. . } { . .

"In the beginning of the lecture the doctor said that he will change the exam`s date, coz he will be in Australia on 27/11..and he will tell us the new date later" Please refer to the slides while studying... Last time we stopped at this stage here, we said advantages and disadvantages of randomized studies, we discussed all of these and we said one of them it's better at dealing with confounding and bias because you can control (anything you can control) this means it's better to deal with these problems... But in observational studies you just observe, so thats why if you have a problem you cannot sometimes control for that problem (ya3ne 2nta lamman tkoon bddak t3mal tajroba bnafsak tasta6ee3 an tata7akkam b jamee3 el 3awaml 2lle 3ndak laken lmman tkoon bddak ta36e 6'ahira mo3ayyana sometimes sa3b 2nnak tit7akkam b jamee3 el mo2athirat 2lle to2ather 3alee) SO in randomized studies (2lle tkoon 3la shkl) which is experimental studies which you did it and you choose the persons (2lle bddak tf7ashom) that u want to examine and you divide them to groups thats why its much better to deal with confounding and bias when you do randomized studies than when you do observational studies We said confounding is an association between risk factor and an outcome, when this association is effected by the relationship of a third period of time... We always gives this example: you have for example effect of smoking on lung cancer,(lets say smoking on oral cancer) but also we have the effect of alcohol consumption on oral cancer thats why you cannot study the effect of smoking on oral cancer alone without considering those who consume alcohol because also alcohol consumption can have an effect on oral cancer, also alcohol can
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effect smoking there is a relationship between alcohol and smoking (as you learned in pathology we have something called synergistic action ya3ne for example if the effect of smoking alone on cancer was 5 % and alcohol 5% you cannot say the effect of smoking and alcohol 5+5 which is 10 % NO its 5 times 5 "ya3ne 25" so thats why this is called synergistic action) SO if we want to see this consider that we want to study the effect of alcohol on oral cancer you have to consider the potential confounder which is smoking smoking can effect on both ways in randomized studies you can control the effect between smoking and alcohol consumption by assigns groups by dividing the samples that we want to study into 2 groups 1 is those who are smokers and the other group who consume alcohol the other group who are normal (non-smoker & and not alcoholic) so you can control because you have the ability to assign groups (to choose your groups) but in observational studies the possible effect is in both ways and cannot be controlled, thats why we go and say : Randomized studies are better at dealing with confounding and bias. Eliminating confounding by randomizing subject: as we said you can randomize (choose randomly) by this you eliminate the effect of confounding, when you choose a random sample there is a possibility of choosing the people who have the problem and choosing the people without the problem and because you include a very big number of subjects, the effect of including those with a problem can be canceled with the effect of including those without the problem.. Randomization should be unbiased, that means when you do randomization ( mosh lazm ykoon fee ta7ayyoz) all the time dont let your self know the groups that you are randomizing, if I want to do an experiment on my student in this theater I should give each one of them a number I should not identify each student by his/her name, otherwise I will not randomize, randomized groups will be equal with respect to confounders; the effect of confounders should be equal among all those who are going to be selected. Randomization eliminates known and unknown confounders: Sometimes the confounder it can be known like for example: when you know confounder of alcohol consumption on oral cancers, by this we say the confounder is known!! But sometimes you dont know the other confounders, sometimes you discover them by the end of the research and sometimes you dont discover them...that's why we have KNOW and UNKNOWN confounders
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Randomization helps in eliminating know and unknown confounders: Other techniques for minimizing known confounders when you identify a confounder and you want to eliminate it, you can do matching, stratification, multivariable adjustment, for example when you take Jordanian population and then you divide it into northern, middle and southern regions you take each region you select the biggest state in the northern region for example which is IRBID and then you take govern Irbid divide into rural and urban and then in each rural you take one randomized school for boys another randomized school for girls, by this we cause stratification so you start with the head of the urban area and then you start to stratify (tballesh t8assimhom) this is very good in eliminating confounders..(I don't want to go in details of matching and multivariable this will be discussed next time Insha'Allah, just know that these are techniques that I use to eliminate the confounders) Randomization eliminate confounding only when unbiased as we said, group assignment should be done at the time of involvement not the before or after, if you want to do randomize a study and you want to select the groups or you divide your samples into the groups that you want to study, this should be done at the time of involvement (ya3ne lmma yejo yishtarko 3ndak bl ba7eth f hathak el wa8t 2nta btballesh, mosh walla yballesho yishtarko w ba3deen 3la mazajak wjadt results mosh naf3a ro7t 8assamthom 2la groups mo5talifa marra thanya!!!) NO that (randomization and grouping) should be done at time of involvement of your subjects into your study, not before and not after NOTE: (no group assignment should be changed by personnel, and should be done by someone with no contact with the subject)!!!!!!!!!! that means if I want to make a study, there should not be a contact between investigator and the subject " like for example if I want to make a study about YOU, I have to bring someone else to make this study because I know YOU all" so it should be done by someone with no previous contact with the subject By using a random number table or generator (ya3ne bn36y kol wa7ed a random number, w lazm kol wa7ed ykoon 3ndo chance 2nno ykoon b had el group aw hdak el group, mosh 2nno a7o6hom zay ma ana bddy 3ashan a6alle3 el result 2lle ana bddiyyaha!!! NO
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lazm tkoon RANDOOOMMM, unless if your study will involve people with those who will take the treatment and those who will not take the treatment, in this case you have to know for example if you want to study something you want to group the people (people with disease and people without disease) you have to give those people the same antibiotic as the other group without the disease in this case you have to know you have to group those with the disease in one group and those without the disease in the other group, but in the cases if there is a randomization, each one or each group have the same chances to belong to each one of the groups In observational studies, the investigator and subjects usually know which groups the subject where assigned to (in the case of obser. studies we know for example when I did my study on emergence of permanent teeth, I previously know that today I'm going to a rural school so thats why I know previously that the subject that I will examine today for example they have an increase period of caries because they live in a rural area not very service areas, (man6a8a 3'eer ma5dooma).. In observational studies its very difficult to control the groups because you know that you are checking a case, so sometimes you expect what to see, but in randomized study you can control that and it can be better to control (The doctor repeated the same example in Arabic but in another case)

