. The full free text is available at: www.biomedcentral.com/1471-2350/5/13.

Effect of paper quality on the response rate to a postal survey: a randomised controlled trial. [ISRCTN32032031]. Clark, T. J., Khan, K. S., and Gupta, J. K. BMC Medical Research Methodology 2001, 1:12. Background: Response rates to surveys are declining and this threatens the validity and generalizability of their findings. We wanted to determine whether paper quality influences the response rate to postal surveys Methods: A postal questionnaire was sent to all members of the British Society of Gynaecological Endoscopy (BSGE). Recipients were randomized to receiving the questionnaire printed on standard quality paper or high quality paper. Results: The response rate for the recipients of high quality paper was 43/195 (22%) and 57/194 (29%) for standard quality paper (relative rate of response 0.75, 95% CI, 0.33–1.05, p ¼ 0.1 Conclusion: The use of high quality paper did not increase response rates to a questionnaire survey of gynaecologists affiliated to an endoscopic society. This is an open source publication. The full free text is available at: www.biomedcentral.com/1471-2288/1/12.

Do English and Chinese EQ-5D versions demonstrate measurement equivalence? an exploratory study. Luo, N., Chew, L. H., Fong, K. Y., Koh, D. R., Ng, S. C., Yoon, K. H., Vasoo, S., Li, S.C., and Thumboo, J. Health and Quality of Life Outcomes 2003, 1:7. Background: Although multiple language versions of health-related quality of life instruments are often used interchangeably in clinical research, the measurement equivalence of these versions (especially using alphabet vs. pictogram-based languages) has rarely been assessed.We therefore investigated the measurement equivalence of English and Chinese versions of the EQ-5D, a widely used utility-based outcome instrument. Methods: In a cross-sectional study, either EQ-5D version was administered to consecutive outpatients with rheumatic diseases. Measurement equivalence of EQ-5D item responses and utility and visual analog scale (EQ-VAS) scores between these versions was assessed using multiple regression models (with and without adjusting for potential confounding variables), by comparing the95%confidence interval (95%CI) of score differences between these versions with predefined equivalence margins. An equivalence margin defined a magnitude of score differences (10% and 5% of entire score ranges for item responses and utility/ EQ-VAS scores, respectively) which was felt to be clinically unimportant. Results: Sixty-six subjects completed the English and 48 subjects the Chinese EQ-5D. The 95% CI of the score differences between these versions overlapped with but did not fall completely within pre-defined equivalence margins for 4 EQ- 5Ditems, utility andEQ-VASscores. For example, the95%CIof the adjusted score difference between these EQ-5D versions was 0.14 to ž0.03 points for utility scores and 11.6 to ž3.3 points for EQ-VAS scores (equivalence margins of 0.05 to ž0.05 and 5.0 to ž5.0 respectively). Conclusion: These data provide promising evidence for the measurement equivalence of English and Chinese EQ-5D versions. This is an open source publication. The full free text is available at: www.hqlo.com/content/1/1/7.

3 . Read the following abstract. The RR for cryotherapy has been removed. Calculate this value using the information provided in the abstract. Interpret this relative risk and the associated CI.

Treatment of retinopathy of prematurity with topical ketorolac tromethamine: a preliminary study. Avila-Vazquez, M., Maffrand, R., Sosa, M., Franco, M., De Alvarez, B.V., Cafferata, M.L., and Bergel, E. BMC Pediatrics 2004:4(1); 15. Background: Retinopathy of Prematurity (ROP) is a common retinal neovascular disorder of premature infants. It is of variable severity, usually heals with mild or no sequelae, but may progress to blindness from retinal detachments or severe retinal scar formation. This is a preliminary report of the effectiveness and safety of a new and original use of topical ketorolac in preterm newborn to prevent the progression of ROP to the more severe forms of this disease. Methods: From January 2001 to December 2002, all 59 preterm newborns with birthweight less than 1,250 g or gestational age less than 30 weeks of gestational age admitted to neonatal intensive care were eligible for treatment with topical ketorolac (0.25 mg every 8 hours in each eye). The historical comparison group included all 53 preterm newborns, with the same inclusion criteria, admitted between January 1999 and December 2000. Results: Groups were comparable in terms of weight distribution, Apgar score at 5 minutes, incidence of sepsis, intraventricular hemorrhage and necrotizing enterocolitis. The duration of oxygen therapy was significantly longer in the control group. In the ketorolac group, among 43 children that were alive at discharge, one (2.3%) developed threshold ROP and cryotherapy was necessary. In the comparison group 35 children survived, and six child (17%) needed cryotherapy (relative risk [DELETED], 95% CI, 0.00– 0.80, p ¼ 0.041). Adjusting by duration of oxygen therapy did not significantly change these results. Adverse effects attributable to ketorolac were not detected. Conclusions: This preliminary report suggests that ketorolac in the form of an ophthalmic solution can reduce the risk of developing severe ROP in very preterm newborns, without producing significant adverse side effects. These results, although promising, should be interpreted with caution because of the weakness of the study design. This is an inexpensive and simple intervention that might ameliorate the progression of a disease with devastating consequences for children and their families. We believe that next logical step would be to assess the effectiveness of this intervention in a randomized controlled trial of adequate sample size. This is an open source publication. The full free text is available at: www.biomedcentral.com/1471-2431/4/15.

