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PART A (General Particulars) 1.

Proposed Project Title:


Predicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areas

2. Principal Investigator: "Detail curriculum #itae is annexed$

Dr. Md. Anisur a!man Professor % &ead' Department of Epidemiology ()P*+M

,. Co-investigator(s): "A copy of t!e curriculum #itae and list of publications in respect of eac! collaborating in#estigator is annexed$ -. Dr. Md. i./anul 0arim Asst. professor' Department of Epidemiology'()P*+M 2 Dr. 1mmul 0!air Alam Medical +fficer' Population Dynamics' ()P*+M.

4. Place o t!e stud" # Institution(s) : *ixteen 1p.illa D+T* centers. $. %ponsoring # colla&orating agenc": 'anglades! (edical Researc! Council 2. )uration: 2 "six$ Mont!s. 3. )ate o Co**ence*ent: As soon as fund /ill be a#ailable. 4. )ate o Co*pletion: 5it!in six mont!s from t!e date of starting. 6. Total Cost: Tk.- 7'88'8889-8. +t!er %upport or Proposed Researc!: (il "-$ )s t!is researc! pro;ect being supported by any ot!er source= "2$ &as an application for funding of ",$ )s t!is pro;ect been submitted to any ot!er organi.ation"s$= ":ont different$ <es <es <es (o (o (o

)f ><es> to -8"-$ or -8"2$ abo#e' please indicate t!e organi.ation"s$ and amount of funds.

11. )ate o %u&*ission:

9-8928-,

1,. %ignature o Principal Investigator:

???????????????????????? Dr. Md. Anisur a!man

1-. %ignature o Co-Investigator(s) : -, ???????????????????????? -@ Dr. Md. i./anul 0arim -7 -2 -3 -4 -6 28 ???????????????????????? Dr. 1mmul 0!air Alam

1.. /ndorse*ent o t!e Institute 0ead: *ignature: Prof. Dr. *aro; 0umar Ma.umder Designation: Director' (ational )nstitute of Pre#enti#e and *ocial Medicine. "()P*+M$ +fficial *eal:

PART-'
PRI1CIPA2 I13/%TIGAT+R(%) I14+R(ATI+1 %0//T -. "i$ (ame: Dr. Md. Anisur a!man "ii$ Designation: Professor % &ead' Department of Epidemiology' ()P*+M "iii$ +fficial Address /it! telep!one: Professor % &ead' Epidemiology (ational )nstitute of Pre#enti#e and *ocial Medicine P!one. +--664482,, 'Email: anisnipsomAya!oo.com "i#$ Present esidential Address /it! telep!one: :lat no.B2' &ouse no. -8' oad -,9A' *ector 2' 1ttara' D!aka. 2. Academic background

(ame of t!e degree **C &*C MBB* MP& Epidemiology


,. :ield Experience:

<ear -632 -634 -647 -66-

)nstitute angpur Dilla *c!ool Titumir Eo#t. College **MC ()P*+M

Board a;s!a!i D!aka D!aka D!aka

emarks -st -st Passed Passed

Fist is attac!ed "it is in t!e resume of t!e principal in#estigator$ @. "a$ esearc! Experience Fist is attac!ed "it is in t!e resume of t!e principal in#estigator$ "b$ +t!er Experiences: Fist is attac!ed "it is in t!e resume of t!e principal in#estigator$ 7. Percentage of time to be de#oted to t!is pro;ect: ,8G 2. (umber of *cientific Publications: Fist is attac!ed "it is in t!e resume of t!e principal in#estigator$

PART - C 1. Proposed Project Title:


Predicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areas

,. /5ecutive su**ar":
Tuberculosis "TB$ !as been a public !ealt! issue for many years and remains t!e ma;or cause of deat! from a single infectious agent among adults in de#eloping countries. TB remains one of t!e leading causes of adult mortality and morbidity in Banglades!. Banglades! ranks sixt! among !ig!er TB burden countries /!ere extra-pulmonary TB patients /ere -2G of all TB cases in 2884. Age' education' income' occupation' race' sex' malnutrition "Hit D deficiency$' &)H positi#ity' diabetes' renal disease' drinking unpasteuri.ed milk' all are t!oug!t to be important predictors of extra-pulmonary tuberculosis. A case control study /ill be conducted in sixteen upa.illas of Banglades!. A total of 744 samples " 26@ cases and 26@ controls$ /ill be recruited from t!e treatment register of t!e D+T* centers of t!e selected upa.illas. *ociodemograp!ic' !ouse!old c!aracteristics' contact /it! index TB cases and disease profile /ill be collected by a inter#ie/er administered semistructured Iuestionnaire. *tatistical tests "2$ /ill be performed to determine t!e association bet/een exposure and outcome #ariables comparing cases and controls. Crude odds ratios "+ $ and 67G confidence inter#als "C)$ /ill be estimated in t!e uni#ariate analysis. )mportant predictors "p J K8.87$ of uni#ariate analysis /ill be included in a back/ard elimination logistic regression model to identify independent predictors. Risk factors for EPTB in Bangladesh may be different to those in low-burden countries, but appropriate studies to investigate this are lacking. T!is study /ill be carried out to predict important risk indicators for EPTB t!at are distincti#e from risk indicators for PTB. As a result' more attention /ill be paid to address EPTB cases and strategy /ill be formulated to combat EPTB focusing more emp!asis on t!ose factors.

Part )

Introduction 'ac6ground
Tuberculosis "TB$ remains a ma;or global public !ealt! problem. )t is t!e second greatest contributor among infectious diseases to adult mortality' causing approximately t/o million deat!s a year /orld/ide. )t is estimated t!at about one t!ird of t!e /orldLs population is infected /it! Mycobacterium tuberculosis.-'
2

Tuberculosis continues to cause a large burden of disease in t!e /orld' en!anced by po#erty' poor public !ealt!' nutritional status and increasing &)H9A)D* pre#alence and t!us TB continues to be a persistent c!allenge for global !ealt! and de#elopment., T!e *out! East Asia egion "*EA $ /it! an estimated @.44 million pre#alent cases carries one t!ird of t!e global burden of TB. T!e control of TB in t!e egion is affected by #ariations in t!e Iuality and co#erage of #arious TB control inter#entions' population demograp!ics' urbani.ation' c!anges in t!e socio-economic standards' &)H and more recently' emerging drug resistance. @ Extrapulmonary in#ol#ement occurs in one fift! of all TB casesM 28G of patients /it! extrapulmonary manifestations of TB !a#e no e#idence of pulmonary infection on c!est radiograp!s or sputum culture.7

Tuberculosis is a ma;or public !ealt! problem in Banglades! since long. Till date TB remains one of t!e leading cause of adult mortality and morbidity and pre#entable deat! in Banglades!. 5it! a population of -78 million' Banglades! ranks sixt! among !ig!er TB burden countries. Almost !alf of t!e population is infected /it! TB. Extra-pulmonary TB patients /ere --G in 2883 and -2G in 2884.2 A total of -@3 ,@2 cases /ere diagnosed in 2883. Most of t!e extra-pulmonary cases /ere female. (e/ smear negati#e and extra-pulmonary cases /ere -7.3G and -8.6G respecti#ely. Proportions of extra-pulmonary and ne/ smear negati#e cases reported from metropolitan cities and by C!est Disease Clinics /ere !ig!er compared to upa.ilas. T!is is due to limited diagnostic facilities a#ailable at upa.ila le#el to detect smear negati#e or extra-pulmonary cases.3

Researc! 7uestion
5!at are t!e differences in t!e distribution of risk indicators bet/een pulmonary and extrapulmonary tuberculosis=

General o&jective
To find out t!e differences in t!e distribution of risk indicators bet/een pulmonary and extrapulmonary tuberculosis

%peci ic o&jectives
-. To assess t!e sociodemograp!ic c!aracteristics differences bet/een pulmonary and extrapulmonary tuberculosis. 2. To find out t!e differences in !ouse!old-c!aracteristics bet/een pulmonary and extrapulmonary tuberculosis. ,. To identify t!e kitc!en en#ironment status of pulmonary and extrapulmonary tuberculosis. @. To find out t!e differences in contact related and lifestyle #ariables bet/een pulmonary and extrapulmonary tuberculosis. 7. To predict t!e differencs in t!e distribution of risk indicators for pulmonary and extrapulmonary tuberculosis.

