Question 1

Over the course of 5 years, a pediatric endocrinologist has seen a marked increase in the prevalence of depression among patients with obesity in her practice.  She partners with a pediatric psychiatrist to devise a short screening test for depression for this specific population.  The new screening test is found to be 90% sensitive and 84% specific.  If this test is used on a sample of patients with obesity in which 35% are known to have depression The authors of the study decide to conduct an ancillary statistical analysis in which a second cohort of workers employed in the manufacture of domestic textiles is used as the population of reference.  Based on the study results from the first cohort of vinyl chloride workers, which of the following is the most likely reason for the ancillary analysis?
A)All-cause mortality among the vinyl chloride workers is statistically lower than among the general population.
B)Compared to the general population, vinyl chloride workers had a nonstatistically significant association with mortality due to melanoma and lung cancer.
C)Considering a cohort of domestic textile workers reduces the possibility of contamination bias.
D)Misdiagnosis of early angiosarcoma of the liver might have influenced the association between vinyl chloride exposure and hepatocellular carcinoma.
E)The expected number of deaths among domestic textile workers will be greater than in the general population.

Accepted Answer

Explanation: Assessing the effect of exposure to a risk factor in a population of workers requires an appropriate unexposed group for comparison. Working populations are generally healthier than the general population and often exhibit lower mortality rates. This is commonly known as the healthy worker effect (HWE). The HWE is a type of selection bias that may result from severely ill or disabled individuals being excluded from or not entering the workforce. Consequently, mortality rates from the general population may not be appropriate as a reference. Generally, standardized mortality ratios (SMRs) that consider the general population as reference will be biased and underestimate the effect of the exposure to a risk factor (eg, vinyl chloride) in a working population. If available, a demographically similar working population (eg, domestic textile workers) without exposure to the risk factor of interest may serve as a better basis for comparison than the general population. Considering another working population as the population of reference would give more valid estimates of the true effect of exposure to the risk factor. In this case, the population of vinyl chloride workers had an all-cause mortality rate lower than that of the general population, given an SMR = 0.87 with a 95% confidence interval (CI) that does not cross the null value (95% CI [0.85, 0.89]). This indicates that, in general, the population of workers was healthier than the general population. Conducting an ancillary statistical analysis in which a second cohort of workers (eg, domestic textile workers) is employed as the population of reference increases the validity of the study. (Choice B) Study results show that vinyl chloride workers had a nonstatistically significant association with mortality due to melanoma (SMR = 1.09, 95% CI [0.73, 1.56]), but a statistically significant association with mortality due to lung cancer (SMR = 0.88, 95% CI [0.81, 0.95]). (Choice C) Contamination bias occurs when the control group in a controlled trial unintentionally receives the treatment or intervention, thereby reducing the difference in outcomes between the control and treatment groups. This type of bias is not a concern in observational studies. (Choice D) Misdiagnosis of early liver angiosarcomas may have influenced findings in the initial study; however, this has no bearing on the decision to employ a different population of reference. (Choice E) Employing a cohort of workers unexposed to the risk factor of interest as the population of reference reduces the bias introduced by the HWE. The assumption is that the expected number of deaths among domestic textile workers will be lower than in the general population, making the comparison between observed and expected deaths more valid. Educational objective: The healthy worker effect is a special type of selection bias that usually occurs in occupational cohort studies when the general population is used as the reference group. The general population consists of healthy and unhealthy individuals; those who are unhealthy are less likely to be employed, whereas the employed workforce tends to have fewer sick individuals. Consequently, comparisons of mortality rates between an employed population and the general population are usually biased. References: Commentary for the then and now forum: the healthy worker effect. (http://www.ncbi.nlm.nih.gov/pubmed/28267105)

Question 2

The following advertisement is focused on LDL particle number (LDL-P) testing, a novel new screening method used for assessing LDL. A 54-year-old man comes to the physician for a routine health examination. He has no complaints and feels well. He has a history of hypertension and his current medications include aspirin, hydrochlorothiazide, and lisinopril. The patient has smoked 1 pack of cigarettes a day for the past 35 years but denies alcohol or illicit drug use. He exercises twice a week and eats a low-fat diet. His father died of a myocardial infarction at age 52. His vital signs are within normal limits. Physical examination shows a BMI of 26 kg/m² but is otherwise unremarkable. The patient is concerned about having a heart attack because of his family history. The physician considers obtaining the patient's LDL-P levels. Based on the advertisement, 95% of patients will most likely have LDL-P levels that lie between which of the following limits? A)250 and 550 nmol/L B)250 and 500 nmol/L C)300 and 500 nmol/L D)350 and 500 nmol/L E)350 and 450 nmol/L

Accepted Answer

Explanation: 11ec2b69_c0df_ddf7_8f63_657f90aa8980_MD0005_00 The advertisement compares the levels of LDL-C and LDL-P and the risk of developing cardiovascular disease over a 5-year period. According to the advertisement, the levels of LDL-P and LDL-C were normally distributed, with LDL-P having a mean of 400 nmol/L and a standard deviation of 50 nmol/L. A normal distribution is defined as a symmetrical, bell-shaped distribution curve. The degree of dispersion around the mean is given by the standard deviation. Wider distributions have larger standard deviations, and narrower distributions have smaller standard deviation values. Normal distributions have a fixed proportion of observations lying within a certain number of standard deviations from the mean. For instance, 95% of all observations lie within 2 standard deviations of the mean. In this case, 95% of patients would have an LDL-P value between 300 and 500 nmol/L (mean of 400 ± 2 standard deviations of 50). (Choice A) 99.7% of all observations lie within 3 standard deviations from the mean. (Choices B and D) These limits are asymmetric and therefore do not correspond to the standard 68%, 95%, and 99.7% proportions given by symmetric standard deviation bounds. (Choice E) 68% of all observations lie within 1 standard deviation from the mean. Educational objective: In a normal (bell-shaped) distribution curve, 68% of observations lie within 1 standard deviation of the mean, 95% of observations lie within 2 standard deviations of the mean, and 99.7% of observations lie within 3 standard deviations of the mean.

Question 3

A cross-sectional study is investigating the association between smoking and latent tuberculosis infection (LTBI) in adults age ≥21 in a rural community.  Interferon-γ release assay (IGRA) results are used to determine LTBI status; subjects with a positive IGRA result undergo chest x-ray to exclude active pulmonary tuberculosis.  Sociodemographic, lifestyle, and health-related information are collected by a standardized questionnaire administered by trained interviewers.  The reported results on IGRA positivity among smokers are as follows:  Which of the following factors strongly suggests a potential causal relationship between smoking and LTBI?
A)Higher levels of risk for disease with higher levels of exposure to smoking
B)No residual confounding by unadjusted risk factors
C)Smoking occurred before LTBI
D)Statistical significance of the association between smoking and LTBI
E)Strength of the association between smoking and LTBI