4. Read the following abstract. The relative risks for reduced blood loss, shivering, and pyrexia have been removed. Calculate these values using the information provided in the abstract. Interpret these relative risks and their associated CIs.

Misoprostol for treating postpartum haemorrhage: a randomized controlled trial [ISRCTN72263357]. Hofmeyr, G.J., Ferreira, S., Nikodem, V.C., Mangesi, L., Singata, M., Jafta, Z., Maholwana, B., Mlokoti, Z., Walraven, G., and Gulmezoglu, A.M. BMC Pregnancy & Childbirth 2004: 4(1); 16. Background: Postpartum haemorrhage remains an important cause of maternal death despite treatment with conventional therapy. Uncontrolled studies and one randomized comparison with conventional oxytocics have reported dramatic effects with high-dose misoprostol, usually given rectally, for treatment of postpartum hemorrhage, but this has not been evaluated in a placebo-controlled trial. Methods: The study was conducted at East London Hospital Complex, Tembisa and Chris Hani Baragwanath Hospitals, South Africa. Routine active management of the third stage of labor was practiced. Women with more than usual postpartum bleeding thought to be related to inadequate uterine contraction were invited to participate, and to sign informed consent. All routine treatment was given from a special ‘Postpartum Haemorrhage Trolley’. In addition, participants who consented were enrolled by drawing the next in a series of randomised treatment packs containing either misoprostol 5  200 microg or similar placebo, which were given 1 orally, 2 sublingually and 2 rectally. Results: With misoprostol there was a trend to reduced blood loss $500 ml in 1 hour after enrolment measured in a flat plastic ‘fracture bedpan’, the primary outcome (6/117 vs. 11/120, relative risk [DELETED]; 95% confidence interval 0.21–1.46). There was no difference in mean blood loss or haemoglobin level on day 1 after birth < 6 g/dl or blood transfusion. Side effects were increased, namely shivering (63/116 vs. 30/118; [DELETED], 1.50–3.04) and pyrexia > 38.5 degrees C (11/114 vs. 2/118; [DELETED], 1.29–25). In the misoprostol group three women underwent hysterectomy of whom 1 died, and there were two further maternal deaths. Conclusions: Because of a lower than expected incidence of the primary outcome in the placebo group, the study was underpowered.We could not confirm the dramatic effect of misoprostol reported in several unblinded studies, but the results do not exclude a clinically important effect. Larger studies are needed to assess substantive outcomes and risks before misoprostol enters routine use. This is an open source publication. The full free text is available at: www.biomedcentral.com/1471-2393/4/16.

5. Read the following abstract. The authors report an adjusted OR of 5.0 for low socioeconomic index. Compute a crude OR using the data that appears in the abstract. Does it differ much from the adjusted OR? Interpret the adjusted odds ratio and its associated CI.