8usti ication o t!e stud"


Differences in t!e likeli!ood of extra-pulmonary TB !a#e been obser#ed in #arious studies among TB patients by demograp!ic c!aracteristics. Moreo#er' diagnosis of extra-pulmonary TB cases /as not so muc! successful. As a result a !uge number of extra-pulmonary tuberculosis patients /ere undiagnosed.2

ecent studies !a#e suggested t!at t!e sites of extra-pulmonary TB may be according to geograp!ic location and population. Clinical manifestations of TB are #ariable and depend on a number of factors t!at are related to microbe' t!e !ost and t!e en#ironment.4 *tudies !a#e examined t!e role of !ost related factors on t!e risk of de#elopment of EPTB. isk factors for EPTB in Banglades! may be different to t!ose in lo/-burden countries' but appropriate studies to in#estigate t!is is lacking. T!is study /ill be carried out to identify possible risk indicators for EPTB t!at are distincti#e from risk indicators for PTB. As a result' more attention /ill be paid to address EPTB cases and strategy /ill be formulated to combat EPTB gi#ing more emp!asis on t!ose factors.

2iterature revie9
T!ere are se#eral studies regarding risk factors of pulmonary and extra-pulmonary tuberculosis. *tudies in Banglades! related to extra-pulmonary tuberculosis and related risk factors are #ery limited. *tudies carried out in different parts of t!e /orld are #ie/ed t!oroug!ly to find out /!at ot!ers !a#e learnt and reported rele#ant to extra-pulmonary tuberculosis.

Extra-pulmonary tuberculosis may affect any organ or tissue' most commonly found in mediastinal lymp!nodes' larynx' cer#ical lymp!nodes' pleurae' meninges' central ner#ous system' spine' bones and ;oints' kidneys' pericardium' intestines' peritoneum and skin. Fess common extra-pulmonary in#ol#ement is eye' nasop!arynx and adrenal gland.6

Clinical eatures:
A patient /it! pulmonary tuberculosis presents /it! one or more follo/ing symptoms in addition to coug!: espiratory symptoms- s!ortness of breat!' c!est pain' coug!ing up of blood Eeneral symptoms- loss of /eig!t' loss of appetite' fe#er' nig!t s/eats *ign and symptoms of extra-pulmonary tuberculosis depend on t!e site in#ol#ed. Most common examples are: TB lymp!adenitis: s/elling of lymp!nodes Pleural effusion: fe#er' c!est pain' s!ortness of breat! Noint TB: pain and s/elling of ;oints *pinal TB : radiological findings /it! or /it!out loss of function Meningitis: !eadac!e' fe#er' neck stiffness and subseIuent mental confusion Eastro-intestinal TB: abdominal pain' c!ronic diarr!ea' sub-acute obstruction' passage of blood in stool and rig!t iliac fossa mass. Eenito-urinary TB : urinary freIuency' dysurea' !ematuria and loin pain

'urden o tu&erculosis 'anglades! %ituation


Tuberculosis is a ma;or public !ealt! problem in Banglades! since long. Till date TB remains one of t!e leading cause of adult mortality and morbidity and pre#entable deat! in Banglades!. 5it! a population of -78 million' Banglades! ranks sixt! among t!e !ig!est TB burden countries. Almost !alf of t!e population is infected /it! TB. )n 2884' t!e estimated pre#alence and incidence rates of all forms of tuberculosis /ere respecti#ely ,43 and 22, per -88 888 population.

%ituation o e5tra- pul*onar" tu&erculosis

EP-TB: Global Situation )n 2884' 7.3 million eases of TB "ne/ cases and relapse$ /ere notified to (TPs' out of /!ic! 2.3 million /ere ne/ positi#e cases' 2.8 million ne/ smear- negati#e pulmonary cases "or cases for /!ic! smear status /as unkno/n$ and 8.4 million ne/ /ere extra-pulmonary TB Elobal case notification of extra- pulmonary cases in 2884 /as 3' 47'232 Among t!em !ig! burden countries contributes 7'32'@82 cases. +ut of t!ese' 2'67'422 /ere extra-pulmonary cases "-,.7G$.-8
-

)n

2883' total case notification of tuberculosis in *out! East Asia region /as 22'82'-@6

