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Writing a study protocol •Introduction •research question •current knowledge •research hypothesis •research objective •Methodology •type of study •prospective, randomized, double-blind, control trial •observational •retrospective •audit •sample size calculation •guided by expected difference in either proportion or numerical data, standard deviation of known data, α and β values, and intended power of study •plan to recruit more subjects in case of drop outs •size of drop outs will affect the basis of assumptions and the initial sample size calculation, and the research hypothesis may show no significant difference (P>0.05) •patient information sheet and patient consent •inclusion criteria, exclusion criteria, restriction •process of randomization •procedure (process of carrying out data collection) •control group •test group(s) •monitoring of the patients during the period of procedure •routine - heart rate, blood pressure, oxygen saturation •data / observations •side effects of test protocol •rescue therapy •treatment plan for adverse effects •criteria for withdrawal from study •Statistical analysis •the data will be subjected to a test for normality •statement about treatment of normal or nonparametric distribution of data •normal distribution •expressed as mean and standard deviation, with 95% confidence interval •t-test for comparison of means obtained from 2 groups of data •analysis of variance test for comparison of means obtained from more than 2 groups • Χ2 test for discrete data •non-normal distribution •expressed as median and range, with limits of 25th and 75th percentiles •Mann-Whitney U test for analysis of data from 2 groups •Kruskal-Wallis test for analysis of data from more than 2 groups •state the P value and decide on the significance level, conventionally it is P<0.05 •submit protocol for ethics committee approval

NC Hwang 2009

Null Hypothesis •study hypothesis •investigator conducting a study usually has a theory in mind •however, very difficult to prove the hypothesis •simpler to disprove a hypothesis than proving it •null hypothesis •differences observed is not due to exposure to factor, and is by chance •always phrased in the negative and that is why it is termed null Longitudinal study •3 types •clinical trial, a cohort study, case-control study •in prospective studies, subjects are grouped according to ‘exposure’ to some factor •randomised or non-randomised, observational •investigates a process over time •the effect of external factors on human subjects •in retrospective studies, subjects are grouped according to outcome, the ‘exposure’ effect is then determined retrospectively Cross sectional study •describes a phenomenon fixed in time •description of disease, disease process, staging of cancer •diagnosis and staging of disease process •laboratory studies of biological processes Randomised control trial •Randomisation is a procedure in which the play of chance enters into the assignment of a subject to the alternatives (control and test groups) under investigation, so that the assignment cannot be predicted in advance •tends to produce study groups comparable in unknown as well as known factors likely to influence outcome apart from the actual treatment being given itself •guarantees that the probabilities obtained from statistical tests will be valid •parallel designs •one group receives the test treatment, and one group the control

•cross-over designs •the subjects receive both the test and the control treatments in a randomised order •each subject acts as own control, allowing paired or matched analysis, and provides an estimate of the difference between test and control •useful in chronic disease that remain stable over time, such as diabetes and asthma, where the purpose of treatment is palliative, not cure

Biostatistics

NC Hwang 2009

•may be referred to as follow-up, longitudinal or prospective study •often termed observational studies, since they observe the progress of individuals over time

•problems of cross-over design •cross-over effect •possibility that the effect of the particular treatment used in the first period will carry over to the second period, and may interfere with how the treatment scheduled for the second period will act, thus affecting the final comparison between the two treatments •to allow for this possibility, a washout period, in which no treatment is given, should be included between successive treatment periods •disease may not remain stable over the trial period •subject drop-outs •more will occur in this design trials than in parallel design trials, due to extended treatment period Non-randomised trials •historical controls •when randomisation is not possible •problem of bias selection already occurring - those who did not receive transplants may be more ill or may not have satisfied the criteria •survival of patients who received heart transplants and patients who did not •pre-test–post-test studies •a group of individuals are measured, then subjected to treatment or intervention, and then measured again •purpose of the study is to study the size of the effect of treatment or intervention (e.g. campaign) •major problem is ascribing the change in measurement to the treatment since other factors may also have changed in that interval Cohort •a cohort is a component of a population identified so that its characteristics can be ascertained as it ages through time •designated groups of persons either born in a certain year or traced over a period of time (who ever worked in a factory) Cohort study •one in which subsets of a defined population can be identified who have been exposed (or will be exposed) to a factor which may influence the probability of occurrence of an outcome (given disease) •usually confined to studies determining and investigating aetiological factors and do not allocate the equivalent of treatments •also for post-marketing surveillance, comparing adverse effects of new drug with alternative treatment

•problems with cohort studies •exposure to factor may be by natural selection or up to the individuals’ decision •bias may influence the measure of interest •other associated factors may also influence measure of interest •cohort study of cardiovascular risk in men sterilised by vasectomy •incidence of breast cancer with consumption of alcohol •size of the study •the required size of a cohort study depends not only on the size of the risk being investigated but also the incidence of the particular condition under investigation •cohort studies not suitable for investigating aetiological factors in rare diseases •interpretation of data •bias pool of study subjects •when cohort is made up of employed individuals, the risk of dying in the first few years of follow up is less than in general population, this is known as healthy worker effect; people who are sick are less likely to be employed •incomplete representation •people who respond (to questionnaires) and people who are lost to follow up Case control study •case-reference study or retrospective study •starts with identification of persons with the disease (or other outcome variable) of interest, and a suitable control group of persons without the disease •the relationship of a risk factor to the disease is examined by comparing the two groups with regard to how frequently the risk factor is present

Biostatistics

•designs •matched design •control subjects can be chosen to match individual cases for certain important variables such as age, gender and weight •unmatched design •controls can be a sample from a suitable nondiseased population •selection of controls •not required that the control group are alike in every aspect to the cases, usually 2 or 3 variables which presumably will influence outcome are matched, such as age, gender, social class •main purpose is to control for confounding variables that might influence the case-control comparison •confounding arises when the effects of two processes are not separated, e.g. disease related to 2 exposure factors •matching can be wasteful if matching criteria leads to many available controls being discarded because they fail the matching criteria •if controls are too closely matched to their respective cases, the relative risk may be underestimated •limitations of case-control studies •ascertainment of exposure relies on previously recorded data or on memory, and it is difficult to ensure lack of bias between the cases and controls •the subjects may be more motivated to recall possible risk factors •difficulty with selection of suitable control group •a major source of criticism Cross sectional studies •subjects are included without reference to either their exposure or their disease •usually deals with exposures that do not change, such as blood type, or chronic smoking habit •resembles a case-control study except that the number of cases are not known in advance, but are simply the prevalent cases at the time of survey •sampling methods •quota sample •to ensure that the sample is representative of general population in say, age, gender and social class structure •not recommended in medical research •grab or convenience sample •only subjects who are available to the interviewer can be questioned •problems •bias in the type of responders and non-responders •exposures have to be determined by a retrospective history Calculation of sample size •consider •control group response •the anticipated benefit or effect (of the treatment) •significance level •power

