Instructions

Answer all questions. Please show your working for calculations. Formatting your assignment:

- Please submit your assignment online as one document in PDF format. This format locks the information and is particularly important if you are using a Mac computer to preserve the formatting;

- Please number every page and include your SID in the header of every page (not your name);

- Clearly number the answer to each question; only include your answer (not the question);

- Use 11 point or 12 point font and 1.5 times spacing (not double spacing);

Question 1

We will be conducting a meta-analysis to investigate whether surgery (cystectomy) combined with radiotherapy has a survival benefit (measured at 3-years) compared to radiotherapy alone for patients with bladder cancer.

a) Conduct a keyword search in (ovid) Medline (untick "Map Term to Subject Heading") using the following search terms:

bladder carcinoma radical radiotherapy preoperative radiotherapy radical cystectomy controlled trial

Combine these with an ‘and' command. Present your search results in a table showing the number of studies found at each step.

b) Your search above should have found one study only. Extract the data from this study to be included in the meta-analysis. Hint: we want to look at 3 year survival comparing the two arms of the trial.

c) There were two other studies found that investigate three year survival, their results are shown in the following table:

Table1: Extracted data from two studies found via other searches

Calculate the study specific odds ratios comparing survival for cystectomy with survival for radiotherapy. Then calculate the Mantel-Haenszel pooled odds ratio.

d) Further analysis finds an I-squared =0.0%. Is your analysis in part c) appropriate?

e) Interpret your pooled odds ratio from part c). A test was conducted to see if the pooled odds ratio is significantly different from 1 and this test has a p-value = 0.0011, use this information to help with your interpretation.

Question 2

The following is an extract from a paper that used directed acyclic graphs. Read the extract and then answer the questions below.

Abstract Background

In sub-Saharan Africa, malnutrition is associated with mortality in adults hospitalized for medical illness. However, it remains unclear whether this association is causal, and if causal, what the potential mediators are. We assessed whether malnutrition is causally related to mortality among hospitalized adults, and whether severe sepsis plays a mediating role.

Methods

We analyzed data from a cohort study of adults hospitalized for any medical illness in Uganda. We measured malnutrition using mid-upper arm circumference (MUAC). We used a directed acyclic graph to identify a minimum sufficient adjustment set of confounders in order to estimate the overall effects of malnutrition on mortality. We then used recently developed statistical methods to determine whether mortality in malnourished patients is mediated by severe sepsis.
.
.
.
Article
.
.
.
Methods

Setting and study population

We analyzed data from an observational cohort study of hospitalized adults. The study occurred on the general medicine ward of Mbarara Regional Referral Hospital in south- Western Uganda. The setting and study population have been described elsewhere [6]. All patients being admitted for any medical illness during the study period (April to June 2011) were eligible for the study, which was set up to perform multiple nutritional assessments on each patient. However, those who were less than 18 (considered unable to provide informed consent) (N = 34) and those who declined to participate in the study (N = 3) were excluded. As we were able to perform the planned nutritional assessments on all consenting patients, no patient was excluded on this basis.

Ethical approval

All participants provided written informed consent. The study was approved by the Institutional Review Committee of Mbarara University of Science and Technology.

Measurement of malnutrition

For this report, we measured malnutrition at admission using the mid-upper arm circumference (MUAC). MUAC has been validated in adults for diagnosing malnutrition and shown to be highly correlated with the body mass index while predicting outcomes better [19, 20, 21]. MUAC is in general highly specific (up to 96 %), but can be poorly sensitive depending on the chosen cut-offs [22]. We used a non-stretchable MUAC tape to obtain MUAC as the circumference of either of the patient's arm at the midpoint between the olecranon and the acromion, with the patient seated or lying supine, and the rested arm flexed at 900 at the elbow. We defined malnutrition as a MUAC <19 cm for females and <20 cm for males [19].

Other predictor measurements

We defined sepsis as the presence of suspected infection plus 2 or more of the systemic inflammatory response syndrome (SIRS) criteria (pulse ≥90 beats/min; respiratory rate ≥20 cycles /min; a temperature ≥38 °C or ≤36 °C; and white blood cell count ≥12,000 cells/cc or <4,000 cells/cc); severe sepsis was defined as the presence of sepsis plus at least 1 organ dysfunction (Glasgow coma score [GCS] < 15, systolic blood pressure <90 mmHg, mean arterial pressure <70mmhg, or platelet counts <100,000 cells/cc) [23]. All temperature measurements were axillary. Diagnoses for infections and focus of infection were based on clinical suspicion and physical examination. We measured at admission, a random blood glucose (RBS) using a hand-held glucometer (Roche Diagnostics, Basel, Switzerland), and defined hypoglycemia as RBS <4.5 mmol/l [24]. We also obtained a complete blood count (Beckman Coulter, Villepinte, France) defining (severe) anemia as a hemoglobin concentration < 8 g/dl in both males and females [25]. HIV status was determined using a standard 3-test rapid testing algorithm (Determine, Abbott Laboratories, Abbott Park, IL; Statpak, Chembio Diagnostics, Medford, New York; and Unigold, Trinity Biotech, Bray, Ireland), and tuberculosis was defined as sputum smear positive pulmonary tuberculosis, or microscopically confirmed extra-pulmonary tuberculosis, or sputum smear negative tuberculosis as diagnosed through a consensus of at least two physicians [26]. All laboratory tests were performed at the Mbarara University Clinical Research Laboratory which participates in external quality assurance by the National Health Laboratory Service (Johannesburg, South Africa).

