eee Question One CANDIDATE SHEET (23 MARKS) Evaluation of lipid profile in adolescents during long-term use of combined oral hormonal contraceptives Contraception 71 (2005) 118-121 Qla. Qib. Q@. Q@. Qs Q@. Qi. Q8a. QS8b. Q@. QU0. ‘What was the stated primary objective of this study? In what ways was that objective, as stated, not achievable? No more than 2 examples required. The authors do not state a prior hypothesis but, if they had, what should it have been? There are two possible correct answers, either is acceptable and stating both will earn maximum marks. Was the design of this study longitudinal, oblique, cross sectional or circular? What was the overall drop out rate for participants in this study? How did the authors seek to eliminate potential confounding factors? Up to 6 points will be awarded. Why did the study require ethical approval? Up to 4 points will be awarded, Which lipid component was determined indirectly? What was the advantage of being able to use a paired (as opposed to an iable? unpaired) t-test to compare average values of each vi Is the t-test a parametric or a non-parametric statistical test? How many of the subjects who completed the study had previously been pregnant? Did the subjects’ lipid profile change significantly between the second and third years of the study? 2 Marks 2 Marks 2 Marks. 1 Mark 1 Mark 6 Marks. 4 Marks 1 Mark 1 Mark 1 Mark 1 Mark 1 Mark Maximum 23 MarksQuestion One Evaluation of lipid profile in adolescents during long-term use of combined oral hormonal contraceptives Christina Aparecida Falbo Guazzelli, Prescilla Chow Lindsey, Fabio Femando de Araijo, Marcia Barbier, Carlos Alberto Pett, Jose Mendes Alinghi Contraception 71 (2005) 118-121 1. Introduction Combined oral contraceptives (COC) are popular among adolescents since they are highly efficient and easy to use. Although the consequences of their use have been exten- sively reviewed in adult women, there have been few studies involving adolescents. The most feared complications of oral hormonal contraceptives include thromboembolic phenomena and cardiovascular disease. Previous studies have demonstrated that atherosclerosis is a process that begins in young adults and can be accelerated by the presence of risk factors such as smoking, alcohol, obesity and —oral_-hormonal contraceptives ‘The objective of this study was to evaluate the effects of the long-term use of monophasic combined hormonal oral contraceptives on the lipid metabolism of adolescents. 2. Materials and methods All adolescents attending the Family Planning Clinic of Sao Paulo Federal University who elected COC as their method Table 1 Lipid profile of of choice were invited to participate in the study. Of the initial 80 participants, 58 completed 1 year of study, 50 completed 2 years and 33 completed 3 years. Therefore, the study population consisted of 33 adolescents who used monophasic oral hormone contraceptive (21 tablets monthly containing gestodene 75 ig and ethinyl estradiol 30 pg each) who were prospectively evaluated for 3 years. The study was approved by the Ethics Commitee of UNIFESP (Universidade Federal de Sao Paulo) and all participants signed an informed consent form. The exclusion criteria were: WHO medical cligibility criteria categories 3 and 4; use of an oral hormonal contraceptive in the three previous months prior to entry in the study; concomitant use of medications that might interfere in lipid metabolism (thiazides, corticosteroids, B-blockers, cyclosporine); smoking; cholesterol values higher than 199 mg/dL at baseline; hemoglobin lower than 12 pidL; body mass index (BMI; weight/height’) higher than 95th percentile; family history of thromboembolic diseases or myocardial infarct before 50 years of age in men and 60 years in women. adolescents using oral hormonal contraceptives for 3 years Parameter Baseline (TO) __After_year (T1)_ ‘After 2 years (T2) ‘After 3 years (T3) Cholesterol 148.06+23.78 _178.82+36.36* HDL-C 40.24410.07 47.97410.51* LDL-C 91.7H19.15 111.21430.08* Triglycerides _ 80.52432.34 98.30440.54** 184.0635.05 50.8510.05* 113.55432.35* 98.33443.619* 184.15136.35* 53.94414.59% 111.39437.51"* _99.AS+44.74°* * p<.001 paired test in comparison with baseline values. se pe0s; CRQT 1of4Question One CRQI All participants were healthy and had normal physical and gynecological exams before starting contraceptive use. These were repeated every 3 months during the 3-year study period. ‘The lipid profile consisted of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipo- protein cholesterol. (LDL-C) and triglycerides before (T0) and after 1 (TI), 2 (T2) and 3 (T3) years of oral hormonal contraceptive use. The levels of each parameter obtained at baseline were considered as control values for cach patient. Total cholesterol values below 199 mg/dL and LDL-C below 129 mg/dl. were considered normal and triglyceride levels were classified as adequate when lower than 131 mg/dL. Measurements were made throughout the 3 years of the study, immediately after each Sample collection. 