NC Hwang 2009

•Control group response •it is first necessary to postulate the response of the control group patients •denoted by π1, to distinguish it from the value that will be obtained from the trial, denoted p1 •experience of other studies may provide π1 •The anticipated benefit or effect •it is also necessary to postulate the size of the anticipated response in treatment group patients, denoted by π2, to distinguish it from the value that will be obtained from the trial, denoted p2 •anticipated benefit δ = π2 - π1 •Type I error •the error of incorrectly rejecting the null hypothesis when it (the hypothesis) is true •the error of concluding that the differences seen in the result is significant when in fact it is not •wrongly accepting that differences in the results as significant when there is no difference •equivalent to the false positive rate (1-specificity) •the probability of making a Type I error is designated α •α, the significance level, is set before the test is carried out •in most cases, it will be two-sided

•one or two-sided •null hypothesis (H°) is that there is no significant difference, and chance has occurred •no assumption about the direction of change or variation •alternate hypothesis states that the difference is real, further that it is due to some specific factor, •where no direction of change is specified, both ends of the distribution curve are important, and the test of significance is two-sided, or two-tailed •where the direction is specified, then only one tail of the curve is relevant, and the test of significance is onesided, or one-tailed

Biostatistics

•significance level •denoted by the letter P, represents the probability of the observed value being due solely to chance variation •the probability of obtaining the observed difference, or one more extreme, if the null hypothesis is true •the smaller the value of P, the less likely the variation is to be due to chance and the stronger the evidence for rejecting the null hypothesis •most scientific work, by accepted convention, rejects the null hypothesis at P < 0.05 •probability of the observed value being due solely to chance is < 0.05 (or < 1 in 20) •this means that we shall reject the null hypothesis on 5% of occasions, when it is in fact true, i.e. there was simply a chance variation and that the 2 treatment are equally effective •critical value for a one-sided test at significance P, will be equivalent to that for a two-sided test at 2P •one-sided P = 0.025 / two-sided P = 0.05 •the decision to use one-sided tests should be made before the data is collected, not after the direction of change is observed and should be clearly stated when presenting results •z: the value on the horizontal axis of a Normal distribution corresponding to the probability α •α: the probability that a random variable, (Normally distributed with mean = 0 and standard deviation = 1) will be greater than z or less than -z •

NC Hwang 2009

•2 main factors produce β error •chance alone •unusual data sample which does not support a difference •statistical methods can produce incorrect conclusions •too small a sample size •the smaller n, the greater must be the real difference before statistical difference may be shown •usually set at a value of β = 0.2 or 20% •Power •the probability that a study can predict a difference, when a real difference actually exists, is termed the statistical power of the study •it is the probability of rejecting the null hypothesis when it (the hypothesis) is false •first decide how much false negative or type II error (β) rate is reasonable •power equals 1-β •the higher the power of the study, the smaller the difference which may be detected •statistical testing errors

•Calculation of sample size •calculations depend on a function (zα + z2β)2, where zα and z2β are the ordinates for the normal distribution •the value of z for the corresponding α and 2β are read off from the Table of Normal distribution •Table to assist in sample size calculations with α = 0.05 β 0.3 0.2 0.1 Power (1-β) 0.7 0.8 0.9 z2β 0.524 0.842 1.282 zα 1.960 1.960 1.960 (zα +z2β)2 6.172 7.849 10.507

•if α is 0.05, then the corresponding z is 1.96 •to link z with the corresponding α, we write z0.05 = 1.96 •zα is the value along the axis of a Normal distribution •thus •0.05/2 = 0.025 is to the left of z = – 1.96 •0.025 is to the right of z = +1.96 •Type II error •error in incorrectly accepting the null hypothesis of no difference between treatments, when it (the hypothesis) is in fact false (and should be rejected) •accepting the null hypothesis when there should be significant difference in the results •accepting that the differences seen in the result is not statistically significant and making the conclusion P>0.05 •the probability of making a type II error is designated β •equivalent to the false negative rate (1-sensitivity)

•COMPARISON OF PROPORTIONS •wish to detect a difference in proportions δ = π2 - π1 •e.g. response rate to placebo and treatment drug •for Χ2 test, the number in each group should be at least

•COMPARISON OF MEANS (UNPAIRED DATA) •wish to detect a difference in means δ = μ2 - μ1 •the number in each group should be at least •where σ is presumed to be the same with both drugs •COMPARISON OF MEANS (PAIRED DATA) •with cross over trial •the number in each group should be at least •where σw is the standard deviation of the paired difference between treatment

Biostatistics

Randomisation •Methods of randomisation •simple randomisation •either manually by tossing coin or throwing a six-sided die or from table of random numbers •a good method in large trials but •does not guarantee equal numbers of patients in each of the two groups •in smaller trials there is a high chance of getting notable imbalance between the groups •groups of different sizes •presence of allocation bias •random permuted block (RPB) randomisation •a method for ensuring that group sizes never get too far out of balance and avoids assigning different numbers to each study group •combinations (e.g. AABB, ABBA) obtained from blocked randomisation can be assigned numbers (say 1-6), the sequence of the combinations can then be dictated by numbers from table of random numbers •a potential problem with the method is that if the block length becomes know, the method is predictable and selection bias can arise •randomly varying block length can help •stratified randomisation •if there are important prognostic factors which, if they were distributed unequally between the treatment groups, would give rise to a serious bias, then it may be prudent to intervene in the randomization process to ensure balance between these factors to ensure balanced treatment allocation for patients within each group or centre •in stratification, RPBs are used within each stratum defined by the prognostic factors •stratification can be cumbersome if there are too many prognostic factors and minimization is a method which is can provide balance in a less cumbersome way •unequal randomization (1:2, 2:1 for sample sizes of test : control groups) / unbalanced (vs balanced ) design •although maximum power can be obtained when the allocations to the groups are in the ratio 1:1, the loss in power is slight if the ratio departs only slightly from 1 •there can be practical advantages to unequal allocation, which might be worth considering in some applications. •carrying out randomisation •randomisation list should be prepared and held by a person not involved in the investigation and not the investigator determining patient eligibility •this person serves as a check for the trial •when a patient is confirmed as eligible for the trial, randomisation is then revealed •over the telephone or by opening sequentially numbered envelopes

NC Hwang 2009

Types of data •qualitative data (varying by description) •nominal data •ordered categorical or ranked data or ordinal data •numerical or quantitative data (varying by number) •numerical discrete data (differ only by fixed amount) •numerical continuous data (differ by any amount) •nominal data •data that one can name or describe •not measured but simply counted •expressed in number (or frequency) or percentage (or relative frequency) •2 or more groups of observation •2 groups - gender of patients, did or did not get exposure to factor •> 2 groups - blood groups, racial groups, anaesthetists, surgeons •ordered categorical or ranked data •if there are more than two categories of classification, it may be possible to order them in some way or assign ranks to categories to facilitate statistical analysis •e.g. ordinal data : mild, moderate, severe