NOTE: in observational studies you can expect the outcomes, but in randomized study you dont One of the disadvantages of randomized studies, subjects sometimes they can leave the study if they know (for example if I divided my students into two groups I will give one of them a drug and the other group I will not give them the drug, ANAS :D knows that he is in the group that will take the drug ,so he say (ana bddeeeeeesh:D ) are you trying the drug on me!! Then he leaves the study!!! Thats why it's very imp. that in the randomization studies you should not be in contact with the subject (the students that are going to be in the study) and they should not know to which group they belong to SO IT HAVE TO BE RANDOM, and no one know his/her group the observer should be blind about the subjects and the subjects should be blind about the observer (ma lazm el observer yo3rof el subject w ma lazm el subject yo3rof el observer had esmo BLINDNESS)the best study design is called DOUBLE BLINDED STUDY what does it mean????????????? The observer is blind about the subject and vice versa... IMP. NOTE: in randomized study, it has to be double blindedbut it's difficult in observational study to be double blinded Blinding in randomized trial helps in preventing both the investigator and the subjects from knowing groups assignment, (thats why I know that Anas is a clever student (temzaaa7) so I shouldnt know that he is a clever student otherwise I may think about putting him in a group that favors the result (a5ally fe group 2nno ykoon el result better) but I dont have to know him, and also Anas should not know his group because maybe he will not like that so this is not good).. When the investigator knows the subject and the subject dont know the investigator so we call this SINGLE BLINDNESS, and vice versa PLEASE be careful about these, coz I will bring examples in the exam and I will ask you if this is single or double blindness..!! For example I will bring you in the exam when the investigator knows nothing about the subject and the
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subject know nothing about the investigator, this type of randomized studying is .???? You should know that this is "DOUBLE BLINDNESS" But if I bring you a Q, the investigator knows about the subject but the subject know nothing about the investigator so this should be "SINGLE BLINDNESS" If the subject and the investigator know everything about each other then this is called "UN-BLINDED STUDY" Double blinded is impossible with observational studies, it's very impossible! to do double blinded in observational study, for example if you are going to do a study about the cusp of Carrabelle in a certain school "in a certain town" so you already know where will you do the study (subjects) but they dont know you so in this case its SINGLE BLINDED.. So in observational studies it's impossible to do double blinded study but it's possible to do single blinded Generalizability: refers to the ability to apply the outcome of the study to populations other than the sample... As we discussed in the first lecture we said that the result should be general I can do it on another sample if I took it from the same population or I can do it on the same population!!!!!!! The result of a trial apply only to the population that resembles the study samples, in the case of trial or in the case of randomized study (we call it clinical study) el nateeja to6abba8 3la el nas 2lle 2nta 2shta3'alt 3aleehom, mn el sa3b 2nne a6abbe8ha 3la nas thaneen, but in observational study maybe the generalizability can be much better.. Generalizability and randomized studies: Randomized subjects are different from the general population because they carry more burdens (a3ba2)...when I want to try a drug that I made it by myself, when I want to try this medication I bring people with the disease and people without the disease and I try the drug here and here, halla2 el mosharek bl ba7eth ma ra7 ykoon mrta7 lesh?? l2anno ta7t el tajroba, f bl taly ra7 ykoon 3alee a3ba2 7as 2nno fe 3b2 w ga3d ya5od el drug w howwa 5ayef "6ab
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balky had el dawa 3mlly 2she mathalan!!" w ymkin 7alto el nafsiyya t2ather 3ala el nata2ej el motawa88a3a 3la el ba7eth.... Ya3neeeeeeeee THE PSYCHOLOGY OF THE SUBJECT (PATIENT) MAY EFFECT ON THE RESULT... Trial conditions are different from those in clinical practice: trial subject receive more attention el nas 2lle bl ba7eth modallaleen, lmma ana ajee a7o6 anas bl ba7eeth bkoon mdalliloo, ma36ee 6'roof momtaza mosh m5allee 3la 6abee3to f bl taly ma btkoon el nata2ej zay ma bdna)... Treatment works under tight research protocol, when I want to try this drug there will be approach very tight and instructions and I will say: ANAS you will wake up early in morning and you have to eat breakfast then you take the drug etc. so he is under abnormal conditions, if I leave him without study maybe he will not eat breakfast every morning so the best way is to make the study under normal conditions of the human I will differentiate to you between treatment efficacy and treatment effectiveness!!! efficacy have well work on research setting, if u want to study something, if u want to see how the things will work in the setting of the research this is called efficacy.. For example: I brought Anas to my study and I tried a drug on him, and I gave him the instructions tight bla bla (katha w katha) then I say this is the efficacy of the drug not the effectiveness because I put Anas on the conditions of the research But for example I put Anas on a normal conditions but he doesn't know, and he started to take the drug and he take it once and leave it once, he take it on 7 a.m. and sometimes he take it on 8 a.m. Because he doesn't know, so in this case I will say the EFECTIVENESS of the medication NOTE: efficacy is different from the effectiveness..!! EFFICACY: related to research setting EFFECTIVENESS: related to clinical setting (el 6'roof el 6abi3iyya el saririyyaa) PLEASEEEEE UNDERSTAND THE DIFFERENCE WELL BECAUSE THERE IS A QUESTION ABOUT THEM IN THE EXAM