2.1. Laboratory assays Enzyme kits and an auto-analyzer were used to determine total cholesterol, HDL- C and triglyceride levels. Cholesterol was measured on supernatant using the ADVIA 1650-Bayer colorimetric enzyme kit. According to solution characteristics, concentrations up to 500 mg/dL. were detectable. HDL-C was quantified using the same technique as for cholesterol, after precipitation with dextran sulfate VLDL-C_ was obtained dividing triglyceride values by 5. This method could be used since triglycerides levels were <400 mg/dL in all samples. 2.2. Statistical analysis The sample size was calculated as a minimum of 30 patients followed-up for 3 years, with a 90% power to detect differences of 1 standard deviation 2o0f4 comparing the four annual averages. Significance was established at 5% ‘A paired ¢ test was used to compare average values of each variable (total cholesterol, HDL-C, LDL-C and triglycerides). Confidence intervals were set at 95% (y=0.95 or 95%) 3. Results ‘The mean age at entry was 16.6 years and average age at menarche was 12.4 years with a standard error of 0.2 years. ‘The mean age at first intercourse was 15.4 and 72.7% of the patients had no previous pregnancies. Compared to baseline values, total cholesterol levels increased significantly afier 1 (TI), 2 (T2) and 3 (T3) years of contraceptive use (Table 1), as did HDL- C values. At baseline, 11 adolescents had HDL-C below 35 mg/dL. After starting contraceptives and throughout the study period, only four measurements were lower than 35 mg/dL. In five adolescents, total cholesterol level rose above normal limits (199 mg/dL) during the 3-year study period None of these patients had BMI above the 95th percentile. Triglycerides and LDL-C also increased significantly after 1, 2 and 3 years of oral hormonal contraceptive use (Table 1). In the second and thitd years of the study, cholesterol, HDL-C, LDL-C and triglyceride levels did not differ significantly from those obtained in the first year. 4. Discussion Atherosclerosis is an important cause of adult mortality and its prevention can be initiated in childhood through adequate evaluation of ~— family _ historyQuestion One (hypercholesterolemia. or early myocardial infarct) and periodic exams of cholesterol levels. Several additional risk factors have been identified, such as smoking, obesity, hypertension, diabetes and high levels of cholesterol. Adolescence is a time of great personal changes and frequently marks the beginning of undesirable habits such as smoking, sedentary lifestyle and improper cating patterns, such as the ingestion of large amounts of food rich in saturated fat. Frequently, it is also the period of sexual initiation, hence the need for contraceptive methods. Adolescents frequently prefer oral hormonal contraceptives because they are highly efficient, reduce dysmenorrhea and improve menstrual cycle control. Consequences of oral contraceptive use have been widely studied in adult women but the adolescent population has been less studied. Therefore, recommendations for the prescription of OC to adolescents are largely based on guidelines originally designed for adult women. In this study, we observed a statistically significant elevation in total cholesterol, HDL-C, LDL-C and trigly- cerides levels. Although this increase alone may not jeopardize the health of a young adult, it could increase the effect of other risk factors In adolescence, interaction of risk factors is common, especially smoking and obesity. Since up to 30-35% of adolescents smoke and this habit could modify their lipid profile, we decided to exclude all smokers from this study. Obesity, a frequent condition in adolescents, has been associated with elevated levels of triglycerides and total cholesterol and a decrease in HDL-C. ‘These lipoprotein modifications may predispose to lipid deposits in the aorta and coronaries, initiating atherosclerosis. It should be noted that five young women who showed persistent and CRQI abnormal increase in cholesterol levels throughout the 3-year study period presented normal BMI and did not smoke. ‘A possible explanation for these findings could be the use of oral hormonal contraceptives. Similarly, in a recent study, total cholesterol levels were significantly higher in contraceptive users compared to non users with similar BMI. Throughout adolescence, _total cholesterol levels as well as HDL-C and LDL-C tend to decrease, while in the last years of puberty, girls may have a slight increase of HDL-C level. Thus, in this study, it is possible that oral hormonal contraceptive use was the cause of persistent elevation in total cholesterol levels in the five young women referred to previously because they were neither obese nor smokers. ‘One of the