Accepted Answer

Explanation: A dose-response (biological gradient) relationship between an increased level of exposure to a risk factor and an increased probability of disease assumes that the more intense the exposure, the greater the risk of disease. The presence of a dose-response relationship is one of the criteria to determine causality (although absence of a dose-response relationship should not be taken as evidence against causality). Any statistically significant association is more likely to be causal if its strength (typically reflected by the absolute value of the statistical parameter, such as the odds ratio [OR]) increases as the exposure to the risk factor increases. causality In this example, compared to a history of smoking ≤10 years, for every 10 additional years of smoking, the OR for latent tuberculosis infection (LTBI) increased in the following manner: 11ec2b69_c0e1_3d8c_8f63_49be791c0015_MD0005_00 Although the cross-sectional study design precludes making causal inferences, the results of the study suggest a potential dose-response relationship between smoking (risk factor) and LTBI (disease). The dose-response relationship builds on the known significant association between smoking and tuberculosis (possibly because smoking depresses the immune system), thereby offering a stronger evidence of a potential cause-effect relationship. (Choice B) Confounding occurs when the association between an exposure and a disease is obscured by the effect of ≥1 extraneous variables that are associated with both. In this case, the adjusted OR accounted for some of the potential confounding effects of several risk factors (eg, sex, age, education level). However, additional confounders (residual confounders) may not have been considered, leading to residual confounding. (Choice C) Temporality (order of events) states that the cause (ie, risk factor) must precede the outcome (ie, disease). Temporality is one of the most important criteria for establishing causality. However, in this case, the study design (ie, cross-sectional study) assesses the association at a single point in time; therefore, it precludes inferring accurate temporal sequence between the risk factor and the disease. (Choices D and E) Statistical association, although always a required criterion to establish causality, by itself in no way implies causation. Compared to weaker statistical associations, stronger ones are more likely to be causal as they are unlikely to be accounted for entirely by alternate explanations (eg, confounding, bias). In this case, although there appears to be a strong, statistically significant association between smoking and LTBI, the presence of a dose-response relationship provides stronger evidence of a potential causal relationship. Educational objective: An association between a risk factor and a disease is more likely to be causal if its strength increases as the exposure level increases (ie, dose-response relationship or biological gradient). Although a very strong factor in favor of causality, a dose-response relationship is not necessary to infer causation.

Question 4

A 30-month-old boy is admitted to the hospital due to a 3-day history of fever, cough, and dyspnea.  He has a history of recurrent infections, including 4 episodes of cervical lymphadenitis that responded slowly to treatment with clindamycin.  Temperature is 38.2 C (100.8 F), blood pressure is 90/60 mm Hg, pulse is 100/min, and respirations are 30/min.  The anterior cervical lymph nodes are palpated bilaterally with several firm, 1- to 1.5-cm nodes that are nontender, nonfluctuant, and without overlying erythema.  Breath sounds are diminished at the left lower lung base.  The abdomen is soft, nontender, and nondistended without hepatosplenomegaly.  A chest x-ray reveals a patchy infiltrate in the left lower lobe and a moderately sized pleural effusion.  A chest tube is placed, and cloudy fluid is obtained.  Laboratory results are as follows:  Microscopy of pleural fluid shows numerous, intact gram-negative rods within neutrophils; cultures ultimately grow Burkholderia cepacia.  The patient's condition improves with appropriate treatment.  Which of the following is most appropriate for infection prophylaxis for this patient?
A)Azithromycin and palivizumab
B)Granulocyte colony-stimulating factor
C)Intravenous immunoglobulin
D)Trimethoprim-sulfamethoxazole and itraconazole

Accepted Answer

Explanation: 11ec2b69_c0da_1190_8f63_61f1259d629e_MD0005_00 This patient with a history of recurrent infections has evidence of intact organisms within neutrophils, suggestive of impaired neutrophilic intracellular killing. The most likely cause is chronic granulomatous disease (CGD), an X-linked immunodeficiency in which a defect in NADPH oxidase prevents the neutrophil respiratory burst and superoxide formation. These reactive oxygen species (ROS) normally lead to the activation of lysosomal proteases involved in pathogen destruction; however, in CGD, organisms are engulfed by phagocytes but cannot be destroyed within phagolysosomes. Although neutrophils are defective, absolute count is normal or elevated with infection, as seen in this patient. Patients with CGD are predisposed to recurrent infections by catalase-positive bacteria and fungi (Staphylococcus aureus, Burkholderia cepacia, Serratia, Nocardia, Aspergillus); these organisms can degrade their own hydrogen peroxide, making it unavailable for use by the defective neutrophils that cannot produce ROS. Infections most commonly involve the skin (eg, abscess), lymph nodes (eg, adenitis), and lungs (eg, pneumonia) and are often difficult to treat, requiring prolonged courses of antibiotics. In addition to treatment of active infection, prophylactic antibiotic (ie, trimethoprim-sulfamethoxazole) and antifungal (ie, itraconazole) therapies are required to decrease the risk for life-threatening infections by the most common organisms. In severe cases, immunomodulatory therapy with interferon gamma may also be considered. (Choice A) Azithromycin and palivizumab are sometimes used in patients with cystic fibrosis (CF) to help prevent lung infection due to mycobacteria and respiratory syncytial virus, respectively. Unlike in this patient, intact organisms within neutrophils would not be seen with CF. Moreover, recurrent infection (including with B cepacia) is typically limited to the sinopulmonary tract, and this patient's recurrent lymphadenitis makes CF less likely. In CGD, mycobacterial infections are less common and do not warrant prophylaxis; patients are not at high risk for viral infections. (Choice B) Granulocyte colony-stimulating factor is used to enhance neutrophil production in patients with neutropenia (eg, autoimmune, chemotherapy-induced), which is not present in this patient. (Choice C) Intravenous immunoglobulin repletes immunoglobulins in patients with low levels, such as in X-linked agammaglobulinemia. Immunoglobulin deficiency typically presents with recurrent sinopulmonary infections by encapsulated bacteria due to lack of opsonizing IgG and mucosal IgA. This patient's lymphadenitis and Burkholderia infection make CGD more likely, and immunoglobulin levels are normal in CGD. Educational objective: Chronic granulomatous disease presents with recurrent infections by catalase-positive organisms (eg, Burkholderia cepacia) due to impaired neutrophilic intracellular killing. Prophylactic trimethoprim-sulfamethoxazole and itraconazole are indicated to prevent high-risk infections. References: Chronic granulomatous disease. (http://www.ncbi.nlm.nih.gov/pubmed/29630223)

Question 5

A 2-month-old girl is brought to the office for a well-child checkup.  The patient is gaining weight appropriately and has met all developmental milestones.  Her mother plans to exclusively breastfeed her until age 6 months.  The patient has no medical conditions and is up to date on all recommended vaccinations.  She lives with her parents, grandmother, and older brother and will start attending day care next month.  No one in the household smokes, and the family has 2 dogs.  Family history includes atopic dermatitis in the patient's father and older brother.  The mother wants to know if she can do anything to lower the girl's risk for developing atopic dermatitis.  Which of the following is the most appropriate recommendation for this patient?
A)Attend day care as planned
B)Eliminate dairy and eggs from the maternal diet
C)Introduce patient to solid food at age 3 months
D)Introduce patient to solid food at age 9 months
E)Remove dogs from the household