EP-TB: Bangladesh situation )n Banglades!' t!oug! t!e pulmonary case detection rate continues to impro#e' t!e extra-pulmonary case detection !ad not yet been met. T!e proportion of extrapulmonary tuberculosis is lo/er' T!ere is no pre#alence rate of extra-pulmonary tuberculosis in Banglades!. T!e percentage of extra-pulmonary tuberculosis cases among total case notification /ere --G in 2883 and -2G in 2884. 2 Proportions of extra-pulmonary cases reported from metropolitan cities and by CDCs /ere !ig!er compared to upa.ilas. T!is is due to limited diagnostic facilities a#ailable at upa.ila le#el to detect extra-pulmonary cases.@

Ris6 actors or T'


Role of background characteristics <ounger age and female gender /ere found as independent risk factors for EPTB' relati#e to PTB.--'
-2

:emales tended to be more likely to !a#e any form of extra-

pulmonary tuberculosis t!an males' except pleural tuberculosis. T!e strengt! of t!is association /as strongest in t!e age range 27-2@ yrs and less pronounced amongst t!e oldest patients. -, T!is sex difference in rates of EPTB !as been pre#iously attributed to #arious factors suc! as cigarette smoking' genetic and !ormonal factors' iron status' alco!ol consumption' delay in diagnosis and associated disease.-@

T!e ot!er reasons for female disease preponderance may be t!e social exclusion of younger /omen /!o are generally !omebound and !a#e poorer nutritional status t!an t!eir male counterparts' social stigma associated /it! TB /!ic! discourages /omen from seeking early medical care' and Hitamin D deficiency due to poor dietary intake as /ell as inadeIuate exposure to sunlig!t because of poor !ousing and t!e culture of /earing burIas. *e#eral studies s!o/ed Pakistani /omen to !a#e lo/ le#els of serum 27-!ydroxy#itamin D. T!ere is a gro/ing e#idence of a strong association bet/een TB and Hitamin D deficiency.-7

A prospecti#e study /as conducted by *!afi 1lla! et al to assess its freIuency in #arious organ systems of t!e body and to e#aluate t!e role of demograp!ic factors like sex and age in its causation. &ig! female preponderance /as noted /it! M: : ratio of -:2. Mean age /as ,7 years and 38G of t!e patients /ere in t!e age group -7@7 years. Fymp! modes /ere most common site of EPTB' in#ol#ed in 22.@G of t!e cases. T!ey concluded t!at EPTB !as !ig! rates in females in t!eir reproducti#e age. T!e ot!er likely socio-cultural factors could be !ig! female illiteracy' female economic dependency and t!eir poor access to !ealt! care. T!us' in t!eir en#ironments' female gender and age bet/een -7-@7 years are t/o important predisposing factors for EPTB.-2 Socio-economic condition and TB Analytic epidemiological study s!o/ed /omen' non-&ispanic blacks' and &)Hpositi#e persons to !a#e a significantly !ig!er risk for extra pulmonary tuberculosis t!an men' non-&ispanic /!ites' and &)H-negati#e persons.-3 EPTB is reported to be more often diagnosed in females and in young patients. Almost one-t!ird of t!e tuberculosis cases in <emen /ere extra-pulmonary "24G$ /as associated /it! po#erty and t!at most of t!e extra pulmonary tuberculosis patients came from rural areas. Multi#ariate assessment of !ost factors s!o/ed t!at risk o TB /as increased /it! #ariation in occupational status. Assessment of en#ironmental factors s!o/ed an

increased risk /it! !ouse!old cro/ding' !istory of !ouse!old exposure to a kno/n TB case' as /ell as amongst t!e Nola et!nic group.-4 Smoking *mokers incur a 2 to @ fold increased risk of in#asi#e respiratory disease. Per!aps t!e greatest public !ealt! impact of smoking on infection is t!e increased risk of tuberculosis' a particular problem in under de#eloped countries /!ere smoking rates are increasing rapidly.
-6

A !ig!er proportion of culture confirmed TB cases /as

found among e#er smokers "current and ex-smokers$ t!an ne#er-smokers. Pulmonary in#ol#ement /as more pre#alent among e#er smokers t!an ne#er smokers and t!e re#erse /as true for extra-pulmonary in#ol#ement. 28 :emale and age /ere associated /it! EPTB' /!ile alco!ol abuse' smoking !abit' contact /it! PTB patients and BCE #accination !ad a protecti#e effect. 2-