Observational studies and treatment effectiveness closer together than in randomized studies, in the case of observational studies the efficacy and effectiveness are exactly the same or very close to one another, (fe 7al el observational lmma bddy aroo7 af7as a6fal fe almadares, bykono fee 6'roofhom el 6abi3iyya!! F 2lle bykoon mf6ir w 2lle mosh mif6r, f hay hyye 6'roofhom el 6abi3iyyaa, so efficacy btkoon nafsha el effectiveness but in randomized studies NO, the efficacy is different) But we still can detect some differences in observational studies between the efficacy and effectiveness..!! observational study, the patients receive additional educational or testing than normal clinical patient ((momkin mathalan hadool el a6fal 2lle ana af7ashom bl madares, 3rfat el modeera 2nno 27na jayyen bokra 3l madares w ra7at yalla bokra jayyekom a6ibba2 asnan 3l madrasa w bdhom yf7asokom f kolkom btejo 3l madrasa w mfarsheen asnankom, 6ab ana jay af7as el plaque index mathalan mo3addal kam 3ndhom plaque, ra7at el modeera m5arbatly kol el sho3'ol taba3y!! f bl taly ymkin t5talef el efficacy 3n el effectiveness l2any ma fa7asthom b 6'rofhom el 6abi3iyya l2anno el modeera tda55alat.)) Thats why we have a different between the efficacy and the effectiveness observational study patients may change their behavior, and this is called Hawthrone effect as I said sometimes if they know, if school children know previously that those investigators are coming and examining them tomorrow they may change their behavior (momkin bdna n8ees m8dar mosha3'abat el 6alb, f ra7 aboo w ommo 7akolo 2nno yseer mohaddab bes howwa bl 3ade 6alb sha8y) so thats why they may change they behavior - Length of time to conduct:- Length of time to conduct observational studies are faster to conduct randomized studies in observational studies you can examine subjects once (betro7 2nta 3la almadrasa btef7a9 hal madares bejoz al6aleb yenfa7a9 mara wa7de fa momken 2nta fe 2sbo3 zaman tef7a9 3ashar madares 2t5ale9 al study) thats why it is very fast to conduct. but in randomized study (bedak 2tjeeb nas 2t7o6hom ta7t al tajroba nas ta36ehom al dawa nas ma ta36ehomsh bedak todroshom 3la
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fatra 6awele 3ashan 2tshof al effect of that medication) you will bring a group of subjects and put them under experiments and tests that take a long time to conduct that is why we are faster in observational than randomized, especially when existing database and the use of case-control design _we will discuss what we mean by control design (fe 2l m7adra al 8adema ) in the next lecture_ (lama ykon 3na 8a3dat bayanat kbera zay mathalan madares al Jordan fa bettaly hek 7ale ne3mel al study be shakel saree3).