•numerical discrete •data consists of counts •number of general anaesthetics and regional anaesthetics performed in this hospital in a year •number of anaesthetic trainees passing the Final MMed in the past 5 years •numerical continuous •such data are measurements that can take any value in a given range •age, estimated blood volume, hourly blood loss •interval scale, •position of zero is arbitrary, a difference between two measurements has meaning, but not their ratio •meaning may change if a ratio or percentage is applied to a different scale, e.g. 10% increase in body temperature in Celsius and Fahrenheit scales •ratio scale, •value of zero has real meaning, negatives are invalid •meaning does not change when ratio or percentage is applied to different units of measure, e.g. 10% increase in body weight in kilograms or pounds •continuous data is often dichotomised to make nominal data and then ordered or ranked for statistical analysis •e.g. diastolic blood pressure which is continuous can be converted to hypertension (>90 mmHg) or normotension (<90 mmHg)

Biostatistics

Summarising data •measures of location or central tendency •mean or arithmetic average •interval or ratio of a quantitative variable •median and quartiles •interval or ratio, (± ordinal) •mode •nominal, ordinal, interval or ratio •measures of dispersion or variability •range or interquartile range •standard deviation •measures of symmetry •Measures of central tendancy •mean or average •the mean ( , pronounced xbar) or average of n observations is the sum of the observations, Σx divided by their number, n (arithmetic average)

NC Hwang 2009

•lower and upper quartiles •practical method of calculating lower or upper quartiles are by the stem-and-leaf plot •e.g. observations 10,13,20,20,22,22,23,24,25,25,27,28,30,30,30,3 1,31,32,32,33,34,35,35,36,37,38,38,39,39,41,41, 41,42,42,43,43,44,44,46,47,48,50,50,51,52,54 2 10 17 12 5 46 1 2 3 4 5 03 0022345578 00011223455678899 111223344678 00124

•advantage •mean uses all the data values, is statistically efficient •disadvantages •vulnerable to outliers, •single observations (not erroneous measurements) which if excluded from the calculations, have noticeable influences on the results •median and quartiles •lower, median and upper quartiles divide the data into 4 equal parts •approximately equal numbers of observations in the 4 sections (equal only when n is divisible by 4) •estimation of quartiles •the data is first ordered from smallest to largest, and then counting upwards the number of observations •median or middle quartile •value above and below which half the measurements fall •for odd number of observations, is the observation at the centre of the ordering •for even number of observations, is the average of the ‘middle’ two observations •advantage •not affected by outliers •disadvantage •not statistically efficient as it does not make use of all the individual data values

•percentiles •25th percentile •the value above which 75 percent of the observed cases fall and below which 25 percent of the observed cases fall •50th percentile •the median, the value above and below which half of the observed values of a variable fall •75th percentile •the value above which 25 percent of the observed values of a variable fall and below which 75 percent of the observed values of a variable fall •mode •this is the value that occurs most frequently, or if the data is grouped, the grouping with the higher frequency •not much use in statistical analysis as its value depends on the accuracy with which the data are measured •bimodal distribution describes a distribution with two peaks in it •Measures of dispersion and variability •range and interquartile range •is given as the smallest and the largest observations •vulnerable to outliers •interquartile range •the distance between the 25th and 75th percentile •not vulnerable to outliers •displayed as box-whisker plots

•standard deviation •a measure of dispersion, i.e. how far variables are away from their mean, often abbreviated as SD •expressed in the same units of measurement as the observations

Biostatistics

NC Hwang 2009

•the value is interpreted as •each x value subtract from the mean , •square this difference, •then add each of the n squared differences •n-1 (or the degree of freedom) •compensates for small sample sizes (n < 30) and higher probability of falling outside the SD •s reflects the variability in the data •if x’s are widely scattered about , then s would be large •variance •a measure of the dispersion of values about the mean •the square of the standard deviation, s2 = •coefficient of variation •expresses the SD as a percentage of the sample mean •c.v. = (s/ ) x 100% •for data with a normal distribution, there is •a 68.26% chance that the actual value 68.26% will be within 1 standard deviation above or one standard deviation below the mean value •a 95.45% chance that the actual value will be within 2 standard deviations •a 99.7% chance that the actual value will be within 3 standard deviations •Measures of symmetry •symmetric distribution •if the distribution is symmetric then the median and mean will be close •data expressed as mean and standard deviation •skewed distribution •a distribution is skewed to the right (left) if the longer tail is to the right (left) •data expressed as median and interquartile range •mean and standard deviation are sensitive to the skewness •skewness •an index of the degree to which a distribution is not symmetric, or to which the tail of the distribution is skewed or extends to the left or right •calculation of skewness, •normality can be confirmed if mean and median are close •the normal distribution is symmetric, and has a skewness value of zero •a distribution with a significant positive skewness has a long right tail •a distribution with a significant negative skewness has a long left tail •skewness is used, along with the kurtosis statistic, to assess if a variable is normally distributed

•kurtosis •a measure of the extent to which observations are clustered in the tails •kurtosis can be used, along with the skewness statistic, to assess whether a variable is normally distributed •for samples from a normal distribution, the values of kurtosis will fluctuate around 0 •for a normal distribution, the value of the kurtosis statistic is 0 •if a variable has a negative kurtosis, its distribution has lighter tails than a normal distribution •if a variable has a positive kurtosis, a larger proportion of cases fall into the tails of the distribution than into those of a normal distribution •normal probability plot •normality of observation can be confirmed from the Normal probability plot

•normality •bell-shaped distribution of a continuous variable symmetrical about its mean •median and mean will be close •skewness value is zero •kurtosis value is zero •normal probability plot •mean or median? •convey different impressions of the location of the data •both give useful information •if the distribution is symmetric, mean is a better summary statistic •if the distribution is skewed, the median is less influenced by the tails •for nominal or ordered categorical data, mean is the proportion of each group Generating data from sample to population •a population is a theoretical concept used to describe an entire group (any collection of people, objects, events, or observations) •this is usually too large and cumbersome to study so investigation is usually restricted to one or more samples drawn from the study population •samples are taken from populations to provide estimates of the population parameters •the estimates of the population parameter is then inferred from the population sample, such as determining the reference normal range •statistics describes the sample •parameters describe characteristics of the population

Biostatistics

•to allow true inferences about the study population from a sample there are a number of conditions •the study population must be clearly defined •every individual in the population must have an equal chance of being included in the sample, i.e. a random sample •random does not refer to the sample, but the manner in which it was selected •the opposite of random sampling is purposive sampling, e.g. every 2nd patient •sampling errors •the smaller the sample size, the greater the error •the greater the variability of the observations, the greater the error •non-sampling errors •these do not necessarily decrease as the sample size increases •result in bias or systematic distortion of the results •Central Limit Theorem •definition: even when the variable is not normally distributed the sample mean will tend to be normally distributed •if random samples of n measurements are repeatedly drawn from a population with a finite mean μ, and a standard deviation σ, then when n is large, the relative frequency histogram for the (repeated) sample means will tend to be distributed normally Normal distribution •bell-shaped distribution of a continuous variable symmetrical about its mean •described by •population mean, μ •population standard deviation, σ •bell is tall and narrow for small standard deviation, and short and wide for large standard deviation •a skewed distribution can be transformed into Normal distribution shape by taking the logarithm of the measurements or working with the square root of the observations •Standard Normal Distribution

