biostatistics 2 7.4.2014 Marek Čierny Q1 A 5-year-old child, who lives with his missionary parents in a rural locality in Sierra Leone, Africa, contracts an illness that is initially characterized by vomiting and periods of moderate fever. Over the next few days, his condition dramatically worsens, he becomes markedly lethargic, and his fever intensifies to the point of delirium and convulsions. At the aid station, a blood smear reveals the infective agent (shown in the image). What is the cause of this child’s illness? (A) Babesia microti (B) Brugia malayi (C) Cryptosporidium parvum (D) Leishmania tropica (E) Plasmodium falciparum Q1 A 5-year-old child, who lives with his missionary parents in a rural locality in Sierra Leone, Africa, contracts an illness that is initially characterized by vomiting and periods of moderate fever. Over the next few days, his condition dramatically worsens, he becomes markedly lethargic, and his fever intensifies to the point of delirium and convulsions. At the aid station, a blood smear reveals the infective agent (shown in the image). What is the cause of this child’s illness? (A) Babesia microti (B) Brugia malayi (C) Cryptosporidium parvum (D) Leishmania tropica (E) Plasmodium falciparum Q1 The double ring trophozoites seen in the red blood cells, and the lack of erythrocytic Schüffner’s dots are consistent with P. falciparum. This is the most severe form of malaria and rapid diagnosis is critical. This type of malaria is wide spread in Africa and young children are extremely vulnerable to the disease largely because they are immunologically naive. Frequently, the manifestations of fever are experienced by children with a falciparum infection. Complications of this infection include renal failure and cerebral malaria. Babesia is a related organism that typically causes mild disease, and is transmitted by ticks in the northeastern United States. Brugia is a helminth parasite associated with elephantiasis. Cryptosporidium is an intestinal protozoan associated with severe diarrhea in the immune compromised and L. tropica is an intracellular protozoancausing skin ulcers. Q1 Q1 CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● The review included a study ● which "investigated all patients presenting at a university outpatient clinic with a complaint of fever or malaise after returning from the tropics" "and in whom a malaria test was performed". ● For each patient the collected data "included the patient’s demographical data, travel history, preventive measures against malaria, details on symptoms and signs at admission, laboratory results, final diagnosis, treatment, and outcome." ● "Likelihood ratios (LR) of the different clinical and laboratory parameters" were compared between two groups: – A: "patients with at least one of the tests positive for malaria" – B: "patient with negative tests for malaria on all occasions" ● What's the type of this study, which was included in the review? ● A) Cross-sectional study B) Case-control study C) Cohort study D) Systematic review E) Clinical trial CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● The review included a study ● which "investigated all patients presenting at a university outpatient clinic with a complaint of fever or malaise after returning from the tropics" "and in whom a malaria test was performed". - INCLUSION CRITERIA ● For each patient the collected data "included the patient’s demographical data, travel history, preventive measures against malaria, details on symptoms and signs at admission, laboratory results, final diagnosis, treatment, and outcome." - FINDINGS ● "Likelihood ratios (LR) of the different clinical and laboratory parameters" were compared between two groups: – A: "patients with at least one of the tests positive for malaria" CASES – B:"patient with negative tests for malaria on all occasions" CONTROLS ● What's the type of this study, which was included in the review? ● A) Cross-sectional study B) Case-control study C) Cohort study D) Systematic review E) Clinical trial CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● In the study: ● the prevalence of malaria in included population was 30% ● Inadequate prophylaxis had 84% sensitivity and 47% specificity for diagnosis of malaria ● A 40y/o patient visits outpatient clinic in Lausanne because he had malaise and fever (38C) for 4 days. Two weeks ago he returned from trip to Kongo. He did not take mefloquine for prophylaxis. ● Using the data from the study, what is the probability that this