Accepted Answer

Explanation: 11ec2b69_c0d9_754e_8f63_590449461ebf_MD0005_00 Atopic dermatitis, or eczema, is a chronic inflammatory skin disorder that typically develops at age <5, often during infancy. Major risk factors include a family history of atopy (ie, eczema, allergic rhinitis, asthma), as in this patient, and mutations affecting epidermal barrier proteins (eg, filaggrin). Pathogenesis of atopic dermatitis involves skin barrier dysfunction as well as a Th2-skewed immune response, which promotes IgE production. Normal newborn immunity is polarized toward a Th2 response but is balanced by a Th1 cytokine profile due to exposure to viral/bacterial microoganisms. Therefore, although the risk for atopic dermatitis cannot be eliminated, a protective factor for development includes shifting the adaptive immune response away from a Th2 predominance, which leads to decreased IgE production and mast cell and eosinophil recruitment. Th2 response As a result, early exposure to nonpathogenic microorganisms, such as early childhood exposure to day care, farm animals, and household dogs, may lower the risk of development of atopic dermatitis (Choice E). Breastfeeding and emollient application (to protect the skin barrier) also have some evidence of reducing the risk. (Choice B) Food sensitization (ie, the presence of IgE antibodies) to common allergens (eg, egg, milk) is increased in patients with atopic dermatitis and may result in rash exacerbation after exposure. However, the hydrolyzed proteins in breast milk have not been shown to affect atopic dermatitis in a child, and maternal elimination diets are therefore not recommended to prevent development of this condition. (Choices C and D) Solid food is typically introduced at age 4-6 months, and neither early nor delayed introduction decreases the risk for atopic dermatitis. Moreover, early introduction (eg, at 3 months) is developmentally inappropriate due to inadequate truncal tone and risk for aspiration, whereas delayed introduction (eg, 9 months) typically results in inadequate caloric and nutritional needs (eg, iron deficiency) and increases the risk for food allergy. Education objective: The pathogenesis of atopic dermatitis involves skin barrier dysfunction as well as a Th2-skewed immune response. Protective factors that may decrease the risk for developing atopic dermatitis shift the adaptive immune response away from a Th2 predominance and include early exposure to microorganisms (eg, day care, dogs). References: Atopic dermatitis and the hygiene hypothesis revisited. (http://www.ncbi.nlm.nih.gov/pubmed/21576944) The Effects of Early Nutritional Interventions on the Development of Atopic Disease in Infants and Children: The Role of Maternal Dietary Restriction, Breastfeeding, Hydrolyzed Formulas, and Timing of Introduction of Allergenic Complementary Foods (http://www.ncbi.nlm.nih.gov/pubmed/30886111)

Question 6

A large study examined the role of a new medication X in patients with known atherosclerotic vascular disease.  Study subjects were randomized into intervention (medication X) versus placebo groups and followed for a mean of 3.9 years.  The following results were reported:  Which of the following is the most accurate statement about the study results?
A)Administration of medication X is associated with hemorrhagic cerebrovascular accident
B)Medication X can potentially prevent revascularization procedures
C)Number needed to treat to prevent 1 myocardial infarction is 25
D)The effect of the intervention is exaggerated due to intention-to-treat analysis
E)The intervention group had statistically significantly fewer major vascular events

Accepted Answer

Explanation: For each major cardiovascular event, the rate ratio is represented by a square and its 95% confidence interval (CI) is represented by a horizontal line. In addition, the CIs and P-values for the overall categories (eg, "any" myocardial infarction, "any" cerebrovascular accident) but not the subcategories (eg, "nonhemorrhagic" and "hemorrhagic" cerebrovascular accident) are also written out. A single participant may experience >1 cardiovascular event, so there is some nonadditivity in the total events reported. Fewer participants in the medication X group underwent revascularization procedures (5.9% compared to 6.3% in the placebo group). The rate ratio for this was 0.89 and the corresponding CI (0.82-0.94) was the only one that did not cross the solid vertical line (gray color) that represents the null value (rate ratio of 1.0). This means that the effect is statistically significant (which is also suggested by the P-value of 0.03 <α = 0.05) and that the rate ratio is in favor of medication X (arrow pointing to the left). Therefore, medication X is potentially beneficial for the prevention of revascularization procedures. (Choice A) Although the risk of hemorrhagic cerebrovascular accident was higher in the medication X group (0.8%) than in the placebo group (0.6%), the CI crosses the solid vertical line (gray color), meaning that the difference between the groups is not statistically significant. Therefore, there is no statistically significant association between medication X use and hemorrhagic cerebrovascular accident. (Choice C) The number needed to treat (NNT) is calculated as 1/ARR, where ARR is the absolute risk reduction. For myocardial infarction, the ARR = 5.0% − 4.9% = 0.1% = 0.001, so NNT = 1/0.001 = 1000. (Choice D) Intention-to-treat analysis analyzes each participant based on randomization group (even if the participant stops the treatment or takes a different treatment). This tends to provide a conservative (rather than exaggerated) estimate of treatment effect. (Choice E) In the last row of the table, 14.3% of participants in the medication X group and 14.8% in the placebo group had a major vascular event; the rate ratio was 0.92. However, the corresponding CI (0.85−1.03) crosses the null value of 1.0 and the corresponding P-value is >0.05; this means that the difference between the groups is not statistically significant. Educational objective: A confidence interval that crosses the null value or a P-value >α error cutoff (typically 0.05) denotes a result that is not statistically significant. Intention-to-treat analysis tends to provide a conservative estimate of the effect of an intervention. References: Intention-to-treat concept: A review. (http://www.ncbi.nlm.nih.gov/pubmed/21897887)

Question 7

A 2-year-old boy is brought to the office due to fever, cough, and irritability lasting 3 days.  Medical history is significant for a perirectal abscess that was drained at age 9 months.  Temperature is 38.9 C (102 F), blood pressure is 100/70 mm Hg, pulse is 124/min, and respirations are 24/min.  Eyes, ears, nose, and throat examinations are normal.  Bilateral patchy crackles are auscultated in the lower lobes.  Chest x-ray confirms bilateral focal pneumonia.  The patient receives empiric antibiotic therapy; however, he is persistently febrile after 3 days.  CT scan of the chest reveals a small, left pleural effusion and enlarged paratracheal and hilar lymphadenopathy, in addition to the bilateral pneumonia.  Fine-needle biopsy of the lymph nodes and lung tissue shows an inflammatory reaction with granuloma formation.  Biopsy cultures grow Burkholderia (Pseudomonas) cepacia.  What is the mechanism most likely responsible for this patient's current infection?
A)Decreased immunoglobulin production
B)Decreased superoxide production
C)Defective opsonization
D)Impaired clearing of airway secretions
E)Impaired neutrophil chemotaxis