Common sites of EPTB Fymp! node tuberculosis comprised t!e greatest number of EPTB Cases in almost all studies.22-27 T!e central ner#ous system /as t!e next most freIuent site of EPTB in#ol#ement' follo/ed in descending order by skeletal' pleural' abdominal' cutaneous' genitourinary' pericardial' miliary' and breast tuberculosis.2, Miliary tuberculosis de#eloped in infants' lymp!adenitis and meningitis in presc!ool c!ildren' and pleural effusion and skeletal tuberculosis in older c!ildren. 2@ T!e distribution of different types of EPTB differed significantly among age groups. Meningeal and bone and or ;oint TB /ere more commonly obser#ed among t!e male patients' /!ile lymp!atic' genitourinary' and peritoneal TB cases /ere more freIuently seen among females. 27

*tudy found t!at a !ig!er number of extra pulmonary tuberculosis patients /ere diagnosed in pri#ate !ospitals and clinics t!an t!e pulmonary tuberculosis patients /!ic! mig!t be attributed to t!e fact t!at extra pulmonary tuberculosis presents more diagnostic and t!erapeutic problems t!an pulmonary tuberculosis /!ic! are less familiar to most of t!e Clinicians.22 Patients /it! bilateral lung in#ol#ement /ere

more likely to !a#e extrapulmonary in#ol#ement' /it! an ad;usted odds ratio "+ $ of @.2- "67G confidence inter#al OC)P' -.42-6.32$' /!ile patients /it! ca#itary lesions "ad;usted + ' 8.,3M 67G C)' 8.-2-8.4@$' and /it! !ig!er le#els of serum albumin "ad;usted + ' 8.@7M 67G C)' 8.27-8.34$ !ad less freIuent in#ol#ement. Clinicians s!ould be a/are of t!e possibility of extrapulmonary in#ol#ement in TB patients /it! bilateral lung in#ol#ement /it!out ca#ity formation or lo/er le#els of serum albumin.23 *tudy suggests t!at in a significant number of patients /it! EPTB fe#er is absent' E* is normal and MT is negati#e. *o' o#er reliance on t!ese clinical and laboratory data may lead to failure to diagnose EPTB.24

Age' education' income' occupation' race' sex' malnutrition "Hit D deficiency$' &)H positi#ity' diabetes' renal disease' drinking unpasteuri.ed milk' all are t!oug!t to be important predictors of extra-pulmonary tuberculosis. Risk factors for EPTB in Bangladesh may be different to those in low-burden countries, but appropriate studies to investigate this are lacking. T!e present study /ill also !elp us to gain insig!t into t!e demograp!ic and social c!aracteristics of EPTB cases in Banglades! t!ereby /ill extend t!e kno/ledgebase of EPTB based on /!ic! better TB control strategies can be de#eloped.

.. (aterials and (et!ods


..1 %tud" design

T!is /ill be a case control study .., %tud" period A total period of t!e study /ill be from Nanuary to Nune 28-2. ..- Place o t!e stud" D+T* centers of eig!teen upa.illas of D!aka di#ision. ... %tud" population %election o cases and controls: T!e samples /ill be classified as eit!er EPTB "cases$ or PTB"controls$. Patients whose disease involved organs or tissues outside the thora , e cluding those patients who also had pulmonary involvement, are considered to have cases of e trapulmonary tuberculosis and will be classified as case patients. EPTB cases /ill encompass lymp!atic' genitourinary' bone and9or ;oint' meningeal' peritoneal' gastrointestinal' cutaneous and unclassified cases. EPTB cases t!at /ill in#ol#e QEPTB disease site /ill be classified according to t!e ma;or site. Patients in /!om t!e sites of disease is exclusi#ely intrat!oracic' "i.e.' confined to lungs' pleura' and intrat!oracic lymp! nodes$ are considered to !a#e cases of pulmonary tuberculosis and /ill be classified as control patients.
.