patient have malaria before performing a physical exam? ● 23% 30% 40% 47% 50% 60% 84% cannot say CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● In the study: ● the prevalence of malaria in included population was 30% ● Inadequate prophylaxis had 84% sensitivity and 47% specificity for diagnosis of malaria ● A 40y/o patient visits outpatient clinic in Lausanne because he had malaise and fever (38C) for 4 days. Two weeks ago he returned from trip to Kongo. We did not take mefloquine for prophylaxis. ● Using the data from the study, what is the probability that this patient have malaria before performing a physical exam? D+ Dn % n % T+ T- CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● In the study: ● the prevalence of malaria in included population was 30% ● Inadequate prophylaxis had 84% sensitivity and 47% specificity for diagnosis of malaria ● A 40y/o patient visits outpatient clinic in Lausanne because he had malaise and fever (38C) for 4 days. Two weeks ago he returned from trip to Kongo. We did not take mefloquine for prophylaxis. ● Using the data from the study, what is the probability that this patient have malaria before performing a physical exam? D+ Dn % n % T+ 84 53 T- 16 47 CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● In the study: ● the prevalence of malaria in included population was 30% ● Inadequate prophylaxis had 84% sensitivity and 47% specificity for diagnosis of malaria ● A 40y/o patient visits outpatient clinic in Lausanne because he had malaise and fever (38C) for 4 days. Two weeks ago he returned from trip to Kongo. We did not take mefloquine for prophylaxis. ● Using the data from the study, what is the probability that this patient have malaria before performing a physical exam? D+ Dn % n % T+ 84 53 T- 16 47 30 70 CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● In the study: ● the prevalence of malaria in included population was 30% ● Inadequate prophylaxis had 84% sensitivity and 47% specificity for diagnosis of malaria ● A 40y/o patient visits outpatient clinic in Lausanne because he had malaise and fever (38C) for 4 days. Two weeks ago he returned from trip to Kongo. We did not take mefloquine for prophylaxis. ● Using the data from the study, what is the probability that this patient have malaria before performing a physical exam? D+ Dn % n % T+ 25 84 37 53 T- 5 16 33 47 30 70 CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● In the study: ● the prevalence of malaria in included population was 30% ● Inadequate prophylaxis had 84% sensitivity and 47% specificity for diagnosis of malaria ● A 40y/o patient visits outpatient clinic in Lausanne because he had malaise and fever (38C) for 4 days. Two weeks ago he returned from trip to Kongo. We did not take mefloquine for prophylaxis. ● Using the data from the study, what is the probability that this patient have malaria before performing a physical exam? ● PPV= TP/(DN + DN) D+ Dn % n % T+ 25 84 37 53 T- 5 16 33 47 30 70 CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● In the study: ● the prevalence of malaria in included population was 30% ● Inadequate prophylaxis had 84% sensitivity and 47% specificity for diagnosis of malaria ● A 40y/o patient visits outpatient clinic in Lausanne because he had malaise and fever (38C) for 4 days. Two weeks ago he returned from trip to Kongo. We did not take mefloquine for prophylaxis. ● Using the data from the study, what is the probability that this patient have malaria before performing a physical exam? ● PPV= TP/(DN + DN) = 25/(25+37)= 40% D+ Dn % n % T+ 25 84 37 53 T- 5 16 33 47 30 70 CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● What type of bias might be introduced in interpreting these results? ● selection bias ● recall bias ● observer-expectancy bias ● confounding ● small sample CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● When implementing the study findings into practise, what are the clinitians at risk of? ● Type I error ● Type II error CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING ● ● A 40y/o patient visits outpatient clinic in Lausanne because he had malaise and fever (38C) for 4 days. His PHM reveals an appendectomy 10 years ago. Two weeks ago he returned from trip to Kongo. He did take mefloquine for prophylaxis. ● Using the data from the study, what is the probability that this patient have malaria before performing physical exam? ● 5% 23% 50% 60% 79% 88% 96% 98% Does This Patient Have Malaria? ● Context Malaria commonly infects residents of and travelers to