Accepted Answer

Explanation: 11ec2b69_c0da_d4e1_8f63_b1155e36abd8_MD0005_00 This patient with Burkholderia (Pseudomonas) cepacia pneumonia and granulomas on biopsy most likely has chronic granulomatous disease (CGD), an X-linked recessive immunodeficiency that typically occurs in boys. Patients are predisposed primarily to recurrent lung infections (eg, pneumonia, empyema, hilar lymphadenopathy) and abscesses (eg, skin, liver, lymph node); perirectal infection is common. The pathogenesis of CGD involves NADPH oxidase. This enzyme is normally responsible for the neutrophil respiratory burst, a process in which reactive oxygen species (eg, superoxide radicals, hydrogen peroxide) are formed and activate lysosomal proteases involved in pathogen destruction. Patients with CGD have mutations in NADPH oxidase and therefore decreased production of superoxide anions. Although neutrophils may use hydrogen peroxide produced by pathogens, organisms that produce catalase can degrade their own reactive oxygen species. Therefore, infections in CGD are typically due to catalase-positive bacteria and fungi (eg, Staphylococcus aureus, B cepacia, Nocardia, Aspergillus). Patients with CGD also develop characteristic granulomas, as seen in this boy, that can involve many organ systems (eg, gastrointestinal tract, genitourinary tract, lungs). The pathogenesis likely involves migration of phagocytes to infection sites but inability to degrade inflammatory signals and invading organisms; this leads to a chronic and focal aggregation of inflammatory cells, or granulomas. (Choices A and C) Decreased immunoglobulin production, as seen in X-linked agammaglobulinemia, generally presents with recurrent sinopulmonary infections. Typical pathogens include encapsulated bacteria (eg, Streptococcus pneumoniae) due to lack of opsonizing IgG. Similarly, complement dysfunction (eg, C3 deficiency) also causes defective opsonization and infection due to encapsulated bacteria. Perirectal abscess, granulomas, and B cepacia infection are not expected with either condition. (Choice D) Impaired airway clearance is a feature of cystic fibrosis (CF), which can predispose to B cepacia pneumonia, but granuloma formation does not occur. In addition, infections in CF are limited to the sinopulmonary tract, so perirectal abscesses would not be seen. (Choice E) Impaired neutrophil chemotaxis is seen in leukocyte adhesion deficiency. Patients are susceptible to recurrent skin and mucosal infections; however, pneumonia with granuloma formation does not occur. Educational objective: Chronic granulomatous disease is due to a defect in NADPH oxidase, resulting in decreased formation of superoxide anions and inability of phagocytes to kill certain bacterial and fungal pathogens. The presentation includes recurrent abscesses and pulmonary infections caused by catalase-positive organisms (eg, Burkholderia [Pseudomonas] cepacia) and granuloma formation. References: Clinical and laboratory profiles of 17 cases of chronic granulomatous disease in North India. (http://www.ncbi.nlm.nih.gov/pubmed/33707834)

Question 8

A 14-year-old boy is brought to the office due to intermittent rhinorrhea, nasal congestion, and nasal itching for the past 2 months.  He has also had periodic itchy, watery eyes and an occasional daytime cough.  The boy's symptoms occur usually after he plays with a neighbor's cat, and they cause the boy to be more tired than usual and have difficulty sleeping.  He has had no fever, headache, weight loss, or sick contacts.  The patient has atopic dermatitis and was hospitalized for bronchiolitis at age 2.  He uses a topical corticosteroid ointment as needed, and his immunizations are up to date.  Family history is significant for a younger brother with asthma.  Vital signs are within normal limits.  Physical examination shows a well-appearing boy with dark, edematous lower eyelids and pale, boggy turbinates with clear rhinorrhea.  Lungs are clear to auscultation.  Skin examination shows dry, scaly patches in the antecubital fossae bilaterally with associated excoriations.  Which of the following is the most effective long-term strategy for relief of this patient's symptoms?
A)Avoidance of the cat
B)Intranasal cromolyn sodium
C)Intranasal decongestant
D)Oral corticosteroid
E)Second-generation antihistamine

Accepted Answer

Explanation: 11ec2b69_c0db_7122_8f63_b10c79772e81_MD0005_00 Allergic rhinitis is characterized by symptoms such as nasal congestion; itchy, watery eyes; clear rhinorrhea; and sneezing in response to a particular allergen. Nasal congestion can cause sleep-disturbed breathing, leading to daytime fatigue and irritability, and cough from postnasal drip. Examination often shows "allergic shiners" (dark, edematous lower eyelids) and pale, boggy turbinates, as seen in this patient. Animal dander is one of the most common identifiable allergens in patients with allergic rhinitis, and the neighbor's cat is the most likely trigger for this patient's symptoms. Allergen avoidance is the first step in management. Eliminating any exposure to the allergic trigger (eg, cat) is optimal. However, it may not always be possible to remove a family pet from the home, in which case reducing exposure can include keeping the animal outside or away from the area where the patient sleeps. In addition, minimizing drapery, carpet, and fabric-covered furniture where allergens can accumulate is beneficial, and using high-efficiency particulate air (HEPA) filters and vacuum filters helps remove allergens. If allergen avoidance is not possible or does not result in complete resolution of symptoms, intranasal corticosteroids (eg, fluticasone spray) are first-line pharmacologic therapy. (Choices B and E) Intranasal cromolyn sodium and second-generation antihistamines (eg, cetirizine) are options for the treatment of allergic rhinitis that does not resolve with allergen avoidance. However, avoiding the cat for a trial period should precede pharmacotherapy, and intranasal corticosteroids should be tried before other agents. (Choice C) Nasal decongestive sprays (eg, oxymetazoline) are not recommended for prolonged use (>3 days) as rebound congestion will result. (Choice D) Oral corticosteroids are prescribed for asthma exacerbations; however, this patient has no wheezing or nighttime cough, making an asthma exacerbation unlikely. Systemic corticosteroids also have more side effects than intranasal corticosteroids, which are preferred for allergic rhinitis not responsive to allergen avoidance. Educational objective: Allergic rhinitis is characterized by nasal congestion; itchy, watery eyes; clear rhinorrhea; and sneezing in response to an allergen. Whenever possible, avoidance of the allergen is the first step in management of allergic disorders. References: Clinical practice guideline: allergic rhinitis. (http://www.ncbi.nlm.nih.gov/pubmed/25644617)

Question 9

Researchers are interested in determining whether oral corticosteroid administration is a more effective treatment for patients with multiple sclerosis exacerbation than intravenous corticosteroid administration.  They plan to conduct a systematic review and meta-analysis to compare the efficacy of these 2 treatments for acute exacerbations in this population.  The primary outcome is defined as the proportion of patients with improvement on the Expanded Disability Status Scale at 4 weeks.  The table lists the studies that meet inclusion criteria for the meta-analysis: The researchers included only studies 2, 3, and 5 in their meta-analysis.  Which of the following statements concerning the possible results of the meta-analysis is most likely true?
A)Compared with intravenous administration, oral corticosteroid administration will be significantly associated with improvement in scores on the Expanded Disability Status Scale
B)Oral corticosteroid administration will not have a statistically significant benefit over intravenous administration for treating acute relapses
C)Patients on oral corticosteroids will have 70% increased odds of improvement compared with patients on intravenous corticosteroids
D)Results may overestimate the true effect size as they are based on a biased sample of the target population of studies
E)The sample size in the meta-analysis will be too small to detect a significant difference between the 2 treatments

Accepted Answer

Explanation: In meta-analysis studies, individual study results are assessed and weighted to obtain a pooled (ie, mean) estimate for the effect. A meta-analysis should produce an accurate synthesis of the studies included in the analysis; however, if these studies are a biased sample of all relevant studies, the estimated mean effect reflects this bias. Publication bias occurs when studies with significant, positive results are published or considered for inclusion in systematic reviews and meta-analyses, but studies with negative or nonsignificant results are not. In this example, of the 5 studies meeting the inclusion criteria for the study, the researchers included in the meta-analysis only the 3 studies showing a positive association between oral corticosteroid administration and improvement in disability scale scores (ie, with odds ratios [ORs] >1). Consequently, the selected studies represent a biased sample of the population of studies, and any estimate of effect derived from the meta-analysis is likely to be biased. The inclusion of studies with positive associations most likely overestimates the true mean effect of oral corticosteroid administration on disability scale scores in patients with multiple sclerosis. (Choices A, B, and C) A statistically significant improvement in disability scores among patients on oral corticosteroids when compared with patients on intravenous corticosteroids was reported only in study 5 (OR = 1.76, with a confidence interval that does not include the null value of 1.0). The other 4 studies did not reach statistical significance. Only 3 studies, including study 5, were included in the meta-analysis. Therefore, any evidence in favor of or against oral corticosteroid administration on disability scale scores reported in the meta-analysis comes from a biased sample of all relevant studies and is therefore also biased. (Choice E) A meta-analysis combines the results of several studies to increase statistical power through an increased sample size. Ideally, the results are the same as conducting a single study with a larger sample size. Therefore, conducting a meta-analysis will resolve the problem of a small sample size in individual studies. However, in this case, it is unknown whether the meta-analysis will have sufficient sample size to detect statistical significance. Educational objective: Publication bias occurs when studies with positive results are published but studies with negative/null results are not. Meta-analysis yields an accurate synthesis of the studies included in the analysis, but a biased sample of all relevant studies in the literature distorts the true mean effect computed by the meta-analysis and leads to publication bias. References: What is publication bias in a meta-analysis? (http://www.ncbi.nlm.nih.gov/pubmed/26276792)