- Minimizing expenses:

Observational studies are less expensive than randomized studies:-

(lesh efre9o ene bede 23mal ba7eth 3la 2tfal madares al Jordan ma bedha ma9are ktheer fa8a6 al ba7eth ra7 ykoon 3la taklofat al na8el lal ba7theen mathalan w 2tha fa8a6 2dawat al fa7e9 al base6a 2lly momken yf7a9o feha 2snan al mar9a) for example when I do research on school children in Jordan I just need money for transport and simple examination equipments thats why it isn't inexpensive but randomized studies are expensive (ba39 al 27yan 3shan 28ne3 b39 al nas yshtarek fe alba7eth w 236e dawa lazem 2dfa3lo mabla3 9a5em la2no momken fe 2y la76a ye7ke ma bedy) for example if I want to do a research on a drug I have to pay lots of money to subjects to convince them to take a testing drug! -Observational study is less expensive specially when existing data base. sorry (hay 2lno86a sa8a6at sahwan men alslide al 8ablo) dont worry about it. "Remove it from slide 23" -Less markedly with prospective cohort design:(fe 3nde designes mo3ayane 9a3eb 2ne 2shra7elko sho ya3ne ) prpspective cohort design (laken momken nerga3elhom la7e8an lma ne7ke 3anhom ra7 tefam hay al no86a ta7dedan sho 3la8et al expensive be hade al design ) it is hard to explain what we mean by this now we will come to it later on and you will understand it. Slide 23:

Observes are just observing the outcomes :10

Thats why it is less expensive you just observe the outcome you dont control actually you can't pay your subjects for example.