tropical regions. The clinical features of infection are notoriously nonspecific but have not been comprehensively evaluated. ● Objective To systematically review and synthesize data related to the predictive value of clinical findings for the diagnosis of malaria in endemic areas and in travelers returning from endemic areas. ● Data Sources, Study Selection, and Data Extraction The databases of MEDLINE and EMBASE (1950-July 2010) were searched to identify studies published in the English language of endemic and “imported” (acquired during travel) malaria. Additional studies were identified from reference lists. Studies were included that had patients suspected of having acute malaria (usually because of fever) and compared the presence or absence of clinical findings with blood smear confirmation. Two authors independently identified studies, appraised study quality, and extracted data on the patient population, outcome assessment, and clinical findings. Differences between reviewers were resolved by consensus. ● Paaladinesh Thavendiranathan, MD; Akshay Bagai, MD; Clarence Khoo, MD; Paul Dorian, MD; Niteesh K. Choudhry, MD, PhD ● JAMA. 2009;302(19):2135-2143. doi:10.1001/jama.2009.1673. Does This Patient Have Malaria? ● Context Malaria commonly infects residents of and travelers to tropical regions. The clinical features of infection are notoriously nonspecific but have not been comprehensively evaluated. ● Objective To systematically review and synthesize data related to the predictive value of clinical findings for the diagnosis of malaria in endemic areas and in travelers returning from endemic areas. ● Data Sources, Study Selection, and Data Extraction The databases of MEDLINE and EMBASE (1950-July 2010) were searched to identify studies published in the English language of endemic and “imported” (acquired during travel) malaria. Additional studies were identified from reference lists. Studies were included that had patients suspected of having acute malaria (usually because of fever) and compared the presence or absence of clinical findings with blood smear confirmation. Two authors independently identified studies, appraised study quality, and extracted data on the patient population, outcome assessment, and clinical findings. Differences between reviewers were resolved by consensus. ● What is the type of this study? A) Cross-sectional study B) Case-control study C) Cohort study D) Systematic review E) Clinical trial Does This Patient Have Malaria? ● Data Synthesis Fourteen studies for endemic malaria were identified that met review criteria. Individual symptoms are of limited diagnostic utility but presence of splenomegaly (summary likelihood ratio [LR], 3.3; 95% confidence interval [CI], 2.0-4.7) or hepatomegaly (summary LR, 2.4; 95% CI, 1.6-3.6) make malaria more likely. Combinations of findings can affect the likelihood of malaria, but their performance varies by setting. Seven studies of imported malaria were identified. The presence of fever (LR, 5.1; 95% CI, 4.9-5.3), splenomegaly (summary LR, 6.5; 95% CI, 3.9-11.0), hyperbilirubinemia (LR, 7.3; 95% CI, 5.5-9.6), or thrombocytopenia (summary LR, 5.6; 95% CI, 4.1-7.5) make malaria more likely. ● Conclusions In endemic areas, the likelihood of malaria is increased by the presence of splenomegaly and hepatomegaly but individual findings are of limited utility and cannot reliably exclude malaria; combinations of findings may be useful to stratify risk in patients. In returning travelers, the clinical assessment can provide substantial diagnostic benefit, although all patients still require laboratory testing because malaria can be rapidly fatal. Take home vocabulary ● Sensitivity, Specificity ● PPV, NPV, impact of prevalence ● Case-control ● selection bias ● Malaria should be suspected in "any patient with fevers and recent travel" ● more specific findings: splenomegaly, jaudance, anemia, thrombocytopenia ● tropical areas Thank you ● Zdroje: ● VALÉRIE D’ACREMONT: CLINICAL AND LABORATORY PREDICTORS OF IMPORTED MALARIA IN AN OUTPATIENT SETTING: AN AID TO MEDICAL DECISION MAKING IN RETURNING TRAVELERS WITH FEVER, Am. J. Trop. Med. Hyg., 66(5), 2002, pp. 481–486 (http://www.ajtmh.org/content/66/5/481.long) ● Steve M. Taylor et al: Does This Patient Have Malaria?, JAMA. 2010;304(18):2048-2056. doi:10.1001/jama.2010.1578 (http://jama.jamanetwork.com/article.aspx?articleid=186881) ● First Aid for the USMLE step 1 2014 ● Lippincott's illustrated pharmacology ● Lippincott's illustrated Q&A microbiology, immunology