main changes observed in the lipid profile of adolescents is the decline in HDL-C starting around 10 years of age, followed by a slight increase in girls around their 14th birthday, probably due to the effect of estrogen on lipoproteins. Users of low-dose oral hormonal contraceptive, especially those containing the new progestogens, such as desogestrel or gestodene, show an increase in serum levels of HDL-C. Similar to the findings deseribed in the literature, the results of the present study seem to indicate that the use of oral hormonal contraceptives may be associated with elevation of HDL-C levels. The role of triglycerides in atherosclerosis is not quite clear but some studies have suggested that their increase may lead to elevation of coagulation factors (VIL, VII and X) and changes in fibrinolytic activity. In most children, hypertriglyceridemia is a manifestation of VLDL-C increase with a generally normal cholesterol level.Question One The use of estrogen, diuretics, alcohol or the presence of diabetes, chronic renal failure and hypothyroidism are the most common causes of secondary hypertriglyceridemia and is explained by the reduction in lipoprotein lipase activity in removing excess serum triglycerides. Some studies have reported an increase in scrum levels of triglycerides in users of oral hormone contraceptives, regardless of their composition. This finding could reflect an increase in the hepatic synthesis, of VLDL-C or a decrease of serum VLDL-C lipolysis by lipoprotein lipase. It could also be attributed to estrogen action in changing liver lipase activity. In this study, triglyceride levels increased significantly after _ starting contraceptives, but did not exceed normal range (130 mg/dL), There are few published studies similar to this one where adolescents using OC were prospectively followed over a long period of time (3 years). This may be due, in part, to difficulties in the follow-up and clinical control of this population. Most studies compare differences between users and nonusers of OC using data collected through questionnaires and a glycocorticoids, CRQI 40f4 single exam. In modem times, sexual initiation starts early and pregnancy is frequently delayed until the thirties. This has created a demand for contraceptive methods that are at the same time efficient and safe to use for a long period of time. Our findings suggest the prolonged use of OC may induce the beginning of atherogenesis. This raises an important question: should adolescent users of OC be submitted to routine periodic lipid profile sereening? While there is no consensus in the scientific literature, most recommend these tests only for women with coronary disease or other risk factors. Nevertheless, oral hormonal contraceptives tend to be used by increasingly younger women and the early detection ‘of lipid alterations could be important, leading to preventive measures such as modification of eating habits, initiation of physical activity and periodic physical exams. All these steps are important in reducing long-term morbidity, even for young people. The clinical relevance of our findings can only be evaluated through large studies with adolescents using COC over a long period of time@crQ Question One EEE MARKING SHEET (23 MARKS) Examiner __ Evaluation of lipid profile in adolescents during long-term use of combined oral hormonal contraceptives Contraception 71 (2005) 118-121 ‘Serious Concerns / Comments Marked Exmr 1 Marked Exmr 2 ‘Scores checked? Marked Exmr 3 ] Marking Complete Clear Fail ] Borderline Clear Pass ] ‘Qla._ What was the stated primary objective of this study? Marks Exmr Marks QIb. In what ways was that objective, as stated, not achievable (no more than 2 examples required) Ala, To evaluate the effects of the long-term use of monophasic combined hormonal oral contraceptives on the lipid metabolism of adolescents Alb. (i) The study involved the use of only one specific monophasic COC and would not allow an assumption that the findings relate to combined hormonal oral contraceptives in general (ii) The 3-year duration of the study cannot be regarded as “long-term” (iit) The study was concerned with observation of lipid profiles, not metabolism (iv) There was no comparator group Max 4 mark, Subtotal az ' pro@crq Question One us MARKING SHEET (23 MARKS) Q2._ The authors do not state a prior hypothesis but, i they had, what should Marks Exmr Marks have been (there are two possible correct answers, either is acceptable and stating both will earn maximum marks)? ‘AZ. i) Long-term use of monophasic combined hormonal oral contraceptives has no significant effect on the lipid metabolism of adolescents. z ii) The lipid metabolism of adolescents is significantly affected by long-term use of monophasic combined hormonal oral contraceptives z Q3._ Was the design of this study longitudinal, oblique, cross sectional or circular? Marks