Question 10

A study was conducted to assess the relationship between the use of an over-the-counter pain reliever during pregnancy and the development of a neural tube defect in the offspring.  Mothers whose children have neural tube defects, as well as age-matched controls (mothers whose children do not have such abnormalities), were interviewed using a standard questionnaire.  The study showed that the use of the pain reliever during pregnancy increases the odds of a neural tube defect, even after adjusting for race, other medication use, comorbidities, family history of congenital abnormalities, and serum folate levels.  The odds ratio is 1.5 (p = 0.03).  Which of the following should be the major concern when interpreting the results of this study?
A)Selection bias
B)Interviewer bias
C)Recall bias
D)Observer bias
E)Confounding

Accepted Answer

Explanation: Recall bias should always be considered as a potential problem in case-control studies because it can cause an overestimation of the effect of an exposure. In this scenario, the women whose children have neural tube defects (cases) are more likely to report use of the drug than the women whose children are healthy (controls). Over-estimation may be due to distress due to the birth of a baby with a congenital abnormality or the desire to find potential explanations for that outcome. Other typical scenarios that may illustrate recall bias are: Spouses whose husbands are diagnosed with lung cancer tend to over-report the number of the cigarettes smoked daily by the patient; patients with melanoma may provide unreliable reports of their tanning ability. (Choice A) No information is given on how the patients were selected for the study. (Choice B) Using a standard questionnaire minimizes the potential for interviewer bias. (Choice D) Observer bias results in misclassification of the outcome (eg, labeling a healthy baby as having an abnormality and vice versa). It is explained by knowledge of the exposure status of the patients by the physician who makes the diagnosis. In this scenario, the diagnosis of the congenital abnormality was made at birth; therefore, there is little potential for observer bias. (Choice E) Two techniques were used to control the potential confounders in this study: matching and adjustment during the data analysis. This included adjustment for comorbidities and other medication use, which should help account for differences in the reasons for pain medication use. Although, given the potential for unmeasured confounders, confounding should always be considered, use of these analysis techniques in this scenario makes confounding less likely than recall bias. Educational objective: Recall bias is a potential problem in case-control studies. It results in over-reporting of the exposure by the cases.

Question 11

A 71-year-old man comes to the office due to slowly progressive shortness of breath for the past year. He enjoys working in his garden, but shortness of breath has forced him to reduce the time he spends there. He also has a mild morning cough productive of whitish sputum. He estimates that his physical activity level is <30 min/day. The patient has a history of hypertension. He is a retired middle school teacher. He smoked 2 packs of cigarettes daily for 20 years and quit 15 years ago. Blood pressure is 127/85 mm Hg, pulse is 78/min, respirations are 14/min, and pulse oximetry is 93% on room air. BMI is 24 kg/m². Occasional end-expiratory wheezes are present on lung examination, and the heart examination demonstrates a regular rate and rhythm. Chest x-ray shows hyperinflation, and pulmonary function test results are consistent with an obstructive defect. Suppose that 115 of the 160 (71.9%) patients age >65 with chronic obstructive pulmonary disease in the study completed all the surveys and questionnaires. Which of the following best explains the potential bias introduced by the nonresponse in the study? A)Compared to respondents, nonrespondents represent an entirely different population B)Nonrespondents caused a violation of the assumption of independence between observations C)Nonrespondents reduced the sample size; therefore, the likelihood for type I error is increased D)Respondents and nonrespondents come from the same population; therefore, the potential for bias is minimal E)Respondents may differ in some important way from nonrespondents

Accepted Answer

Explanation: Nonresponse bias may occur when a proportion of study participants become nonrespondents. Nonresponse typically affects studies that use questionnaires or surveys to collect data from participants. Although respondents and nonrespondents come from the same sample of participants, they may or may not represent the same population. Therefore, nonresponse may potentially bias a study if nonrespondents are systematically different from respondents in important characteristics (eg, exposure or disease status) that the study is designed to identify. If researchers determine that respondents do not differ in meaningful ways from nonrespondents with regard to exposure or disease status, then nonresponse only reduces the sample size of the study. This leads to an increased probability of a type 2 error (probability of failing to reject a false null hypothesis [false negative]) and reduced statistical power. (Choices A and D) Depending on whether respondents differ in meaningful ways from nonrespondents, they may or may not come from the same population. This example does not provide enough information to establish whether respondents differ from nonresponders. (Choice B) The assumption of independence between observations is a foundation for many statistical tests. It states that the value of one data point (observation) does not depend on the value of any other data point. In this example, nonresponse has no bearing on the assumption of independence of observations. (Choice C) The probability of a type I error (rejecting a true null hypothesis [false positive]) usually increases as sample size increases, and not as sample size decreases due to nonresponse. Educational objective: Nonresponse increases the potential for bias in 2 different ways: it introduces a bias in estimates when nonrespondents differ from respondents in the outcome of interest; and it contributes to a decrease in statistical power given that the sample size has been reduced. However, a significant nonresponse rate in a study does not necessarily translate into bias.

Question 12

A 33-year-old woman comes to the clinic for a routine health maintenance examination.  She has no lower abdominal pain, vaginal bleeding, or vaginal discharge.  Her past medical history is remarkable for 1 episode of uncomplicated urinary tract infection treated with a short course of antibiotics.  She is currently not taking any medications.  She has had 5 sexual partners in her life and has used barrier contraception the majority of the time.  Her latest sexual relationship began 3 months ago.  Her last cervical cancer screening examination was a Pap smear performed at the age of 23 that showed no abnormalities.  She does not use tobacco, alcohol, or illicit drugs.  During her visit, she requests screening for cervical cancer and appears extremely concerned as her older sister was recently diagnosed with it. 
Based on the study results, which of the following testing sequences would be most effective for ruling out cervical neoplasia in this patient?
A)Perform HPV testing → if positive (≥1 pg HPV DNA/mL), perform Pap smear → if positive (ASCUS or worse), refer for biopsy
B)Perform HPV testing → if positive (≥1 pg HPV DNA/mL), refer for biopsy
C)Perform Pap smear → if positive (ASCUS or worse), perform HPV testing → if positive (≥1 pg HPV DNA/mL), refer for biopsy
D)Perform Pap smear → if positive (ASCUS or worse), refer for biopsy