NC Hwang 2009

•in practice, the parameters μ and σ must be estimated from the sample data •for this purpose, a random sample from the population is first taken •if the sample is taken from a Normal distribution, and provided that the sample is not too small, similarly, approximately 95% of the collected data will be within – 1.96 s to + 1.96 s •1.96 is the 5% percentage point of the normal distribution •2.58 is the 1% percentage point of the normal distribution •application - scoring of fine motor skill

Standard error •SD(x)/√n •the standard deviation of the sampling distribution for a statistic •can apply to: mean, difference between means, skewness, kurtosis, Pearson correlation, regression coefficient, proportion, difference between proportion •a measure of how much the value of a test statistic may vary from sample to sample •standard error of the mean •standard deviation of the mean, SD( ) or standard error of mean SE( ) or SE •defines the precision with which a mean is estimated •SE( ) or SD( ) = SD(x)/√n or s/ √ n • exercise: calculation of SE Mean (x) alanine aminopeptidase value for 25 subjects is 1.0 U; SD is 0.3 U SE = SD/√n = 0.3/√25 = 0.3/5 = 0.06 •Comparing SD and SE

•mathematical property of the Normal distribution •68.26% of the distribution lies between μ ± 1σ •95.45% of the distribution lies between μ ± 2σ • μ – 1.96 σ and μ + 1.96 σ (for exactly 95%) •99% of the distribution lies between μ ± 3σ • μ – 2.58 σ and μ + 2.58 σ

Biostatistics

•standard error of skewness •a measure of the variability of the skewness statistic •examine how far it is from zero by dividing the measure of skewness by its standard error •the larger the absolute value of this quotient, the less reasonable it is to assume that the variable comes from a distribution with zero skewness, such as the normal distribution •standard error of kurtosis •a measure of the variability of the kurtosis statistic •examine how far it is from zero by dividing the measure of kurtosis by its standard error (SE Kurt) •the larger the absolute value of this quotient, the less reasonable it is to assume that the variable comes from a distribution with zero kurtosis, such as the normal distribution. Confidence interval •gives an estimated range of values which is likely to include an unknown population parameter, the estimated range being calculated from a given set of sample data •if independent samples are taken repeatedly from the same population, and a confidence interval calculated for each sample, then a certain percentage (confidence level: xx,yy) of the intervals will include the unknown population parameter •the lower and upper boundaries or values of a confidence interval •the values which define the range of a confidence interval •confidence intervals are usually calculated so that this percentage is 95%, but 90%, 99%, 99.9% confidence intervals for the unknown parameter can be produced •the width of the confidence interval gives us some idea about how uncertain we are about the unknown parameter •a very wide interval may indicate that more data should be collected before anything very definite can be said about the parameter •confidence intervals are more informative than the simple results of hypothesis tests (where H0 is rejected or not) since they provide a range of plausible values for the unknown parameter •confidence interval for a mean •define a range of values within which the population mean μ is likely to lie •that is, a range of values that is likely to cover the true but unknown population mean value (say, 95% of time) •95% CI for a large sample (>60) where s/ √n is SE( ) = + 1.96 x s/√n

NC Hwang 2009

•a reported CI from a particular study may or may not include the actual population mean •but if the study were to be repeated 100 times, of the 100 resulting 95% CI, we would expect 95 of these to include the population mean •small samples •less precise statements about population parameters can be made than with large samples • and s will not always be necessarily close to μ and σ, respectively •sample size is already taken into account in the calculation of the standard deviation of the mean, SD( ), using √n, i.e. s/√n •of practical importance only when the sample size is very small (less than 15) and when the distribution in the population is extremely nonnormal •exercise: calculation of CI Mean ( ) alanine aminopeptidase value for 25 subjects is 1.0 U; SD is 0.3 U. Calculate 95% CI 95% CI = + (1.96 x SE) where SE = SD/√n = 1.0 + (1.96 x 0.3/√25) = 1.0 + (1.96 x 0.06) = 1.0 + (0.1176) 95% CI is from 0.8824 to 1.1176 lower and upper boundaries of 95% CI = (0.8824, 1.1176) T-distribution •t distribution with (n–1) degrees of freedom •introduced by WS Gossett, who used the pen-name ‘Student’, and is often called Student’s t distribution •like the normal distribution, the t distribution is a symmetrical bell-shaped distribution with a mean of zero, but is more spread out, having longer tails •the exact shape of the t distribution depends on the degrees of freedom (d.f.), n–1, of the standard deviation s •degrees of freedom refers to the number of observations completely free to vary, the fewer the degrees of freedom, the more the t-distribution is spread out •Normal distribution vs t-distribution

•the upper and lower values are the 95% confidence limits

•Confidence interval using t-distribution •confidence interval is calculated using t’, the appropriate percentage point of the t distribution with (n–1) degrees of freedom •small sample CI = + (t’x s/√n) •for small degrees of freedom, the percentage points of the t-distribution are larger in value than the corresponding percentage points of the normal distribution •because sample standard deviation s may be a poor estimate of the population σ, and when this uncertainty is taken into account, the resultant CI is wider

Biostatistics

•reflecting this increased conservatism, the critical value for the t-test:

NC Hwang 2009

Statistical tests

•Unpaired T-test •for analysing data in 2 groups of subjects in a parallel group clinical trial or the unmatched case-control study •requires that the population distributions are normal •when comparing 2 means, the validity of the t test also depends on the equality of the 2 population standard deviations •the standard error for the difference between the means, SE ( 1- 2) = s√(1/n1 + 1/n2) •where s is the common standard deviation and is derived from s1 and s2 •the t value is calculated as t = ( 1- 2) / s√(1/n1 + 1/n2), d.f. = n1 + n2 - 2 •confidence interval is •One sample T-test •tests whether a sample mean is different from some specified value, μ, which need not be zero •t = ( -μ) / (s/√n), d.f. = n–1

•NORMAL DISTRIBUTION Comparison of 2 means •if the sample size is large, n > 30 •then the sample standard deviation, s, is considered to be an adequate estimate of the population σ •thus, the standard error of the sample mean becomes, SE( ) = (s/√n) •if n < 30 •the sample standard deviation, s, is not an adequate estimate of the population σ •Student's t-test is employed (Gosset in 1908) •small sample size, uneven SD •first approach is to seek a suitable change of scale to remedy this, so that the t test can be used; taking logarithms of the individual values •alternatives are to use a non-parametric test or to use either the Fisher-Behrens or the Welch tests •Paired T-test •attributes and demographic data, disease condition are matched to make two groups of subjects as similar as possible •the two groups •can be two groups of subjects in a matched case-control study •can be of the same subjects observed before and after a treatment as in a cross-over trial •this test is a statistical test of the null hypothesis that two population means are equal •any observed differences between the groups, if statistically significant, can be attributed to the variable of interest paired t = /(s/√n), d.f. = n-1 •the corresponding P value or significance level, is obtained from the Table of percentage point for Student’s t distribution 95% CI = + (t0.05 x s/√n)