Exar Marks ‘AB. Longitudinal ; ‘Qh What was the overall drop out rate Tor participants im this study? Marks Exmr Marks Aa. 47/80 = 58.75% Q5._ Flow did the authors seek to eliminate potential confounding Iactors? Marks Exmr Marks Up to 6 points will be rewarded ‘AS. _ By excluding subjects in the following categories:- al oO (i) Use of a hormonal contraceptive in the three previous months prior to entry into t Gi) Concomitant use of medications that might interfere with lipid metabolism (ii) Smoking (ix) Baseline cholesterol values greater than 199 mg/dl (©) BMI greater than 95" percentile (vi) Family history of myocardial infarction before 50 years of age in men and 60 years in women. Max 10 mark, Subtotal ___ 0 2 PTOQuestion One Deel MARKING SHEET (23 MARKS) Q6._ Why did the study require ethical approval? Up to points willbe rewarded Marks Exmr Marks A6. (i) Because it involved clinical research, (i) Because the subjects were healthy vohmteers 4 (iii) Because the subjects were students (who are a potentially | vulnerable subject group) Gv) Because the research involved invasive tests (blood tests) Qi__ Which lipid component was determined indirectly? Marks Exmr Marks ‘AT. VLDC-C QSa._ What was the advantage of being able to use a paired (as opposed to an Marks Exmr Marks unpaired) t-test to compare average values of each variable? QSb. Is the test a parametric or a non-parametric statistical test? ‘ASa. Greater statistical power A8b. Parametric QB. How many of the subjects who completed the study had previously Marks Exmr Marks been pregnant? Av. 9 Qi. Did the subjects: lipid prof third years of the study? ‘Ai0. No Marks Exmr Marks Max 9 marks, Subtotal TOTAL MARKS (out of 23) _ PLEASE TICK ONE OPTION NOW: Clear Fi Bordertine| Clear Pass — EndCANDIDATE SHEET (13 MARKS) Hormone treatment increases breast cancer risk, study shows Mayor S, BMJ 327: 359 QI. Which 2 of the following terms correctly describe the design of the study to 2 Marks which this commentary relates? i) Drug trial ii) Cohort study iii) Qualitative research iv) Randomised controlled trial v) Observational study vi) Meta-analysis vii) Clinical guideline Q2. What were the principal outcome measures of the study to which the article 2 Marks relates? Q3a. For women who used preparations of HRT containing both oestrogen and 1 Mark progestogen, what was the order of magnitude of increased risk of developing breast cancer compared with never users of HRT? Q3b. Was this increased risk statistically significant? 1 Mark QBe._ Explain your answer to (b) 1 Mark Qda. At age 65, what was the excess mumber of cases of breast cancer per 1000 1 Mark women for those who used oestrogen + progestogen HRT for 10 years, compared with never users? Qdb. At age 65 what was the excess number of eases of breast cancer per 1000 women 1 Mark for those who used unopposed oestrogen HRT for 10 years, compared with never users? QS. The article contains the following quote, “since our results show a substantially 4 Marks greater increase in breast cancer with combined HRT, women need to weigh the increased risk of breast cancer caused by the addition of progestogen against the lowered risk of uterine cancer” In order to respond to this suggestion, what additional information, not given in this study, would women need? Give two items of information. Maximum Marks 13Question Two Hormone treatment increases breast cancer risk, study shows ‘Susan Mayor London Long term use of combined hormone replacement therapy (HRT) doubles the risk of breast cancer, according to a major epidemiological study published last week that showed for the first ime the higher risk with combined oestrogen and progestogen treatment. From 1996 to 2001 the million women study recruited 1 084 110 women in the United Kingdom aged 50-64 years. When they were invited to attend for routine mammography the women were asked to complete a questionnaire that included questions about their use of HRT. They were followed up for mortality and incidence of cancer The results of the study, published in the Lancet (2003; 362:419-27), showed that current users of all types of HRT, including oe only, combined oestrogen and progestogen, and tibolone (synthetic hormone treatment), had a higher risk of breast cancer than women who had never used HRT (adjusted relative risk 1.66 (95% confidence interval 1.58 to 1.75; P<0,0001). The risk of breast cancer increased with longer use of HRT, but the effect seemed to wear off within a few years of stopping treatment. Also, the relative risk of death was 22% higher in current users than in women who had never used HRT (relative risk 1.22 (1.00 to 1.48; P=0.05)). The risk was even higher in women who used combined HRT ~ the type of HRT that is generally recommended for women with a uterus (relative risk 2.00 (1.88 to 2.12; P<0.001)). The researchers estimated that use of HRT in women aged 50-64 years