Accepted Answer

Explanation: This randomized clinical trial compares cervical cancer screening by DNA testing for oncogenic human papillomavirus (HPV) to the Papanicolaou (Pap) test. Patients were randomized to receive either a Pap test first or an HPV test first; the tests were then performed sequentially during the same visit (both tests were performed for ethical reasons). Women with an abnormal Pap test result or a positive HPV test underwent colposcopy and biopsy, as did a random sample of women with negative test results. An analysis of the diagnostic utility (sensitivity and specificity) of different combinations of screening strategies was conducted. To exclude cervical neoplasia in this patient, tests with high sensitivity would be the most helpful as negative results on such tests help to rule out a diagnosis (SnNout). Sensitivity is the ability of a test to correctly identify patients with the disease. Highly sensitive tests are the most likely to detect a disease and the least likely to give false negative results. They are most appropriate for screening. Among the answer choices listed, the strategy of screening only with HPV testing followed by colposcopy and biopsy in case of a positive result (>1 pg HPV DNA/mL) had the highest sensitivity at 97.4% (Table). The HPV and Pap co-testing strategy had a sensitivity of 100%, but this is not listed as an answer choice (see Exhibit). Exhibit (Choice A) HPV screening followed by Pap triage in case of a positive HPV result had a lower sensitivity at 53.8%, so this strategy would not be ideal for screening purposes. This strategy had a high specificity (99.1%), which is helpful for confirmatory (rather than screening) tests. (Choice C) Pap screening followed by HPV triage had a sensitivity of 53.8%. (Choice D) Screening with Pap only (with positivity defined as ASCUS or worse) had a sensitivity of 56.4%. Educational objective: A negative result on a highly sensitive diagnostic test helps to rule out a diagnosis.

Question 13

The following advertisement is focused on LDL particle number (LDL-P) testing, a novel new screening method used for assessing LDL. Based on the study shown in the advertisement, initial levels of LDL-C and LDL-P were obtained in 5584 individuals and the cumulative incidence of cardiovascular events was tracked.  Which of the following choices best identifies the study design used in the advertisement?
A)Case-control study
B)Cross-sectional study
C)Prospective cohort study
D)Randomized clinical trial
E)Retrospective cohort study

Accepted Answer

Explanation: The advertisement describes a study consisting of 5584 individuals without pre-existing cardiovascular disease who were categorized into study groups based on their LDL-P and LDL-C levels. They were then monitored for 5 years to assess the incidence of cardiovascular events. This is consistent with a prospective cohort study. In a prospective cohort study, a group of subjects (ie, the cohort) is selected and their exposure status is determined (eg, low LDL or high LDL). The cohort is then followed for a certain period and observed for development of the outcome (eg, cardiovascular events). (Choice A) A case-control study is designed by selecting patients with a particular disease (cases) and patients without that disease (controls) and then retrospectively determining their exposure status. (Choice B) A cross-sectional study, also known as a prevalence study, is characterized by the simultaneous measurement of an exposure and outcome within a specific population. It is a "snapshot study" that frequently uses surveys, making it relatively inexpensive and easy to perform. (Choice D) A randomized clinical trial directly compares 2 or more treatments. The subjects are usually randomly assigned to a treatment group or control group and then monitored for development of the outcome of interest. (Choice E) In a retrospective cohort study, the exposure status is determined at a particular point in the past and patients are tracked retrospectively, typically through their medical records. Educational objective: Prospective cohort studies are organized by selecting a group of individuals (ie, the cohort), determining their exposure status, and then following them over time for development of the disease of interest.

Question 14

A 24-year-old man comes to the emergency department with palpitations.  He has had short-lived episodes of palpitations for several years, but this one is persistent.  He has no past medical history and takes no medications.  ECG shows regular narrow-complex tachycardia (QRS duration of 90 msec) at a rate of 175/min.  His blood pressure is 135/80 mm Hg and physical examination is notable for tachycardia but otherwise unremarkable.  Vagal maneuvers are ineffective in breaking the tachycardia.  The patient receives a rapid intravenous push of adenosine (6 mg) followed by saline chaser.  Soon after the bolus, his heart rate becomes 230/min and irregular, and the rhythm rapidly degenerates into ventricular fibrillation.  The patient loses consciousness, and the pulse is not palpable.  He is immediately defibrillated and regains consciousness.  He has poor recollection of the recent events but has no other complaints.  Repeat ECG shows normal sinus rhythm at a rate of 89/min, short PR interval of 110 msec, prolonged QRS complex of 130 msec, and delta waves in multiple leads.  Which of the following best classifies this patient's encounter?
A)Medicolegal error
B)Near-miss
C)Negligent adverse event
D)Non-preventable adverse event
E)"Save" event

Accepted Answer

Explanation: 11ec2b69_c0dc_0d63_8f63_f50b35e34e94_MD0005_00 This patient presented with supraventricular tachycardia and was managed appropriately with vagal maneuvers followed by intravenous adenosine to attempt acute termination of the tachycardia. Unfortunately, he turned out to have underlying Wolff-Parkinson-White (WPW) syndrome, given his repeat ECG showing a short PR interval, wide QRS complex, and delta waves. In patients with WPW syndrome, adenosine administration can provoke atrial fibrillation with rapid conduction via the accessory pathway, which can eventually degenerate into ventricular fibrillation, as occurred in this patient. Although adenosine should not be used routinely in patients with WPW syndrome, at the time of the patient's initial presentation, the providers would not have known that he had underlying WPW syndrome. The patient was treated appropriately with adenosine and subsequently developed rapid atrial fibrillation that degenerated into VF as a rare and potentially lethal side effect of adenosine in the setting of WPW syndrome. This is a classic example of non-preventable adverse effect in the setting of the appropriate use of medications for approved indications. (Choices A, B, and E) Medical error is a broad category that includes diagnostic errors (eg, missed or misdiagnosis) and therapeutic errors (eg, ordering or administration of inappropriate medical treatment). Medical errors can be recognized early and never reach the patient ("saves"), can reach the patient but cause no apparent harm ("near misses"), or can lead to a potentially serious event ("preventable adverse event"). Preventable adverse events occur as a result of failure to follow evidence-based best practice guidelines at the individual and/or system level. (Choice C) Negligent adverse event is a category of preventable adverse event that occurs due to gross negligence on the part of health care providers. An example of a negligent adverse event would be a drug reaction in a patient who received a drug despite having a known allergic reaction to that particular drug. The patient in the vignette was appropriately treated with adenosine for narrow-complex regular tachycardia; therefore, the development of VF is not considered a negligent adverse event. Educational objective: Preventable adverse events occur from failure to follow evidence-based best practice guidelines. Non-preventable adverse events are complications that cannot be prevented given the current state of medical knowledge and occur despite appropriate medical practice. References: The spectrum of medical errors: when patients sue. (http://www.ncbi.nlm.nih.gov/pubmed/22924008) Classification of medical errors and preventable adverse events in primary care: a synthesis of the literature. (http://www.ncbi.nlm.nih.gov/pubmed/12485545)