Severity of underlying illness

We measured severity of underlying illness using the Modified Early Warning Score (MEWS) which incorporates blood pressure, pulse, temperature, respiratory rate, and the neurological status at admission and strongly predicts mortality in hospitalized adults [27]. MEWS gives: 3 points for each of systolic blood pressure <70 mmhg, pulse rate ≥130 beats/min, respiratory rate ≥ 30 cycles/min, and GCS score ≤8; 2 points for each of SBP 70-80 or ≥200, pulse 111- 129, respiratory rate <9 or 21-29, temperature <35 or ≥38.5 Celsius, and GCS 9-13; and a point each for SBP 80-100, pulse 40-50 or 101-110, respiratory rate 16-20, and GCS score of 14. The accrued total score can be incorporated into analyses, usually as a categorical variable [28].

Outcome
The outcome was 30-day mortality. All patients were followed in hospital to death or discharge, and after discharge, they were further followed using mobile telephone calls and out-patient clinic appointments to determine 30-day vital status.

Figure 1: A directed acyclic graph (DAG) for the causal effect of malnutrition on mortality.

a) What is the primary relationship of interest in the DAG?

b) How many confounders are shown for this primary relationship of interest?

c) Does socioeconomic status need to be accounted for in any models that investigate the primary relationship of interest, based on the DAG?

d) How many different paths does HIV status have to the mortality outcome?

e) What was the primary reason for use of the DAG in the paper?

Question 3

a) Explain a "component cause" using the Rothman framework. In your answer you need to mention how sufficient and necessary causes relate to a component cause.

b) Is this statement true or false? Lack of consistency does not necessarily constitute evidence against a causal association.

c) Read the following paper and then answer the question below.

Buitrago-Lopez et. al. Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis. BMJ 2011;343:d4488 http://www.bmj.com/content/343/bmj.d4488.full

Based on the above meta-analysis address the six main Hill criteria for assessing causation. If it is not possible to assess a criteria based on the meta-analysis then explain what type of evidence you would be looking for and the sort of study that might be needed to address that criteria. The six main Hill criteria are: Experimental Evidence; Temporality; Strength of Association; Dose response; Biological plausibility; and Consistency.

Question 4

The following is an extract from the abstract of a published article that investigated neuroblastoma screening in infants. Read the extract and then answer the questions below.

Abstract Background

Neuroblastoma has many characteristics which suggest that preclinical detection might improve outcome. The Quebec Neuroblastoma Screening Project was initiated to determine whether mass screening could reduce mortality in a large cohort of infants. As an early endpoint, we report whether screening could reduce the incidence of poor-prognosis neuroblastoma in children with advanced stage disease over 1 year of age.

Methods
All 476?603 children born in the province of Quebec during the 5-year period of May 1, 1989, to April 30, 1994, were eligible for urinary assay of homovanillic acid and vanillylmandelic acid at 3 weeks and 6 months of age. Children with a positive screen were referred to one of four paediatric cancer centres in the province for uniform evaluation and treatment if necessary. Standardised incidence ratios (SIRs) were calculated for neuroblastoma in the province and two similar population-based controls, the state of Minnesota and the province of Ontario, during the same period of time and with similar ascertainment procedures.

Findings
Compliance with screening in Quebec province was 91% at 3 weeks (n=425?816) and 74% at 6 months (n=349?706). Through July 31, 1995, with a follow-up of the birth cohort of 15-75 months, 118 cases of neuroblastoma were diagnosed, 43 detected preclinically by screening, 20 detected clinically before screening at 3 weeks of age, and 55 detected clinically after 3 weeks of age having normal screens (52) or never screened (3). Retrospective analysis of stored samples confirmed that 49 of 52 patients missed by screening had levels of catecholamine metabolites that were too low to be detected at 6 months or earlier. Based on US Surveillance, Epidemiology and End Results data, 54-5 cases of neuroblastoma would have been expected in Quebec province during the study period, for an SIR of 2-17 (95% CI 1-79-2-57, p<0-0001). For the two control groups, 43 and 80 cases of neuroblastoma were detected, respectively, compared with 37-9 and 85-4 expected, overall SIR 1-00 (not significant). SIRs for Quebec province by age at diagnosis in yearly intervals show a marked increased incidence under 1 year of age (SIR 2-85, 2-26-3-50), with no reduction in incidence in subsequent years. Limiting analysis to only patients diagnosed over 1 year of age with advanced-stage disease, 22 cases were detected in Quebec province versus 14-4 expected (SIR 1-52, 0-95-2-23). Data in the two control groups show no significant increase or decrease in any-stage disease in children under or over the age of 1 year, except for an increase in early-stage disease in Minnesota children over 1 year: 10 versus 3-8 expected (SIR 2-67, 1-27-4-58).

a) How many cases (in total) of neuroblastoma were detected in Quebec during the study?

b) How many cases were expected to be found in the Quebec province?

c) Were more or less cases found compared to expected in the Quebec province?

d) Did the increased detection in cases in the less than one year age group lead to decreased incidence in the older age groups?

e) What is the most likely explanation for the increased number of neuroblastoma cases found?

Question 5

a) In no more than one paragraph present an example where either an ecological or spatial analysis would be the most appropriate study design. Please give justifications for your answer.