has resulted in 20 00 extra cases of breast cancer over the past decade, of which 15 000 would be associated with combined HRT. Valerie Beral, professor of epidemiology at the Cancer Resear at the Radcliffe Infirmary, Oxford, and one of (ce our results show a substantially great J HRT, women need to weigh the increased risk Estimated cumulative incidence of breast cancer and hormone Cee OULU EL ue ke Ce ee a — 10 years’ use of combined HAT =- = 10 years’ use of estrogen only HAT Never used HAT Co ‘Aga (years) to start HRT should be between each woman and her doctor.” He pointed out the er, crease until after one year 0Question Two @crQ bee} MARKING SHEET (13 MARKS) Hormone treatment increases breast cancer risk, study shows. Mayor S, BMJ 327: 359 Serious Concerns / Comments. Marked Exmr 1 Marked Exmr 2 Scores checked? Marked Exmr 3 Marking Complete Clear Fait [ Bordering Clear Pass QU. Which 2 of the following ten 1) Drug tial vi) Meta-analysis vil which this commentary relates? iv) Randomised controlled trial ¥) Observational study ical guideline correctly describe the design of the study to Marks Exmr Marks 8i) Cohort study i) Qualitative research ‘AL. ii, Cohort study vy. Observational study QZ. What were the principal outcome measures of the stady to which the article relates? Exmr Marks ‘AZ. Mortality Incidence of (breast) cancer Qa. For women who used preparations of HIRT containing both oestrogen and Marks Exmr Marks progestogen, what was the order of magnitude of increased risk of developing breast cancer compared with never users of HRT? ‘A3a. 2 (or double or two-fold) a o=_ Max 5 marks. Subtotal 1 PIO.cra Question Two MARKING SHEET (13 MARKS) QBb._Was this increased risk statistically significant? Marks Exmr Marks dt A3b. Yes A QGex_ Explain your answer to (b) Marks Exmr Marks ‘A3e._ 95% confidence interval does not span 1 , Qa, Atage 65, what was the excess number of cases of breast cancer per Marks Exe Marks 1000 women for those who used oestrogen + progestogen HRT for 10 years, compared with never users? ‘Ada. 19 (but accept 18 or 20) ; Qab. Atage 65 what was the exces number of cases of Breast cancer per Marks Exmr Marks 1000 women for those who used unopposed oestrogen HRT for 10 years, compared with never users? Atb. 5 a Qo > Max 4 marks. Subtotal Pro@crQ Question Two Bed MARKING SHEET (13 MARKS) QE. The article contains the following quote, "since our results show & Marks Exar Marks substantially greater increase in breast cancer with combined HRT, women need to weigh the increased risk of breast cancer caused by the addition of progestogen against the lowered risk of uterine cancer” In order to respond to this suggestion, what additional information, not given in this study, would women need? Give two items of information. "AS. ‘The magnitude of risk of uterine cancer from taking unopposed oestrogen. (2 marks) ‘The risk of death from uterine cancer, compared to the risk of death from breast cancer. (2 marks) The morbidity of treatment for uterine cancer, compared with the morbidity of treatment for breast cancer. (2marks) MAX 4 marks Max 4 marks, Subtotal TOTAL MARKS (out of 13) PLEASE TICK ONE OPTION NOW: | Clear Fai co 3 EndQuestion Three CANDIDATE SHEET (18 MARKS) Coverage and Uptake of Systematic Postal Screening for genital Chlamydia Trachomatis Infection and prevalence of infection in the United Kingdom general popula ‘Macleod J et al. BMJ Vol 330 23 April 2005 940-942, QI. What were the 3 main objectives of the study? Q2. What type of survey is this, cross-sectional, oblique, longitudinal or circular? Q3a. How did the authors avoid selection bias? Q3b. Why might you lack confidence in the method, as stated, they used? Q4. What type of chlamydia test was used in the study? Q5. What did the authors do to attempt to increase the screening uptake? (Up to 4 points will be rewarded.) Q6. What do the authors report as the overall uptake of screening? QTa. Look at Table 1 ‘What was the cumulative number of people that responded to the full range of forms of invitation? Q7b. In the 16-24 age group, who had the higher prevalence, men or women? QBa. Look at Table 2 Which group had the highest prevalence of infection? Q8b. Give the prevalence of infeetion in this group with confidence intervals Q9. Give 2 major weaknesses of postal screening for chlamydia 3 Marks 1 Mark 1 Mark 1 Mark 1 Mark 4 Marks 1 Mark 1 Mark 1 Mark 1 Mark Mark 2 Marks Maximum 18 Marks loflQuestion Three Primary care Coverage and uptake of systematic postal screening for genital Chlamydia trachomatis and prevalence of infection in the United Kingdom general population John Macleod, Chris Salisbury, Nicola Low, Anne McCarthy, Jonathan A C Sterne, Aisha Holloway, Rita Patel, Emma Sanford, Andrea Morcom, Paddy Horner, George Davey Smith, Susan Skidmore, Alan Herring, Owen Caul, F D Richard Hobbs, Matthias Egger Introduction Randomised trials show that