Comparison of several means •Analysis of variance •the t-test is generalised to more than 2 groups by means of a technique termed analysis of variance •for this method, there are both between- and withingroups degrees of freedom •the between-groups and within-groups degrees of freedom are quoted in this order for every case •depending on the number of factor(s) included for analysis •one-way analysis of variance •two-way analysis of variance •one-way analysis of variance is used when the subgroups to be compared are defined by just one factor •e.g. comparison of means between different socioeconomic classes, or different ethnic groups, or by a disease process •this method assesses how much of the overall variation in the data is attributed to differences between the group means, and comparing this with the amount attributable to differences within group •two-way analysis of variance is used when the data are classified in 2 ways, e.g. by age-group and gender •NON-NORMAL DISTRIBUTION •non-parametric statistical tests are used for analysing numerical data that make no assumption about the underlying normality of distribution •particularly useful when there is obvious non-normality in a small data set which cannot be corrected with a suitable transformation Comparison of 2 groups of observations •Wilcoxon signed (+/-) rank test •a non-parametric equivalent of the paired t-test •it makes no assumptions about the shapes of the distribution of the two variables •the absolute values of the differences between the two variables are calculated as (+/-) for each case and ranked from smallest to largest

Biostatistics

•the test statistic is based on the sums of ranks for negative and positive differences •procedure •the absolute values of the differences between the paired observation are calculated (+/-) for each case and ranked from smallest to largest •exclude any differences which are zero, then rank in order, ignoring signs (i.e. + or –) •2 pairs having the same difference are given the mean of what would have been their successive ranks (i.e. 2nd & 3rd would have been ranked as 2.5 & 2.5) •add up the ranks of positive differences and negative differences separately •each of the (+) & (–) ranks is totalled, and the smaller referred to the Table of critical values for Wilcoxon matched pairs signed rank test for P value •Wilcoxon rank sum test •a non-parametric equivalent of the unpaired t test or two-sample test •procedure •rank the observations from both groups together in ascending order of magnitude •if any of the values are equal, average their ranks •add up the ranks in the group with the smaller sample size •compare this sum with the critical ranges in the Table of critical ranges for the Wilcoxon rank sum test •Mann-Whitney U test •a non-parametric equivalent of the unpaired t test or two-sample test •similar approach as Wilcoxon rank sum test with entirely comparable results Comparison of > 2 groups of observations •Kruskal Wallis one way analysis of variance •a non-parametric equivalent of the one way analysis of variance for normal distribution

NC Hwang 2009

•Χ2 test •is used to •examine the association between discrete (categorical or qualitative) variables •test whether an observed frequency distribution differs significantly from a postulated theoretical (expected) one (Goodness of Fit) •test whether there is an association or dependence between the row variable and the column variable, or •test whether the distribution of individuals among the categories of one variable is independent of their distribution among the categories of the other •advantage •it allows comparison of many more categories, drawn-up into a contingency table •the null hypothesis predicts that any number of categories have equal chance of any other factor •when the table has only 2 rows or 2 columns, this is equivalent to the comparison of proportions •applicable for •a parallel group clinical trial, an unmatched case-control study, or a cross-sectional survey •Χ2 test for 2 x 2 table •first calculate the values expected in the 4 cells of the table assuming the null hypothesis is true •estimated cell value = row total x column total / total n •the Χ2 test is calculated from , d.f.= 1 for a 2 x 2 table •the Χ2 test is valid when n is > 40, regardless of the expected values, and if less than 20% of the expected values are less than 5 and none are < 1 •when n is between 20 and 40, the test is only valid if all the expected values are at least 5 •Yates’ correction for continuity •always advisable although it has most effect when the expected numbers are small •for converting the discrete data, as Χ2 distribution used to calculate the P value is continuous, like the Normal distribution •when the numbers are very small, the Χ2 test is not a good enough approximation even with a continuity correction and the Fisher’s exact test for a 2×2 table should be used •Fisher’s exact test for a 2 x 2 table •to determine P value •to be used if any expected counts in a 2 x 2 table is less than 5, as the P value given by the Χ2 test is not strictly valid •larger tables •chi-squared test can also be applied to larger tables, generally called r x c tables •r denotes rows and c denotes columns , d.f.= (r-1)x(c-1) •there is no continuity correction or exact test for contingency tables larger than 2x2 •chi-squared test should not be applied to tables showing only proportions or percentages

•The Chi-squared test for contingency tables •contingency table

•can be used to represent •qualitative variables •discrete quantitative variables •continuous quantitative variables whose values have been grouped

Biostatistics

Correlation •techniques for dealing with the relationship between 2 or more continuous variables •correlation •examines linear association between 2 variables •not whether one variable predicts another variable •strength of the association summarised by the correlation coefficient •regression •examines dependence of one variable, the dependent variable, on the other, the independent variable •relationship summarised by a regression equation consisting of a slope and an intercept •Correlation coefficient, r •summarises the strength of the association between 2 variables •allows testing of the hypothesis that the population correlation coefficient r is zero i.e. whether an apparent association between the variables would have arisen by chance •Pearson correlation coefficient •when the correlation coefficient is based on the original observations •Spearman rank correlation coefficient •when it is calculated from the ranks of the data •dimensionless quantity ranging from -1 to +1 •a positive correlation is one in which both variables increase together •a negative correlation is one in which one variable increases as the other decreases •when variables are exactly linearly related, then the correlation either equals +1 or -1 •unaffected by units of measurement •different correlations

NC Hwang 2009

•Variance explained, r2 •squaring of the correlation coefficient and multiplying by 100 gives r2 or variance explained, the proportion of the variance of one variable explained by the other •e.g. r of 0.9, r2 = 0.81 x100; approximately 80% of the variance of one variable can be accounted/explained/predicted by the other •Pearson correlation (coefficient, r) •this is a parametric measure of the degree of association between 2 numerical variables

•to test whether this is significantly different from zero, calculate SE(r) = √{(1-r2)/(n-2)} and t = r/SE(r) •and compare this with the Table of t-distribution with n2 degrees of freedom for P value •assumes both variables are random samples and at least one has a normal distribution •outlying points away from the main body of the data suggest the variable may not have a normal distribution •in this case it may be better to replace the observation by their ranks and use the Spearman rank correlation coefficient •Spearman rank correlation (correlation, rs) •this is a non-parametric measure of the degree of association between 2 numerical variables •the values of each variable are independently ranked and the measure is based on the differences between the pairs of rank of the 2 variables

•where d is the difference between each pair of ranks •this correlation will have a value between -1 and 1, and its interpretation is similar to that of the Pearson correlation coefficient •the significance of the association is tested by comparing rs with the critical values of the Spearman rank correlation coefficient table, significant if rs is > critical value •should not be used •if the relationship is non-linear •in situations where one of the variables is determined in advance •should be used with caution •in the presence of outliers •when the variables are measured over more than one distinct group e.g. disease and healthy groups Statistical method for assessing agreement between two methods of clinical measurement •any two methods that are designed to measure the same variable will have a good correlation when a set of samples are chosen. •most of the data will cluster about the line of equality, and r will approach 1.