Tuberculous pleuritis /ill not be classified as EPTB because pleura is belie#ed to be in#ol#ed by direct in#asion from freIuently accompanying pulmonary parenc!ymal TB or !ypersensiti#ity reaction by M. tuberculosis rat!er t!an blood stream dissemination. Cases of disseminated TB and cases /it! concurrent EPTB-PTB /ill be excluded from our principal analysis' because t!ey are not distinctly classifiable as eit!er EPTB or PTB. )n order to determine t!e possible ramifications of t!is definition of EPTB' /e /ill perform a separate analysis t!at /ill be compared disseminated and concurrent EPTB-PTB /it! EPTB only and /it! PTB only. )n addition' /e /ill

perform a separate analysis in /!ic! disseminated and concurrent EPTB /ill be added to our existing EPTB classification. T!e presence of extra-pulmonary in#ol#ement in patients /it! pulmonary TB /ill be based on eit!er of t!e follo/ing criteria: -$ Demonstration of acid-fast bacilli or t!e gro/t! of Mycobac-terium tuberculosis from tissueM 2$ Presence of granulomas /it! or /it!out caseation necrosis in tissueM ,$ Positi#e polymerase c!ain reaction "PC $ results for t!e D(A of M.
tuberculosis from tissuesM or

@$ A clinical diagnosis by duty p!ysicians based on symptoms' laboratory' radiograp!ic findings' and treatment response to anti-TB medications. Addresses of t!e cases and controls /ill be noted from t!e D+T* center registers /it! a #ie/ to trace study sub;ects at !ome for exploration of exposure information.

..$ %a*ple si:e T!e study /ill enroll 26@ people per group' for a total of 744 people. " using *P** *ample po/er soft/areM )BM$. 5it! t!is sample si.e' t!ere is an 48G likeli!ood t!at t!e study /ill yield a statistically significant result' and allo/ us to conclude t!at t!e percentage of sub;ects in >selected exposure> is different for PTB t!an for EPTB. T!e sample si.e of 26@ is based on t!e assumption t!at groups differ by -8 percentage points. T!e test /ill be 2-tailed' /!ic! means t!at an effect in eit!er direction /ill be interpreted. Based on t!ese same parameters and assumptions t!e study /ill enable us to report t!e difference in proportions /it! a precision "67.8G confidence le#el$ of approximately plus9minus 8.83 points. *pecifically' an obser#ed difference of 8.-8 /ould be reported /it! a 67.8G confidence inter#al of 8.8, to 8.-3 . )n computing t!e sample si.e to be 26@ /e assume t!at t!ere /ill be no missing data. )f t!e actual rate of missing data is 2G' /e /ould need a sample si.e of ,88 per group. 5e used an alp!a of 8.87' /!ic! is often t!e default #alue' in computing t!e reIuired sample si.e of 26@ per group.

..; %a*pling tec!ni7ue Con#enient sampling tec!niIue /ill be adopted due to scarcity of t!e cases. All a#ailable cases and one control "age sex matc!ed$ for eac! case /ill be recruited /it!in t!e data collection period. T!e cases and controls /ill be selected from D+T* treatment registers /!o enrolled in t!e last 7 mont!s and meet t!e selection criteria.

..< )ata collection instru*ent Data collection instruments /ill be a pre-tested structured Iuestionnaire and a c!eck list. ..= )ata collection tec!ni7ue :irstly an official letter /ill be issued from MBDC to t!e 1&%:+ of t!e selected upa.illas /it! a copy to Ci#il *urgeon of t!e corresponding district informing t!e study purpose. Anot!er letter /ill be sent to t!e executi#es of t!e B AC and Damien foundation reIuesting necessary assistance in t!e field. *ix data collectors /ill be trained on se#eral setting before collecting data. T!ey /ill be guided and assisted by t!e local (E+ program officer and E+H assigned Tuberculosis and Feprosy Clinic Assistant "TFCA$. Data /ill be collected t!roug! face to face inter#ie/ of t!e !ouse!old at t!eir residence by using t!e Iuestionnaire. Addresses of t!e respondents /ill be taken from t!e D+T* centers treatment registers /it! a #ie/ to trace study sub;ects at !ome for exploring exposure information. Before t!e inter#ie/' t!e detail of t!e study /ill be explained to t!e eligible respondents. )nformed #erbal consent /ill be obtained from e#ery respondent and inter#ie/s /ill be !eld in pri#ate. T!e c!aracteristics of t!e !ead of t!e !ouse!old /ill be obtained by inter#ie/ing !ead and in case of c!ildren necessary information /ill be primarily collected from t!e mot!er of t!e c!ildren. To ensure Iuality control' proper attention t!roug! direct super#ision /ill be gi#en by t!e researc! in#estigators. A researc! officer /ill continuously super#ise t!e data collection and t!e researc! in#estigator /ill also make regular onsite field c!ecks. )n addition' all t!e Iuestionnaires /ill be c!ecked for consistency