systematic screening for genital Chlamydia trachomatis might reduce the incidence of pelvic inflammatory disease by about 50%. We investigated the coverage and uptake of systematic chlamydia screening by post, estimated prevalence of chlamydia, and explored factors associated with these measures. Methods We invited men and women aged 16-39, randomly selected from 27 general practices in the West Midlands and Avon, to collect their own specimens (urine in men, urine and vulvovaginal swab in women) and post them to us, and to complete a questionnaire on risk factors. Invitations and testing kits went to patients' registered address, and we confirmed residence at this address. We used postal reminders, telephone calls, home visits, and "flagging" of records at study practices to encourage participation. Our colleagues in the reference laboratory (SS and AHe) used nucleic acid amplification tests to detect C trachomatis and confirmed positive results. Postal delays did not affect positivity rates (data not shown). Participants with chlamydia received results and treatment at their practice. Notification of partners was undertaken at either the practice or a genitourinary clinic. Statistical analyses of coverage of chlamydia screening (proportion receiving an invitation to be screened), uptake (proportion returning a specimen), and prevalence took into account clustering at the practice level and sampling probability. Results Of 19, 773 people aged 16-39 who had been invited, we contacted 73% (14, 382) successfully. Uptake of screening was 34.5% (95% confidence interval 31.2% to 38.0%) overall, and 31.5% (28.6% to 34.6%) in 16-24 year olds (table 1). After a single postal invitation, uptake was 22.2% (18.6% to 26.2%) in 16-24 year olds and was higher in women than men (table 1). A postal reminder and face to face contact (in ahome visit, orQuestion Three “flagged” patients being invited to participate when they attended their practice) each increased uptake by around 5%. Screening coverage and uptake varied by practice. Coverage was lower in areas with higher proportions of residents from minority ethnic groups, and uptake was lower in practices with higher deprivation scores. The overall prevalence of chlamydia was 2.8% (2.2% to 3.4%) in men and 3.6% (3.1% to 4.9%) in women, but it was higher in people who were younger than 25 (men 5.1%, 4.0% to 6.3%, women 6.2%, 5.2% to 7.8%). Prevalence was below 1% in men older than 24 and women older than 29 years. Prevalence was higher among the subgroup of 16-24 year old women who only participated after repeated contacts (table 1). Having one or more new partners in the past 12 months was the strongest predictor of infection (table 2). The prevalence of chlamydia was also higher in single compared with married women and in men aged 20-24 than in people aged 16-19 years. Prevalence did not vary substantially between practices (I’ = 34% of variation attributable to heterogeneity between practices. We found weak evidence that chlamydia was more common in practices in more deprived areas (adjusted odds ratio for a 10 point increase in deprivation score, 1.2, 1.0 to 1.4, P= 0.077). Conclusion Evidence for the long term effectiveness and impact of chlamydia screening programmes remains limited. Randomised trials to determine the most effective strategy are required. 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Macleod J et al. BMJ Vol 330 23 April 2005 940-942 Serious Concerns / Comments Marked Exmr 1 Marked Exmr 2 | ‘Scores checked? Marked Exmr 3 | Marking Compote clearFat[] _Bontetine clear Pass [] Qi. What were the 3 main objectives of the study? Marks Exmr Marks Al. “To measure coverage and uptake of postal chlamydia screening To estimate the prevalence of genital Chlamydia trachomatis infection To explore factors associated with these methods QZ What type of survey is this, crow sectional, oblique, longitudinal Marks Exmr Marks or circular? ‘2. Cross sectional Ga How did the authors avord selection bias? Marks Exmr Marks Q3b. Why might you lack confidence in the method, as stated, they used? selected randomly Aa. Subjects | A3b._No definition (or description) of how random selection was applied Max 6 marks. Subtotal _} RQ Ve 1 ProBcrQ Question Three MARKING SHEET (18 MARKS) QG__ What type of chlamydia test was used in the study? Marks Exmr Marks Ad, NAAT test ‘i QS. What did the authors do to attempt to increase the screening uptake? Marks Exmr Marks Up to 4 points will be rewarded ‘AS. Confirmed residence at the given address = Sent postal reminders Made telephone calls -Home visits made Flagged records in study practices (Q6._ What do the authors report as the overall uptake of screening? Marks Exmr Marks NG. 345% i Took at Table 1 Marks Exmr Marks Qa. What was the cumulative number of people that responded to the full range of forms of invitation? QD. In the 16-24 age group, who had