Randomized control trials are expensive :-

Because you need sometimes to pay for all of the interventions (kol al 2jra2at al bedak te3malha bedak tedfa3ha, bedak tedfa3 thaman ta9nee3 al dawa al ra7 tjarbo, bedak tedfa3 la subjects bedo fatra 6aweely. bedak mathalan tsha3el nas ma3ak be al ba7th la fatra 6awely bedak tedfa3elhom rawateb fa be al taaly bedo yekon expensive mathalan bedak tes7ab menhom 3aynat dam, bedak te3malhom Lab tests la hay al 3aynat) so in randomized studies you have to make lots of procedures and pay for them tests and lab samples and stuff like that! Thats why it will be very expensive.

Addressing a broader range of questions: Observational study are able to answer a broader range of questions:(el observational studies be tefta7lak 2faa8 ktere, adrobelkom mathal : Ana 23melt study 3la timing of emergence of tooth eruption laken be ma 2ne raye7 w 6ale3 2f7a9 kol al 26faal be al Jordan lesh ma 2f7a9 al 2shya2 al tanye other dental findings fa men al 2shya2 altanyee al fa7a9tha bel mar9a al cusp of Carrabelle we 23melt ba7th 3n al cusp of Carrabelle ya3ne be 2mkanak teshmal 2shya2 kteer we teft7lak 2fa8 laken ) the observational studies opens up your horizon, for example when the Dr. did his research of tooth emergence he thought to himself why don't I study other things such as cusp of Carrabelle with usual clinical trials you just answer the specific question
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you want to investigate (2nta bedak 2tjarb dawa 3la mar9a we al nateja taba3tak hal al dawa kowayes wela mosh kowayes hal dawa be3alej Al marad wela ma be3alej Hal dawa elo side effect wela la )

You just answer one single question related to this specific problem of your research but in observational studies you can answer a very good number of questions. Many situations where is unethical or impractical randomize subjects you cant randomize person to smoke or not to smoke but (ba39 al 27yan fe randomization ma be 2mkanak teje 3la nas yala 2nto mosh moda5enen da5no we btdroshom, ba39 al 27yan unethical 2no te3mal 2l randomized studies ya3ne 3eer 25la8ee right? Lethalek beycoon al nata2j daye8a jedan). Randomized control studies are rarely helpful in identifying causes of disease outbreaks (ya3ne ba39 al 27yan fe randomized studies ma be 2mkanak 2nak tet3araf 3la 2sbab al mara9 la2no 2nta fa8at todros she2 wa7ad ok 3aleban 2nk btodros association between something and another thing) sometimes in randomized studies you can't identify the causes of a disease and it is difficult to develop the outcome relationship.

Indications of observational studies:

When we do observational studies?

We do it in instances where it is unethical or impractical to perform a randomized study

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(lama ykon mosh monasb 25la8eyan 2w mosh 3amaly randomized study ba3mal observational study ya3ny mosh ma38ol 2ny 2jeeb nas 23dad kpera kteer we nas 236ehom al dawa we nas la2 fa bettaly be9eer moklef 7.edan al ba7eth lethal bajebo 3la group 2z3eer lethaalek fe ba39 al 27yan ba3mal randomized study la2 bashmalo o ba3mal observational study 2shal ok ).

When time is the essence of obtaining the results (ba39 al 27yan 2na bdee nata27. fe fatra 8a9era fa lesh 2ne 23mal randomized study ya5oth menne santen 2w thalath ba3mal observational be shahar o ba5ale9 fa ba39 al 27yan al time elo dor mohem)

And now We start in a new topic:

Research design II
Types of randomized control trials:-

Now we so far know that we have two broad types of studies: 1) Observational study. 2) Randomize study. We knew what are the advantages and the disadvantages of each. Now we come to different type of each of two studies (hala kol wa7da menhen 2tkon 2lha 28sam mota3adeda ya3ne) randomized control trails may be in simple randomize design, cross over design or factorial studies.
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 In simple randomize design :-We randomize to two or more groups ( benjeb al nas bn3malhom randomization ben8asemhom 3shwa2e ela majmo3ten aw thalath majmo3at we 3la hada 2smo simple randomize design) so you bring your subjects and randomize them and then divide them into groups