and completeness by t!e in#estigators. A subset of Iuestionnaires /ill be re-c!ecked in t!e field for #alidity. ..> )ata processing and anal"sis After data collection' eac! Iuestionnaire /ill be c!ecked for completeness and consistency. T!e data /ill be entered into computer /it! t!e !elp of *oft/are R*tatistical Package for *ocial *ciencesS "*P**$ for /indo/s #ersion -6.8. 1ni#ariate comparisons bet/een t!e group /it! pulmonary TB and t!e group /it! extrapulmonary in#ol#ement /ill be performed using PearsonLs c!i-sIuare test or :is!erLs exact test for categorical #ariables and *tudentLs t-test for continuous #ariables. 1sing #ariables /it! p #alues of K8.28 from t!e uni#ariate comparisons' multiple logistic regression models /ill be constructed to identify predictors of t!e presence of extra pulmonary in#ol#ement. )n logistic regression' back/ard elimination /ill be used to select #ariables to be maintained in t!e final model' using a p #alue of K8.87 as t!e criterion for statistical significance of associations. T!e area under t!e recei#er operator c!aracteristic " +C$ cur#e /ill be used to e#aluate t!e performance of t!e models. Ad;usted odds ratios and 67G C) /ill be reported.

%tud" actors ?e" varia&les


%ociode*ograp!ic varia&le Age *ex eligion Education of t!e respondent +ccupation of t!e respondent ParentLs education ParentLs occupation A#erage mont!ly )ncome Total family members :amily type :amily mobility esidence type Area of residence 0ouse!old c!aracteristics &ouse o/ners!ip :loor material 5all material oof material (o of bedrooms Area of bedrooms Cro/ding (o of external /indo/s 5indo/ material 5indo/ +pening status Type of latrine Drinking /ater source *ource of lig!ting ?itc!en environ*ent 0itc!en position 0itc!en distance 0itc!en #entilation *to#e type :uel type

Cooking time Contact in or*ation Type of contact Contact relation Contact regularity :reIuency of contact 2i est"le related varia&les *moking status (o. of smoker in t!e family *!aring same room /it! smoker *!aring same bed /it! smoker Time of start smoking Time of Iuit smoking (o of sticks smoked per day (onsmoking tobacco use Addiction type )isease related varia&les Type of TB Type of symptoms *ite of extrapulmonary TB Time of first appearance of symptoms Met!od of diagnosis Time of Diagnosis Place of diagnosis *mear test result (iscellaneous BCE #accination :ood security status

$. @tili:ation o results# polic" i*plications T!e present study /ill be conducted to gain insig!t into t!e demograp!ic and social c!aracteristics of EPTB cases in Banglades! t!ereby /ill extend t!e kno/ledgebase of EPTB based on /!ic! better TB control strategies can be de#eloped.

;. 4acilities " esources' eIuipment' c!emicals' sub;ects "!uman' animal$ etc. study$: 6. . !acilities "#ailable )nfra-structure of go#ernment !ealt! ser#ice centre /ill be used for management of t!e researc! pro;ect. )n addition' t!e institutional facilities of t!e principal in#estigator and co-in#estigators /ill be used for conduction of t!e study. eIuired for t!e

6.$. "dditional !acilities Re%uired Manpo/er: T/o researc! +fficer' *ix data collectors

<. Approval o t!e 0ead o t!e )epart*ent#Institute "&&ro#ed

Activities %2 no 1 , . $ ; < = > 1C (ont! Aee6 Proposal De#elopment and acceptance Fiterature e#ie/ *election of study area Planning and Designing Preparation of esearc! )nstrument Pre Test Data Collection Data Analysis' )nterpretation eport 5riting eport *ubmission 1 8anuar" , . 1 4e&ruar" , . 1 ,

Period o stud" (arc! . 1 April , . 1 (a" , . 1 8une , .