the higher prevalence, men ATa. 4,740 i ATb. Woman ; oe 2 Max 8 marks. Subtotal proBcrqQ Question Three MARKING SHEE’ (18 MARKS) Failure to reach those at high risk Took at Table 2 Marks Exmr Marks Q8a. Which group had the highest prevalence of infection? Q8b._Give the prevalence of infection in this group with confidence intervals ‘ABa. Those having 2 new sexual partners in the past year ; A8b. 13.9 (9.3 t0 20.7) : QD. Give D major weaknesses of postal screening for chlamydia Marks Exmr Marks "AD. _ Coverage incomplete (or Uptake low) - Max 4 marks, Subtotal TOTAL MARKS (out of 18) PLEASE TICK ONE OPTION NOW: Clear Fail Bordertine| Clear Pass EndBcrQ Question One ee Risk of venous thromboembolism with cyproterone or levonogestrel contraceptives. Vasilakis- Searamozza C et al. Lancet 2001 358, 1427-9 Qla. What was the study design? 1 Mark Q1b. Why is this design suitable to investigate venous 1 Mark thromboembolism in pill users? Qic. List three limitations of this study design. 3 Marks Q2. How did the authors ensure that the women included in 1 Mark the study were current users of the oral contraceptives being studied? Q3. What 4 criteria did the authors apply to ensure that the 4 Marks. ‘controls’ were well matched to the 'index cases"? Q4. What statistical method was used to compare cases 1 Mark and controls? Q5a. Looking at tabl 1 Mark How many times more likely are women taking cyproterone to develop venous thromboembolism compared to women taking levongestrel? Q5b. _ Is the value statistically significant? 1 Mark Q5c. Explain briefly your answer to Q5b, 1 Mark Q5d. Why were the odd ratios (unadjusted and adjusted) 1? 1 Mark Q6. _ Hirsutism and polycystic ovary disease were more common 1 Mark amongst eases and controls. How did the authors show that the increased risk of venous thromboembolism is associated with cyproterone rather than hirsutism and polycystic ovary disease? TOTAL 16 MARKS oq ae 1Question One Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives Extract from: Vasilakis-Scaramozza C, Jick H. Lancet 2001; 358(9291):1427-9 Results of several small studies suggest that individuals who take oral contraceptives containing cyproterone are at increased risk of venous thromboembolism. Such contraceptives are often prescribed for women with a history of hirsutism and acne. Our study population consisted of all women (n=24,401) aged 16-39 years, in the General Practice Research Database, who had received at least one prescription for a low dose oestrogen oral contraceptive containing cyproterone. The database has been used extensively in the past for similar studies. Also included in our study population was a random sample of 75,000 women (of 261,450) who had received levonorgestrel between January 1 1992 and December 31 1999. We chose only a sample of levonorgestrel users for efficiency purposes. From the computer records, we identified all women who were current users of oral contraceptives containing cyproterone or levonorgestrel and who had been admitted to hospital with a first-time diagnosis of idiopathic venous thromboembolism after January 1 1992. We judged a patient a current user if their oral contraceptive prescription was scheduled to last until 28 days or fewer before the index date (date of diagnosis of venous thromboembolism) We asked family doctors for a copy of any referral or hospital discharge letters relating to the diagnosis of venous thromboembolism. Two researchers (CVS, HJ) unaware of which oral contraceptive individuals had received, reviewed the discharge letters and ascertained the status of the individuals. We judged all individuals who received anticoagulation therapy and who had positive Doppler imaging or ventilation perfusion scan results as having had a venous thromboembolism. When discharge letters were not available, potential cases were considered probable if they had a computer-recorded clinical diagnosis of venous thromboembolism and had received anticoagulation therapy. We excluded from analysis women with a history of conditions predisposing to thrombosis, such as history of recent immobilisation, surgery, pregnancy or trauma, and anyone without at least 1 year of history on computer before the index date. We identified up to six controls for every case, matched for age within 1 year and, as far as possible, family practice. All controls had been exposed to cyproterone or levonorgestrel at the index date of their corresponding patient. We did not assess the effect of past exposure to other types of oral contraceptive. Exclusion criteria applied to patients were also applied to controls. Page 1 of 3Question One Cases (n=26) Controls (n=144) Age (mean [SD}) (years) 29.2 (6.4) 29.4 (6.2) Body mass index (kg/m*) <20 14%) 17 (12%) 20-24 8 (31%) 80 (55%) 225 13 (50%) 30 (21%) Unknown, 4 (15%) 17 (12%) ‘Smoking status Non-smoker 13 (50%) 69 (48%) ‘Smoker 8 (31%) 49 (34%) Ex-smoker 1 (4%) 15 (10%) Unknown 4(15%) 11 (8%) Hirsutism 4 (15%) 4 (3%) Acne 8 (31%) 1 (28%) Polycystic ovary disease 2 (8%) 3.