Socioeconomic disparities in intimate partner violence against Native American women: a cross-sectional study. Malcoe, L.H., Duran, B.M., and Montgomery, J.M. BMC Medicine 2004: 2(1); 20. Background: Intimate partner violence (IPV) against women is a global public health problem, yet data on IPV against Native American women are extremely limited. We conducted a cross-sectional study of Native American women to determine prevalence of lifetime and past-year IPV and partner injury; examine IPV in relation to pregnancy; and assess demographic and socioeconomic correlates of past-year IPV. Methods: Participants were recruited from a tribally operated clinic serving low-income pregnant and childbearing women in southwest Oklahoma. A self-administered survey was completed by 312 Native American women (96% response rate) attending the clinic from June through August 1997. Lifetime and past-year IPV were measured using modified 18-item ConflictTactics Scales.Asocioeconomic index was created based on partner’s education, public assistance receipt, and poverty level. Results: More than half (58.7%) of participants reported lifetime physical and/or sexual IPV; 39.1% experienced severe physical IPV; 12.2% reported partner-forced sexual activity; and 40.1% reported lifetime partner-perpetrated injuries. A total of 273 women had a spouse or boyfriend during the previous 12 months (although all participants were Native American, 59.0% of partners were non-Native). Among these women, past-year prevalence was 30.1% for physical and/or sexual IPV; 15.8% for severe physical IPV; 3.3% for forced partner-perpetrated sexual activity; and 16.4% for intimate partner injury. Reported IPV prevalence during pregnancy was 9.3%. Pregnancy was not associated with past-year IPV (OR ¼ 0.9). Pastyear IPV prevalence was 42.8% among women scoring low on the socioeconomic index, compared with 10.1% among the reference group. After adjusting for age, relationship status, and household size, low socioeconomic index remained strongly associated with past-year IPV (OR ¼ 5.0; 95% CI, 2.4, 10.7). Conclusions: Native American women in our sample experienced exceptionally high rates of lifetime and past-year IPV. Additionally, within this low-income sample, there was strong evidence of socioeconomic variability in IPV. Further research should determine prevalence of IPVagainst Native American women from diverse tribes and regions, and examine pathways through which socioeconomic disadvantage may increase their IPV risk. This is an open source publication. The full free text is available at: www.biomedcentral.com/1741-7015/2/20.

6. Read the following abstract. The crude ORs for fissured tongue and for benign migratory glossitis have been removed from this abstract. Calculate these values using the information provided in the abstract. Interpret these odds ratios and the associated CIs.

Tongue lesions in psoriasis: a controlled study. Daneshpazhooh, M., Moslehi, H., Akhyani, M., and Etesami, M. BMC Dermatology 2004: 4(1); 16. Background: Our objective was to study tongue lesions and their significance in psoriatic patients. Methods: The oral mucosa was examined in 200 psoriatic patients presenting to Razi Hospital in Tehran, Iran, and 200 matched controls. Results: Fissured tongue (FT) and benign migratory glossitis (BMG) were the two most frequent findings. FT was seen more frequently in psoriatic patients (n ¼ 66, 33%) than the control group (n ¼ 19, 9.5%) [OR: [DELETED]; 95% CI, 2.61–8.52] (p-value < 0.0001). BMG, too, was significantly more frequent in psoriatic patients (28 cases, 14%) than the control group (12 cases, 6%) (OR: [DELETED]; 95% CI, 1.20–5.50) (p-value < 0.012). In 11 patients (5.5%), FT and BMG coexisted. FT was more frequent in pustular psoriasis (7 cases, 53.8%) than erythemato-squamous types (56 cases, 30.4%). On the other hand, the frequency of BMG increased with the severity of psoriasis in plaque-type psoriasis assessed by psoriasis area and severity index (PASI) score. Conclusions: Nonspecific tongue lesions are frequently observed in psoriasis. Further studies are recommended to substantiate the clinical significance of these seemingly nonspecific findings in suspected psoriatic cases. This is an open source publication. The full free text is available at: www.biomedcentral.com/1471-5945/4/16.

7. Read the following abstract. The authors report an adjusted OR of 0.19 for presence of contraindication. Compute a crude OR using the data that appears in the abstract. Does it differ much from the adjusted OR? Interpret the adjusted OR and its associated CI.