Biostatistics

•a high correlation for any two methods designed to measure the same variable just means that a wide spread sample was obtained and does not automatically imply that there is good agreement between the two methods. •a Bland-Altman plot (Difference plot) is used to analyse the agreement between two different methods designed to measure the same variable, or to compare a new measurement technique or method with a gold standard, each having some errors in their measure. •it is identical to a Tukey mean-difference plot. •Bland and Altman Difference Plot •the Bland and Altman Plot is a scatter diagram of the differences plotted against the averages of the two measurements. •comparison of Correlation Plot (upper scatterplot) and Difference Plot (bottom scatterplot)

NC Hwang 2009

Regression •looking for dependence of one variable, the dependent variable, on the other, the independent variable •relationship summarised by a regression equation consisting of a slope and an intercept •the slope represents the amount the dependent variable increases with unit increase of the independent variable •the intercept represents the value of the dependent variable when the independent variable is zero •multiple (multivariate) regression examines simultaneous relationship between one dependent variable and a number of independent variable •Linear regression •assumption: a change in one variable, x, will lead directly to a change in another variable, y •e.g. haemoglobin increase with age, not the other way around •y variable (resultant change) is termed dependent variable •x variable is termed the independent variable •regression line •regression equation describes the relationship between y and x y = a + bx y = α + βx for population parameters a is the intercept and b is the regression coefficient calculation of b

Difference

calculation of intercept, a = y – bx •unwise to use equation to predict an outcome based on extrapolation of observed parameters •Multiple regression •model of multiple regression •y = a + b1x1 + b2x2 + ……bkxk •applications •to look for relationships between continuous variables, allowing for a third (possibly confounding) variable •e.g. predicted haemoglobin = 5.24 + 0.11(age) + 0.097(PCV) •corresponding t-value is b/SE(b) with d.f. of n minus the number of estimated parameters •from these, P value is derived from Table of t distribution •95% confidence intervals b + t0.05SE(b) •if the interval includes zero, the conclusion should be that that relationship between y and x remains the same whether or not x changes

Average •it is obvious that there is no relation between the difference and the mean in the Difference Plot. •the lack of agreement can be estimated by the mean difference, which will provide an estimate of bias. •the 95% limits of agreement will be the mean difference plus and minus 2 times the standard deviation of the differences. •95% confidence intervals can be calculated for the mean and upper and lower limits. •outliers are immediately apparent with the Difference Plot but not obvious with the Correlation Plot. •it is a good practice to check the data for the outlier, to exclude a mistake in entering the data. •if necessary, outliers can be excluded from the calculations for the limits of agreement.

Biostatistics

•Degrees of freedom •the number of degrees of freedom depends on 2 factors •the number of groups we wish to compare •the number of parameters we need to estimate to calculate the standard deviation of the contrast of interest •for Χ2 test for comparison of 2 proportions, 1 df •for t-test •2 sets of degrees of freedom •one degree of freedom betweengroups •one for within-groups •for comparing 2 means, 1 df for between groups, there are also dfs for estimating σ •for paired data, df = number of subjects minus 1 •for unpaired data, df = n1 + n2 minus 2, that is n –1 for each group •for linear regression •given n independent pairs of observations, 2 degrees of freedom are removed for the 2 parameters that have been estimated, thus d.f. = n-2 •for multiple regression •d.f. are n minus the number of estimated parameters Predictions : Diagnostic tests and implications •Sensitivity •what is the probability that the test result will be positive when a disease is present? •presence of acute myocardial infarction and positive T-Troponin test •difficult laryngoscopyand restriction of atlantooccipital joint extension •Specificity •what is the probability that the test result will be negative when a disease is absent? •absence of acute myocardial infarction and negative T-Troponin test •difficulty in laryngoscopy and Mallampati class I and II •sensitivity and specificity are characteristics of the test, not the population to which the test is applied •Prevalence, sensitivity, specificity •example

NC Hwang 2009

•Prevalence of iron deficiency anaemia = 809/2579 = 31% •Sensitivity of positive test result in presence of iron deficiency anaemia = 0.9 or 90% •Specificity of negative test result in presence of iron deficiency anaemia = 0.85 or 85% •Predictivity

•predictive value of a positive test: •attempts to calculate the probability of the patient having the disease (D+) when the test is positive T+, or P(D+ given T+) • = a/(a + b) •predictive value of a negative test: •attempts to calculate the probability of the patient not having the disease (D-) when the test is negative T-, or P(D- given T-) • = d/(c + d) •discrimination - overall correct classification rate, how well the model separates those in D+ and D- = (a+d)/g •false classification rate = (c+b)/g or = 1 - discrimination •Predictivity or sensitivity? •predictive value is what the clinician wants •positive test, is the disease present? •negative test, is the disease absent? •correct classification rate •sensitivity is supplied with the statistical test •disease present, was the test positive? no disease, was the test negative? •Likelihood ratio (LR) •the likelihood that a given test result would be expected in a patient with the target disorder compared to the likelihood that that same result would be expected in a patient without the target disorder. •Compares likelihood for T+ in D+ and T+ in D•Ratio of T+ for D+ and D•A very low LR (say, below 0.1) virtually rules out the chance that the patient has the disease.

expressed as fraction or percentage: •prevalence of disease = e/g or P(D+) •sensitivity of a test = a/e or P(T+ given D+) •specificity of a test = d/f or P(T- given D-) •false negative rate = 1- sensitivity = c/e (Type II error) •false positive rate = 1- specificity = b/f (Type I error) •Likelihood for D+ if T+ = a/e (or sensitivity) •Likelihood for D- if T+ = b/f (or 1-specificity) •Likelihood ratio for T+ = (a/e)/(b/f)

Biostatistics

•example

NC Hwang 2009

Pre-test probability→pre-test odds→post-test odds→post-test probability •example

•Sensitivity = 90% •Specificity = 85% •Likelihood for D+ if T+ = 0.9 or 90% •Likelihood for D- if T+ = 0.15 or 15% •LR for T+ = 0.9/0.15 or 90/15 = 6 •a patient with serum ferritin concentration <65mmol/l would be 6x more likely to be seen in someone with, as opposed to someone without, iron deficiency anaemia •Applications •LR is used to assess how good a diagnostic test is, and to help in selecting (an) appropriate diagnostic test(s) or sequence of tests. •LRs have advantages over sensitivity and specificity because they are less likely to change with the prevalence of the disorder. •LRs can be calculated for several levels of the symptom/sign or test. •LRs can be used to combine the results of multiple diagnostic test. •LRs can be used to calculate post-test probability for a target disorder. •Pre-test probability •the proportion of people with the target disorder in the population at risk at a specific time or time interval = point prevalence or period prevalence •prevalence may depend on how a disorder is diagnosed. A good example is dementia. •Pre-test odds •the odds that the patient has the target disorder before the test is carried out = pre-test probability/(1 – pre-test probability) or = prevalence/(1 - prevalence). •Post-test odds •the odds that the patient has the target disorder after the test is carried out = pre-test odds x likelihood ratio •Post-test probability •the proportion of patients with that particular test result who have the target disorder = post test odds/(1 + post-test odds) •Calculation of post-test probability •Obtain pre-test probability (prevalence) •Pre-test odds = prevalence / (1 - prevalence) •Post-test odds = pre-test odds x LR •Post-test probability = post-test odds / (post-test odds + 1) •If LR > 1, post-test probability > pre-test probability •If LR < 1, post-test probability < pre-test probability