(2%) Asthma 2 (8%) 23 (16%) Exposure duration Levonorgestrel <6 months 0 9 (6%) Levonorgestrel >6 months 14 (54%) 105 (73%) Cyproterone <6 months 5 (19%) 7 (5%) Cyproterone >6 months 7 (27%) 23 (16%) Table 1: Characteristics of cases and controlsQuestion One Cases Controls Unadjusted odds Adjusted odds ratio (95% Cl) (95% Cl) Levonorgestrel 14 114 1.0 1.0 Cyproterone 12 30 3.2 (1.4 -7.6) 3.9 (1.1 - 13.4) “Adjusted for body mass index, smoking status and history of hirsutism, acne, polycystic ovary disease and asthma. Table 2: Matched unadjusted and adjusted odds ratios for venous thromboembolism We calculated odds ratio estimates with conditional logistic regression analyses, controlling for potential confounders (smoking, body mass index [BMI], and diagnosis of hirsutism, acne, polycystic ovary disease and asthma). We used patients exposed to levonorgestrel as the reference group for these calculations. Analyses were done with SAS (version 8.00). We identified 26 women taking oral contraceptives containing cyproterone or levonorgestrel who had had an idiopathic venous thromboembolism. The disorder was confirmed in 14 of the 26 individuals, and judged probable in the remainder. The effect estimates for confirmed and probable cases were closely similar, so they were combined for subsequent analyses. Ten individuals had an outcome of pulmonary embolism (five exposed to cyproterone, five exposed to levonorgestrel) and 16 and had an outcome of deep vein thrombosis (seven cyproterone, nine levonorgestrel). Table 1 shows the characteristics of the study population. Polycystic ovary disease and hirsutism were more common among cases than controls. Both conditions were also associated with use of cyproterone (four of five women with polycystic ovary disease and seven of eight women with hirsutism were cyproterone users). Page 3 of 3@cRQ Question One — MARKING SHEET (16 MARKS) Examiner: Risk of venous thromboembolism with cyproterone or levonogestrel contraceptives. Vasilakis- Scaramozza C et al. Lancet 2001 398, 1427-9 Serious Concerns / Comments Marked Exmr 4 Marked Exmr 2 Scores Marked Exmr 3 Checked? Marking Complete Clear Fail Borderline Clear Pass Qia, What was the study design? Marks Exmr Marks ‘Ala, Case control stad ¥ z Qib. Why is this design suitable to investigate venous Marks Exmr Marks thromboembolism in pill users? ‘Alb, Case control studies are good for investigating Fare events + Ql, List three limitations of this study design. Marks Exmr Marks ‘Ale. Difficulty of ensuring that the controls are similar (matched) to the cases, 3 Design cannot demonstrate causality, only association. Cannot calculate ineidence or relative risk, only odds ratios. Retrospective therefore information may not be available or of poor quality Cannot be used to assess the effectiveness of a treatment. Effect of confounding factors. Susceptible to bias. Max 5 marks, Subtotal cr a 1 PTOQuestion One BcrQ MARKING SHEET (16 MARKS) Q2.___ How did the authors ensure that the women included in the Marks Exmr Marks study were current users of the oral contraceptives being studied? AE, Current user = if their oral contraceptive proscription was scheduled to last until 28 days or fewer before the index date 2 (date of diagnosis of venous thromboembolism). Q3. What four criteria did the authors apply to ensure that the Marks Exmr Marks ‘controls’ were well matched to the ‘index cases"? AS. Matched to be within I year ofage Controls came from family practice. 4 All controls had been exposed to cyproterone or levonorgestrel at the index date of their corresponding patient. Exclusion eriteria applied to patients were also applied to controls. (i. What statistical method was used to compare cases and Marks Exmnr Marke controls? Aa. Conditional logistic regression analysis Qian ooking at table Z Marks Exmr Marks How many times more likely are women taking cyproterone to develop venous thromboembolism compared to women taking levongestrel? Ma 39 I Qik, Ta this valve statistically significant? Marks Exmr Marks Rob. Yes I oo Max 8 marks. Subtotal _ PTO.@crQ Question One MARKING SHEET (16 MARKS) ‘Qie. Explain briefly your answer to (@) Marks Exmr Marks ‘Abe. Confidence intervals do not go through T ‘Qi. Why were the odds ratios (unadjusted and adjusted) 1? Marks Exmr Marks ‘Asd, This was the reference group. —_ 6. Hirsutism and polycystic ovary disease were more common Marks Exmr Marks amongst cases and controls. How did the authors show that the increased risk of venous thromboembolism is associated with cyproterone rather than hirsutism and polycystic ovary disease? AG. ‘They controlled for these conditions as potential confounders. L oO Max 3. marks, Subtotal TOTAL MARKS (out of 16) PLEASE TICK ONE OPTION NOW: Clear Fai Borderline| — 8 Clear Pass End