Breastfeeding practices in a cohort of inner-city women: the role of contraindications. England, L., Brenner, R., Bhaskar, B., Simons-Morton, B., Das, A., Revenis, M., Mehta, N., and Clemens, J. BMC Public Health 2003: 3(1); 28. Background: Little is known about the role of breastfeeding contraindications in breastfeeding practices. Our objectives were to (1) identify predictors of breastfeeding initiation and duration among a cohort of predominantly low-income, inner-city women, and (2) evaluate the contribution of breastfeeding contraindications to breastfeeding practices. Methods: Mother–infant dyads were systematically selected from three District of Columbia hospitals between 1995 and 1996. Breastfeeding contraindications and potential predictors of breastfeeding practices were identified through medical record reviews and interviews conducted after delivery (baseline). Interviews were conducted at 3–7 months postpartum and again at 7–12 months postpartum to determine breastfeeding initiation rates and duration. Multivariable logistic regression analysis was used to identify baseline factors associated with initiation of breastfeeding.Cox proportional  hazards models were generated to identify baseline factors associated with duration of breastfeeding. Results: Of 393 study participants, 201 (51%) initiated breastfeeding. A total of 61 women (16%) had at lease one documented contraindication to breastfeeding; 94% of these had a history of HIV infection and/or cocaine use. Of the 332 women with no documented contraindications, 58% initiated breastfeeding, vs. 13% of women with a contraindication. In adjusted analysis, factors most strongly associated with breastfeeding initiation were presence of a contraindication (adjusted OR [AOR], 0.19; 95% confidence interval [CI], 0.08– 0.47), and mother foreign-born (AOR, 4.90; 95% CI, 2.38–10.10). Twenty-five percent of study participants who did not initiate breastfeeding cited concern about passing dangerous things to their infants through breast milk. Factors associated with discontinuation of breastfeeding (all protective) included mother foreign-born (hazard ratio [HR], 0.55; 95% CI, 0.39–0.77) increasing maternal age (HR for 5-year increments, 0.80; 95% CI, 0.69–0.92), and infant birth weight > or ¼ 2500 grams (HR, 0.45; 95% CI, 0.26–0.80). Conclusions: Breastfeeding initiation rates and duration were suboptimal in this inner-city population. Many women who did not breastfeed had contraindications and/or were concerned about passing dangerous things to their infants through breast milk. It is important to consider the prevalence of contraindications to breastfeeding when evaluating breastfeeding practices in high-risk communities. This is an open source publication. The full free text is available at: www.biomedcentral.com/1471-2458/3/28.

8. Read the following abstract. The number needed to treat (NNT) for 60% of attempts at sexual intercourse being successful, and the number needed to harm (NNH) for treatment-related adverse events have been removed. Calculate these values using the information provided in the abstract. Interpret these values and their associated CIs.

Sildenafil (Viagra) for male erectile dysfunction: a meta-analysis of clinical trial reports. Moore, R.A., Edwards, J.E., and McQuay, H.J. BMC Urology 2002: 2(1); 6. Background: Evaluation of company clinical trial reports could provide information for meta-analysis at the commercial introduction of a new technology. Methods: Clinical trial reports of sildenafil for erectile dysfunction from September 1997 were used for metaanalysis of randomized trials (at least four weeks duration) and using fixed or dose optimization regimens. The main outcome sought was an erection, sufficiently rigid for penetration, followed by successful intercourse, and conducted at home. Results: Ten randomized controlled trials fulfilled the inclusion criteria (2,123 men given sildenafil and 1,131 placebo). NNT or NNH were calculated for important efficacy, adverse event and discontinuation outcomes. Dose optimization led to at least 60% of attempts at sexual intercourse being successful in 49% of men, compared with 11% with SIMON: Statistical Evidence in Medical Trials 06-simon-chap06 Revise Proof page 164 10.11.2005 11:18am 164 What Do All These Numbers Mean? placebo; the NNT was [DELETED] (95% confidence interval 2.3–3.3). For global improvement in erections the NNT was 1.7 (1.6–1.9). Treatment related adverse events occurred in 30% of men on dose optimized sildenafil compared with 11% on placebo; the NNH was [DELETED] (4.3–7.3). All cause discontinuations were less frequent with sildenafil (10%) than with placebo (20%). Sildenafil dose optimization gave efficacy equivalent to the highest fixed doses, and adverse events equivalent to the lowest fixed doses. Conclusion: This review of clinical trial reports available at the time of licencing agreed with later reviews that had many more trials and patients. Making reports submitted for marketing approval available publicly would provide better information when it was most needed, and would improve evidence-based introduction of new technologies. This is an open source publication. The full free text is available at: www.biomedcentral.com/1471-2490/2/6.

9. The following Kaplan-Meier survival curve represents survival probabilities for mechanically ventilated patients with severe acute respiratory syndrome (SARS). Estimate the median survival for the subgroup of patients with pneumothorax. Estimate the median survival for the subgroup without pneumothorax. In each subgroup, estimate the fraction of patients who will be expected to survive at least 25 days. 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 Days after ventilator use Survival probability Without pneumothorax With pneumothorax This image is from an open source publication. You can find the original article at: www.ccforum.com/content/9/4/R440 and this particular figure at: www.ccforum.com/content/9/4/r440/figure/F1.

10. The following Kaplan-Meier survival curve represents the probability that a patient avoids readmission after an initial visit to a hospital in  Manchester, UK. For patients in the affluent class, estimate the proportion who were readmitted in the first 200 days. Estimate that same proportion for patients in the deprived class. 1.0 .9 .8 .7 0 28 56 84 112 140 168 196 224 252 280 308 336 364 Time (days) Readmission free proportion Affluent.

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