•Likelihood ratio for T+ = (731/809)/(270/1770) = 6 •Prevalence of iron deficiency anaemia = 809/2579 = 31% •Pre-test odds = prevalence / (1-prevalence) = 31/69 = 0.45 •Post-test odds = 0.45 x 6 = 2.7 •Post-test probability = 2.7 / (2.7 + 1) = 2.7/3.7 = 0.73 •with a result of 60 mmol/l, the post-test probability of the patient having iron deficiency anaemia is increased to 73%, from pre-test probability of 31%, and this suggests that the serum ferritin is a worthwhile diagnostic test •Odds •odds are a ratio of probabilities •the odds in favour of an event or a proposition are p/(1−p), where p is the probability of the event or proposition. •the odds ratio is a way of comparing whether the probability of a certain event is the same for two groups. •given that a subject has or does not have a disease, •odds always measures the incidence of event (exposure) to non event (non-exposure).

•with the disease, odds of event are a/c, or a/(1-a) •without the disease, odds of event are b/d, or b/(1-b) •Odds ratio (OR) •the odds that a given test result, event or exposure would be expected in a patient with the target disorder or outcome compared to the odds that the same result, event, or exposure would be expected in a patient without the target disorder or outcome. •odds ratio is the ratio of two odds

•odds ratio, OR is (a/c)/(b/d) = ad/bc •an odds ratio of 1 implies that the event is equally likely in both groups. •an odds ratio > 1 implies that the event is more likely in the first group. •an odds ratio < 1 implies that the event is less likely in the first group.

Biostatistics

•example of odds and odds ratio

NC Hwang 2009

Meta-analysis •results from 2 or more primary studies are combined statistically. •Fixed-effects model •assumes a single true value underlying all the study results. •if all studies were infinitely large, they would yield identical estimates of the effect. •observed estimates of effect differ from each other only because of random error from within-study variation. •ignores between-study variation or heterogeneity. •confidence interval is very narrow •Random-effects model •assumes that studies included are a random sample of a population of studies addressing the question posed in the meta-analysis. •each study estimates a different underlying true effect and the distribution of these effects is assumed normal about a mean value. •takes into account both within-study variability and between-study variability. •between-study variability beyond which can be explained by within-study variability inflates the random-effects estimate of random error. •gives smaller studies proportionally greater weight in the pooled estimates •if results from smaller studies are further from null results, this model will tend to produce larger estimates of beneficial or harmful effects than will the fixed-effects model. •will provide a more conservative or less conservative estimate of treatment effect than fixed-effects model. •confidence interval is wider. •Forest (meta-analysis) plot •an odds ratio plot, also known as a Forest plot or a metaanalysis plot, graphs odds ratios (with 95% confidence intervals) from several studies. •this plots a series of lines and symbols representing a meta-analysis or overview analysis. •the confidence interval of an effect (e.g. odds ratio) estimate is represented by a line.

•the odds of having serum ferritin concentration <65mmol/l compared to >65mmol/l •in the presence of iron deficiency anaemia, = 731/78 = 9.4 •In the absence of iron deficiency anaemia, = 270/1500 = 0. 18 •the odds ratio, OR = 9.4/0.18 = 52

•Risk •risk of an event is the probability that an event will occur within a stated period of time •the risk of developing the disease within the follow-up time is a/(a+b) for the exposed population c/(c+d) for the unexposed population

•Relative risk •a summary of the outcome of a cohort study RR = (a/(a+b))/(c/(c+d)) or a*(c+d)/c*(a+b)

•the effect estimate is marked with a solid black square. •the size of the square represents the weight that the corresponding study exerts in the metaanalysis; this is the Mantel-Haenszel weight.

Biostatistics

•the pooled estimate is marked with an unfilled diamond that has an ascending dotted line from its upper point. •confidence intervals of pooled estimates are displayed as a horizontal line through the diamond; this line might be contained within the diamond if the confidence interval is narrow. •epidemiologists often like to make the x axis logarithmic. This makes odd ratios greater than 1.0 and less than 1.0 symmetrical (for example, an odds ratio of 2.0 becomes symmetrical with an odds ratio of 0.5).

NC Hwang 2009

•the paradox disappears when causal relations are derived systematically, through formal analysis. •coding of an effect is subjective. •decision to include or reject a particular study is subjective. •there are two different ways to measure effect: correlation or standardized mean difference. •interpretation of effect size is purely arbitrary. •it has not been determined if the statistically most accurate method for combining results is the fixed effects model or the random effects model. •the underlying risk in each studied group is of significant importance, and there is no universally agreed-upon way to weight the risk. •Funnel plot •If publication bias is not present, the funnel plot should be roughly symmetrical.

•Weakness of meta-analysis •sources of bias are not controlled by the method. •heavy reliance on published studies, (publication bias or "file-drawer effect“) • as only results with significant parameters are published in academic journals., the distribution of effect sizes are biased, skewed or completely cut off. •This can be visualized with a funnel plot of sample size (y-axis) and effect sizes (x-axis). •There are several procedures available to correct for the file drawer problem, once identified, such as simulating the cut off part of the distribution of study effects. •Simpson's Paradox or Yule-Simpson effect •an apparent paradox in which the successes of groups seem reversed when the groups are combined. •due to incorrect assumptions, incomplete or misguided information, or a lack of understanding a particular concept. •occurs when frequency data are hastily given causal interpretation.

•not a very reliable method of investigating publication bias, although it does give us some idea of whether our study results are scattered symmetrically around a central, more precise effect. •funnel plot asymmetry may be due to publication bias, clinical heterogeneity between studies (for example different control event rates) or methodological heterogeneity between studies (for example failure to conceal allocation). •example of a funnelplot without the file drawer problem

Sample size

Treatment effect

Biostatistics

•example of a funnelplot with the file drawer problem

NC Hwang 2009

Treatment effect How large was the treatment effect?

•if CI around RRR is not reported, •if P=0.05, then lower limit of CI for the RRR lies exactly on zero (a relative risk of 1, cannot conclude the treatment has or has no effect) •as P value decreases below 0.05, the lower limit of CI for RRR rises above zero •converting odds to risk •risks = odds/1+odds •if 1/5 of patients in a study suffered a stroke after surgery, the odds of their having a stroke are (1/5)/(4/5), or 0.2/0.8, or 0.25 •converting from odds to risk, the risk is 0.25/(1+0.25), or 0.2 (20%) •converting risk to odds •odds = risk/1-risk •the greater the magnitude of the risk, the greater is the divergence between the risk and odds. •as risk falls, the odds and risk come closer together.