Question 15

A randomized controlled trial investigated the effect of body awareness therapy (BAT) and aerobic exercises on pain and quality of life in patients with tension-type headache.  Participants were randomly assigned to 1 of 3 groups:  BAT group, aerobic exercise (AE) group, and control group.  Main outcomes were pain severity evaluated by a Visual Analog Scale (VAS); pain-related disability measured by the Pain Disability Index (PDI); impact of headaches measured by the Headache Impact Tests (HIT); and quality of life measured by the Short Form Health Survey (SF-36).  Baseline characteristics concerning age, weight, height, BMI, VAS, and HIT were not statistically different among the groups (p > 0.05).  However, there was a statistically significant difference among the groups (p < 0.05) in mean baseline PDI values.  Further evaluation of baseline PDI values revealed the following: Which of the following is likely to be the most valid measure of central tendency for baseline PDI data?
A)Mean and median both equally valid
B)Mean, median, and mode all equally valid
C)Mean only
D)Median only
E)Mode only

Accepted Answer

Explanation: 11ec2b69_c0e1_d9cd_8f63_cdb7980ad841_MD0005_00 Continuous variables are often summarized through measures of central tendency such as the mean, median, and mode. Continuous variables that follow a normal distribution are symmetrical, with values for the mean, median, and mode that lie very close to each other (mean ≈ median ≈ mode). For normally distributed continuous data, the mean is the most valid choice for central location. Continuous variables that do not follow a normal distribution are asymmetrical and exhibit negative or positive skewness (ie, observations with extreme values [outliers] on either side of the distribution): A negatively skewed distribution has >1 small-valued outliers and mean < median < mode. A positively skewed distribution has >1 large-valued outliers and mean > median > mode. For skewed distributions, the median is a more representative and valid measure of central location than the mean. This study found that the mean baseline Pain Disability Index (PDI) values are statistically different among the body awareness therapy (BAT) group, the aerobic exercise (AE) group, and the control group (43.85, 33.27, and 28.71, respectively; p < 0.05). However, the distribution of baseline PDI appears to be skewed in all 3 groups as follows: AE group: Positively skewed with mean (33.27) > median (31.48) > mode (30.94) BAT group: Positively skewed with mean (43.85) > median (30.41) > mode (27.53) Control group: Negatively skewed with mean (28.71) < median (30.85) < mode (31.01) In particular, the distribution of baseline PDI in the BAT group is considerably skewed, as the mean, median, and mode are relatively distant from each other. Consequently, the median, not the mean, represents the most valid measure of central tendency for summarizing and comparing baseline PDI values among the 3 groups (Choices A, B, and C). (Choice E) The mode is commonly used to describe categorical variables (qualitative). Educational objective: In a positively skewed distribution, the mean is the central tendency measure most shifted in the positive direction (to the right), followed by the median, and then the mode, whereas in a negatively skewed distribution, the mean is the central tendency measure most shifted in the negative direction (to the left), followed by the median, and then the mode. In such situations, the median is a more valid measure of central tendency than the mean.

Question 16

A 19-year-old male presents to the emergency department with acute onset of breathlessness.  He was feeling short of breath for the last few weeks, but it was not that severe.  He denies any chest pain or cough.  He is a non-smoker and non-alcoholic.  His father has asthma. His respiratory rate is 22/min and pulse rate is 98/min.  There is diffuse wheezing all over the lung fields.  PEFR is 230 L/min, and this improves markedly after bronchodilator therapy.  Which of the following is the most frequent cause of this disorder?
A)House dust mite
B)Cat allergen
C)Dog allergen
D)Cockroach allergen
E)Air pollution

Accepted Answer

Explanation: The above patient is suffering from asthma. Allergens that may be responsible for asthma include house dust mite allergens, cat allergens, dog allergens, and cockroach allergens. Of all the aforementioned allergens, house dust mites have the strongest association with asthma; these may be responsible for 60-90% cases of asthma. (Choice E)Although lung disease is associated with air pollution, there is no documented evidence of the association of asthma with air pollution. Educational objective: The allergen most frequently associated with asthma is house dust mites.

Question 17

A large-scale clinical trial is being planned to evaluate the effect of a nonselective beta blocker, propranolol, on the clinical course of portal hypertension.  The comparison is with placebo.  The primary outcomes of the study are all-cause mortality and major gastrointestinal hemorrhage.  Secondary outcomes are minor gastrointestinal hemorrhage and the number of hospitalizations.  Classification of the episodes of gastrointestinal hemorrhage into "major" and "minor" is based on clinical assessment as well as laboratory data such as change in hemoglobin level.  The investigators are concerned about the possibility that major gastrointestinal hemorrhage events could be over-reported in the placebo group.  Which of the following is the most useful technique to reduce this possibility?
A)Blinding
B)Matching
C)Randomization
D)Restriction
E)Stratified analysis

Accepted Answer

Explanation: Observer bias is defined as a misclassification of events that can result from knowing the exposure status of a patient. In this clinical scenario, physicians who are aware of participant allocation (ie, whether the participant was allocated to receive propranolol or placebo) may tend to classify hemorrhagic episodes as "major" if a patient belongs to placebo group and "minor" if a patient belongs to the treatment group. Blindingthe physicians to the treatment status of a patient can balance this effect. The other techniques listed are used to control confounding variables: (Choices B and D) Matching and restriction are typically employed in other study designs (eg, case control studies, cohort studies). The initial step in matching involves selecting variables that could be confounders (eg, age, race); cases and controls are then selected based on the matching variables so that both groups have a similar distribution in accordance with the variables. Restriction involves limiting study participation to individuals with specific characteristics. (Choice C) Randomization helps to balance numerous known and unknown extraneous factors (confounders) evenly between the treatment and placebo groups. It is commonly used in clinical trials. However, randomization would not prevent over-reporting if the physicians are not blinded. (Choice E) Stratified analysis is a statistical tool used to control confounding at the analysis stage of a study. Educational objective: Observer bias can be effectively reduced by using the blinding technique.

Question 18

A 56-year-old man with exertional chest pain comes to the office because his exercise stress echocardiogram showed evidence of mild ischemia in the posterior wall.  He was recently diagnosed with type 2 diabetes mellitus and hypertension.  He is a current smoker but is willing to quit.  His father died of a heart attack at age 51.  Physical examination is unremarkable. Laboratory results are as follows:
 Based on the information in the drug advertisement,
According to the drug advertisement, the investigators reported the median value and the median percentage change from baseline for triglyceride levels in the study patients.  Which of the following best explains the reason for reporting median values as opposed to mean values?
A)High number of missing values
B)Narrow range of values
C)Skewed distribution
D)Small sample size