it is simple and very powerful and this is done when enough subjects are available and can be recruited (lma ykon fe 3nde 3dad jayed men al nas momken 2ne 2sta8demhom lal ba7eth mathalan bede 23mal study 3lekom masha2allah (250) 6aleb fa bettale be kol sohole momken 28asemkom ela majmo3teen : majmo3a 236eha 2s2la sahla , we majmo3a 2s2ele sa3ba 7ta 23mal hek lazem 28asmkom 3ashwa2yan mosh hek 2tha bede 23mal hal al study mosh ma38ol mathalan hay al jeha sha6ra 5otho al 2s2la al sa3ba ra7 23ref 2no ra7 2tjawboha we mathalan hay al jeha 293af ta79eleyan fa 236ekom al 2s2ela al sahla la2 lazem 2tha bede 2droskom 28asemkom ela majmo3teen we 236ekom nafs darajat al so3obe ma 2kom 3aref ana men 8asamet ya3ne lazem 23rof ana eno kol al 6olab sawasya fe ta79elhom mathalan al thaka2e 7ta 2tkon al nata2j ma38ola o man68eye) for example if I want to do a study on you for example we have a large number 250 masha'ALLAH and I should randomize you and should not know who is a good student and who is not and so on thats what we call it simple randomized design . We do it when we have enough number of subjects. In cross over design :Subjects are randomized to one study group after a specific period of time; the same subjects are switched to the other groupso in crossover design there is one group not two For example: when we give a group of students set of questions then after a month we give the same group another set of questions. So when we study the same group twice this is called crossover design.
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Advantages: Gives two subjects for the price of one Instead of taking two groups we take one & we pay for one group rather than two.

Less variability and more power Because we study the same group twice there is no variation,, for example if I decide to study the intelligence in your class & I randomize you into two groups there may be group more intelligent than the other,,, so when we study one group twice there is less variability and less variation means more powerful. Each subject serves as his/her own control Increase subject motivation You increase the participation in your study And all subjects will be in treatment group at some stage,, for example if we suppose u have two groups for study and you give one of them a drug and dont give the other the participants in the first group may be worried and may not participate in your study,, but when they know they are all wont take the drug in the first experiment and they will in the second here you increase the motivation of them to participate in the study. 5. Good when you cannot recruit enough subjects When do we do crossover design?? When its difficult to take two groups so we take one and study it twice. Disadvantages: Bias due to carryover effects leading to failure to ascribe successes or failure to correct group. For example: to treat a specific infection,, lets suppose you give a group antibiotic A for 3 months then you give them antibiotic B for the next 3 months,, and the infection reappear in the 4th month,, then you dont know if the reappearance is due to failure of antibiotic B or if the infection is actually is present during the 1st three months but not manifested.
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To overcome carryover effect >>>>>>washout period Means always let an enough period of time between the 1st experiment and the 2nd one to ensure that the effect of the experiment 1 finished before the beginning of experiment 2.

Factorial studies: The third type of randomized control trials, its designed to answer more than one question by randomizing each subject to more than one condition. For example: you make randomization to study the effect of plaque on gingivitis and make another randomization to study the effect of plaque on caries,, in this case you answer more than one question: The 1st >>>what is the effect of plaque on gingival health? The 2nd>>>what is the effect of plaque on caries? And this is called Factorial studies Advantages: 1. Get two studies in price of one. 2. Cost effective Disadvantages: Different conditions may affect one another (interact) For example: what is the effect of lack of oral hygiene on caries and what is the effect of lack of oral hygiene on periodontal disease,, and may the 1st case affect on the 2nd case.

Before I finish sorry sometimes I speak in Arabic in this course and I hope this is not a big problem for Malaysian students,, plz anyone of the Malaysian if you dont understand the example plz raise your hand and I am ready to repeat the example in English.

Done By: Musap AL-rawi and Omar AL-jaaf

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((I tried to translate all the examples but I couldnt:S sorry,I hope that It will not be a big problem)) This is my first script,so forgive me if there is mistakes,I tried my best Special thanks for mohammad rafay3ah and karam mukhallalati Hazem frieh: 7abeeby sa33oooby treed mosa3ada?? :P If the world were a single state, <3 1StAnBuL<3 would have been its capital." Napoleon Bonaparte"

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