•absolute risk (pain) reduction 0.2-0.15 = 0.05 or 5% •relative risk of having pain 0.15/0.20 = 0.75 •relative risk reduction (1-0.75) x 100% = 25% •depends on the sample size •with sample size of 100 each arm •95% CI for RRR of 25% is -28.15 to 77.76, including 0 •lignocaine + propofol probably no benefit •with sample size of 1000 each arm •95% CI for RRR of 25% is (8.35 to 41.61) •confident that true RRR is close to 25% •confidence interval around relative risk reduction

Sample size

•OR or RR? •for low event rates, the OR and RR will also be closer together when the magnitude of the treatment effect is small (both are close to 1), than when the treatment effect is large. •OR, RR, ARR, RRR – example •treatment of oesophageal varices

•odds of death vs survival (ligation) = 18/46 = 0.39 •odds of death vs survival (sclerotherapy) = 29/36 = 0.81 •OR of death (ligation) = 0.39/0.81 = 0.48 •OR of death (sclerotherapy) = 0.81 / 0.39 = 2.1 •risk of death (ligation) = 18/64 = 0.28 (or 0.39/1+0.39) •risk of death (sclerotherapy) = 29/65 = 0.45 (or 0.81/1+0.81) •RR of death (ligation) = 18/29 = 0.62 •RR of death (sclerotherapy) = 29/18 = 1.6 •Absolute risk reduction (ARR) = 0.45-0.28 = 0.17 or 17% •Relative risk reduction (RRR) = 0.17/0.45 = 0.38 or 38%

Biostatistics

Are the likely treatment benefits worth the potential harm and cost? •Number needed to treat •the number of patients who must receive an intervention of therapy during a specific period of time to prevent one adverse outcome or produce one positive outcome •the inverse of the ARR, or NNT = 1/ARR •where ARR = CER (Control Event Rate) - EER (Experimental Event Rate) •always rounded up to the nearest whole number. •if there is a higher probability that a patient will experience an adverse outcome if we do not treat, •the more likely the patient will benefit from treatment and •the fewer such patients we need to treat to prevent one adverse outcome •the best NNT would be 1, •every patient with treatment benefited •no patient given control benefited •generally NNTs between 2 and 5 are indicative of effective treatments, but NNTs of 20, 50 or 100 may be useful for prophylactic treatments, like interventions to reduce death after heart attack •relevance of which depends on the intervention and the consequences •example 1

NC Hwang 2009

•example 2

•Number needed to harm •for adverse effects, the number needed to harm (NNH) can be calculated in exactly the same way as an NNT •for an NNH, large numbers are obviously better than small numbers, because that means that the adverse effect occurs with less frequency

Biostatistics

Survival curves •Survival curves plot percent survival as a function of time. •Time zero is the time that each patient entered the study. •In many clinical studies, "time zero" spans several calendar years as patients are enrolled. •At time zero, by definition, all patients are alive, so Y = 100%. •Whenever a patient dies, the percent surviving decreases. •If the study (and thus the X axis) were extended far enough, Y would eventually reach 0. •Simple survival curve •15 (100%) patients entered the protocol at different times and were individually followed for 36 months. At 36th-month, 6 are still alive.

NC Hwang 2009

•If the curve is plotting deaths due to a particular form of cancer, a decision has to be made before the study is started regarding patients who die of another cause, say, an automobile accident. •can count them either as deaths or as censored subjects. •Creating a survival curve •2 methods: •With the actuarial method, the X axis is divided up into regular intervals, perhaps months or years, and survival is calculated for each interval. •With the Kaplan-Meier method, survival is recalculated every time a patient dies. This method is preferred, unless the number of patients is huge. This method is logically simple but tedious. •Kaplan-Meier method •To calculate the fraction of patients who survived on a particular day, simply divide the number alive at the end of the day by the number alive at the beginning of the day (excluding any who were censored on that day from both the numerator and denominator). •This gives the fraction of patients who were alive at the beginning of a particular day who were still alive at the beginning of the next day. •To calculate the fraction of patients who survive from day 0 until a particular day, multiply the fraction of patients who survive day 1, times the fraction of those patients who survive day 2, times the fraction of those patients who survive day 3 ... times the fraction who survive day n. •This method automatically accounts for censored patients, as both the numerator and denominator are reduced on the day a patient is censored. •Because the product of many survival fractions are calculated, this method is also called the product-limit method. •Note that “day” refers to day of the study, not a particular day on the calendar. Day 1 is the first day of the study for each subject. •Survival curve with censored subjects •A subject is censored at a certain time for one of two reasons: •subject stopped following the study protocol at that time •the trial ended with the subject still alive

•Application of survival curve •Survival curves can plot time to any well-defined end point, such as •occlusion of a vascular graft, •date of first metastasis, •rejection of a transplanted kidney, •restoration of renal function, •discharge from a hospital, or •graduation. •The event must be a one-time event. •Recurring events should not be analyzed with survival curves. •Censored survival data •In most survival studies, some surviving subjects are not followed for the entire span of the curve. •This can happen in two ways: •the patients who drop out of the study, and/or are loss to follow-up •the patients who enrol later are not followed for as many years as patients who enrol early and the trial ended with these patients still alive •In either case, the subject survived up to a certain time but have no useful information about what happened after that. •Information about these patients is said to be censored. •Before the censored time, they were alive and following the experimental protocol, so these subjects contribute useful information. •After they are censored, any information on the subjects cannot be used.

Biostatistics

•95% CI of a survival curve •We can be 95% sure that the true population survival curve lies within the 95% CI shown on our graph at all times.

NC Hwang 2009

•Median survival

•Median survival cannot be determined if more than half the subjects are still alive when the study ends.

•Assumptions •Random sample •representative of that population. •Independent observations •choosing any one subject in the population should not affect the chance of choosing any other particular subject. •Consistent entry criteria. •Patients are enrolled into studies over a period of months or years. In these studies it is important that the starting criteria do not change during the enrolment period. •improved diagnostic technology detection may make subject “live longer” with the diagnosis. •Consistent criteria for defining "survival " •it is crucial that the event defining survival be assessed consistently throughout the study. •Time of censoring is unrelated to survival •The survival of the censored patients is assumed to be identical (on average) to the survival of the remainder. •In well-run studies, a very small fraction of patients leave the study. •check what fraction of the patients dropped out of the study and why •A survival curve would be misleading, for example, if many patients quit the study because they were too sick to come to the clinic or because they felt too well to take medication. •Average survival does not change during the course of the study. •If patients are enrolled over a period of years, the overall survival is assumed to be the same over time. •The survival curve is misleading if the patients enrolled in the study early are more (or less) likely to die than those who enrol in the study later.

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