Accepted Answer

Explanation: In the drug advertisement, the median value and median percentage changes were reported for triglyceride levels, but mean values and mean percentage changes were reported for the other variables examined. Three measures of central tendency are most often used to describe data sets: Mean equals the sum of observations divided by the number of observations. Median equals the observation in the center when all the observations are ordered from smallest to largest. When there is an even number of observations, the median is defined as the mean of the middle 2 data points. Mode equals the observation that occurs most frequently. 11ec2b69_c0e0_2c19_8f63_a32640536dc2_MD0005_00 Although the symmetrical bell-shaped curve is cited as the ideal distribution curve, most data sets generated during "real-world" statistical analysis have asymmetrical distributions. When a distribution curve is asymmetrical, it is either positively or negatively skewed. With a negative skew, larger numbers predominate in the data set and the long slope of the curve (the tail) extends in the negative direction (mean < median < mode). With a positive skew, smaller numbers predominate in the data set and the long slope of the curve (the tail) extends in the positive direction (mean > median > mode). As evidenced by the above image, in strongly skewed distributions, the median is a better measure of central tendency than the mean. How does one decide on which measure of central tendency to use? For continuous data that are normally distributed, the mean is the best choice for central tendency. For ordinal data or continuous data that are highly skewed, the median is the best choice for central tendency. Ordinal data can be ordered in a logical fashion (eg, freshman, sophomore, junior, and senior). For nominal data, using the mode or describing the frequency or proportion of subjects in each category is best. Nominal data cannot be ordered in a logical fashion (eg, male and female). (Choice A) A high number of missing values may have a significant impact on some or all measures of central tendency, including the median (especially if the missing values are in the middle of the data set). A skewed data set is a better reason for why the investigators used the median instead of the mean in their triglyceride analysis. (Choice B) The range equals the difference between the largest and smallest observation. It is a measure of dispersion and is used to describe the variability in a sample or population. It is usually used in conjunction with a measure of central tendency to provide an overall description of a set of data. Changes in range may not always equate to changes in central tendency. For example, a wide or narrow range may still be skewed or have a normal distribution. (Choice D) The sample size does not always correlate with the measures of central tendency. For example, a smaller sample size may be normally distributed, making the mean score the best measure of central tendency. Instead, sample size correlates with the power of a study and the likelihood of reaching statistical significance. Educational objective: In strongly skewed distributions, the median is a better measure of central tendency than the mean.

Question 19

A group of researchers wants to investigate an outbreak of acute diarrhea that occurred in a coastal town in northern Massachusetts.  Approximately 50 people who were from the town or were visiting the surrounding area had severe hemorrhagic diarrhea, in most cases requiring hospitalization for several days.  A fatal case was reported.  The researchers believe that the outbreak is related to seafood prepared at one of the coastal restaurants.  Which of the following study designs is most appropriate to test this hypothesis?
A)Case-control study
B)Correlational study
C)Cross-sectional study
D)Longitudinal study
E)Randomized clinical trial

Accepted Answer

Explanation: 11ec2b69_c0e0_c85a_8f63_45063586412e_MD0005_00 A case-control study design is appropriate to investigate an acute infectious disease outbreak as it explores the association between exposure and disease, can be conducted when the number of affected subjects is small, and generally allows for quick localization of the outbreak source. A case definition is constructed. Subjects who developed the disease (satisfied the case definition) should be questioned about their recent exposures (eg, eating a particular dish at a particular restaurant), and unaffected subjects should be chosen as controls to reflect the exposure experience of the general population. If cases are more likely to be exposed than controls (ie, statistically significant odds ratio >1), then an association between exposure and disease can be established. Correlational studies attempt to measure associations between multiple variables and are generally conducted by natural observation, surveying, or archival research. They help develop but not test hypotheses. Because many combinations of variables are examined, there is a risk (due to chance alone) of finding an association that may not actually be true (Choice B). A longitudinal study is a type of observational correlational study in which repeat measurements of the same variables are taken over a prolonged period (Choice D). A case-control study design is better suited for outbreak investigation as it focuses on a specific disease and associated exposures. (Choice C) Cross-sectional studies begin with risk factor/exposure status (eg, ate/did not eat seafood at a coastal restaurant) and compare disease prevalence to provide a snapshot. They are helpful in determining prevalence rather than investigating outbreaks or etiologies. (Choice E) A clinical trial in which a group of individuals is randomly assigned to eat seafood prepared at coastal restaurants would be neither appropriate nor ethical. Educational objective: A case-control study is the most appropriate study design to investigate an outbreak of an acute infectious disease. It generally allows for quick localization of the outbreak source.

Question 20

A 54-year-old man comes to the office for follow-up of type 2 diabetes mellitus. The patient also has a history of hypertension, obesity, and chronic kidney disease (CKD). Medications include an antihyperglycemic agent and insulin. Blood pressure is 148/92 mm Hg and pulse is 81/min and regular. BMI is 34 kg/m². Physical examination is otherwise unremarkable. Laboratory results are as follows: Based on his serum creatinine level, his CKD has progressed, and the calculated glomerular filtration rate (eGFR) is now 42 mL/min/1.73 m², down from 55 mL/min/1.73 m² as measured 6 months ago. As stated in the ad, the proportion of subjects reaching A1c <7.0% was one of the prespecified secondary endpoints evaluated at week 26. Compared to the placebo group, a greater proportion of subjects in the 2 kanebaflozin groups achieved A1c <7.0%; however, researchers did not perform or report tests for the statistical significance of the differences in secondary endpoints among the 3 groups. Which of the following is the most likely reason that these statistical tests were not conducted? A)At baseline, there was no difference in mean A1c among the 3 groups B)No statistical test is necessary as the large intergroup differences are clinically significant C)Testing for multiple secondary endpoints increases the likelihood of a type I error D)The overlap of confidence intervals among the 3 groups implies the results were statistically significant E)The placebo group had an adjusted mean increase rather than a mean decrease in A1c

Accepted Answer

Explanation: The hypothesis testing process requires that error rates (eg, type I and type II errors) be defined a priori. Type I error (alpha) is the probability of rejecting a null hypothesis when the null hypothesis is true. Conducting multiple independent hypothesis tests without proper adjustment to the alpha level increases the rate of type I error. This means that, when evaluating multiple secondary endpoints (eg, fasting plasma glucose, proportion of subjects reaching A1c <7.0%, changes in renal parameters), there is a higher probability of erroneously finding a statistically significant result with one of these endpoints (eg, higher likelihood of type I error) due to chance alone. This phenomenon is known as the multiplicity, or multiple testing, problem. In general, the rate for type I error will increase depending on the alpha level for individual tests and the number of independent tests. For example, the rate for type I error in a study attempting to evaluate 5 secondary endpoints would be ~23%, whereas the classically accepted value is usually set ≤5% (statistically significant p-value). Statistical techniques can be used to account for the multiple testing problem (eg, the alpha level or p-value is sometimes adjusted). (Choice A) Results showed comparable mean baseline A1c among the 3 groups (7.8%, 8.0%, and 8.1% for placebo, kanebaflozin 100 mg, and kanebaflozin 300 mg, respectively). This suggests adequate randomization in the study and should not affect differences in the proportion of subjects achieving A1c <7.0% at 26 weeks. (Choice B) The proportion of subjects achieving A1c <7.0% at 26 weeks in the 2 kanebaflozin groups (26.7% and 34.5% for kanebaflozin 100 mg and 300 mg, respectively) might be clinically significant when compared to the smaller proportion of such subjects in the placebo group (15.8%). However, clinical significance should not be misinterpreted as statistical significance and must not drive the decision of whether to conduct a statistical analysis in a study. (Choice D) Nonoverlapping confidence intervals indicate a statistically significant difference between compared groups. However, the opposite is not necessarily true. Although there appears to be an overlap in confidence intervals around the estimates of the proportion of subjects reaching A1c <7.0% in each of the groups (15.8%, 26.7%, and 34.5%), this overlap does not imply statistical significance. (Choice E) In contrast to the kanebaflozin groups, for which there were mean decreases in A1c from baseline at 26 weeks (−0.34% and −0.46%), there was a mean increase in the placebo group (+0.05%). However, this does not provide any information regarding the statistical significance of the differences among the groups. Educational objective: There is an increased risk for type I errors (ie, false positives) when multiple simultaneous hypotheses are tested at set p-values. Interpretation of findings in clinical trials when multiple outcome measures are used without adjustment of the significance level may result in spurious findings and invalid conclusions.

Exam 2: Foundations of Independent Practice