=. 4lo9 c!art %tud" period: 1st Aee6 o 8anuar" to .t! Aee6 o 8uneB ,C1--,C1.

>. /t!ical considerations

Prior conducting t!e study' et!ical clearance /ill be taken from t!e ()P*+M Et!ical e#ie/ Committee. The study will neither include any invasive procedure nor any private issue and no drug will be tested. Before initiation of the interview a brief introduction on the aims and objectives of the study will be presented to the respondents. They will be informed about their full right to participate or refuse to participate in the study. A complete assurance will be given that all information provided by them will be kept confidential and their names or anything which can identify them and only will be disseminated and published for public interest. After completion of these procedures the interview will be started with their due permission. The research will be conducted in full accord with ethical principles.

1C. )isse*ination polic" 5it! t!e proper permission of funding agency t!e study findings /ill be disseminated t!roug! seminar and discussion meeting /it! policy makers. Attempts /ill also be taken to publis! t!e data in international ;ournals.

Re erences
-. 5orld &ealt! +rgani.ation "5&+$M Elobal tuberculosis control' 5&+ report 2886.

2. *udre P' Tendam E and 0oc!i A. Tuberculosis: a global o#er#ie/ of t!e situation today. Bull 5orld &ealt! +rgan -662' 38:-@6-76.

,. Be!a#ioral barriers in tuberculosis controlT.*il#ia 5aisbord t!e C&A(EE Pro;ect Academy for Education de#elopment. *EA-TB,.

@. Tuberculosis in t!e *out!-East Asia egion- T!e Pro;ect (o : *E )CP T1B. (e/ Del!i.

egional

eport: 2884' 5&+

5. &erc!line TE. Tuberculosis. !ttp:99emedicine.medscape.com9article92,8482-o#er#ie/ . last updated 6 DecM 28--. 2. 5orld &ealt! +rgani.ation "5&+$. *EA +: Tuberculosis Control in t!e *out! East Asia egion. 5&+ report 2886. 3. Tuberculosis Control in Banglades!' Annual eport 2884'(TP. 4. American T!oracic society: Diagnostic *tandards and classification of tuberculosis in adults and c!ildren. Am N espir Crit Care Med 2888M -2-:-,3267. 6. Euideline' (ational Tuberculosis control Programme' Banglades!' @t! edition. -8. 5orld &ealt! +rgani.ation "5&+$. *EA +: Tuberculosis Control in t!e *out! east As/ia egion. 5&+ report 2884. --. *reeramareddy CT' Panduru 0H' Herma *C' Nos!i &* and Bates M(. Comparison of pulmonary and extra-pulmonary tuberculosis in (epal- a !ospital based retrospecti#e study. BMC )nfec Dis 2884 NanM 2@4:4. 12. Al-+taibi : and El &a.mi MM. Extra-pulmonary tuberculosis in *audi Arabia. )ndian N Pat!ol Microbiol. 28-8 Apr-NunM7,"2$:223-,-. -,. :orssbo!m M' D/a!ein M' Foddenkemper and ieder &.F. Demograp!ic c!aracteristics of patients /it! extrapulmonary tuberculosis in Eermany. Euro espir N 2883M ,-"-$: 66--87. -@. Cail!ol ;' Decludt B and C!e D. *ociodemograp!ic factors t!at contribute to t!e de#elopment of extrapulmonary tuberculosis /ere identified. Nournal of Clinical Epidemiology 74 "2887$ -822U-83-. 15. C!andir *' &ussain &' *ala!uddin (' Amir M' Ali :' Fotia ) and 0!an AN. Extrapulmonary tuberculosis: a retrospecti#e re#ie/ of -6@ cases at a tertiary care !ospital in 0arac!i' Pakistan. N Pak Med Assoc. 28-8 :ebM28"2$:-87-6. -2. 1lla! *' *!a! *&' e!man A1. 0amal A' Begum ( and 0!an E. Extrapulmonary tuberculosis in Fady eading &ospital Pes!/ar' (5:P' Pakistan:

*ur#ey of biopsy results. N Ayub Med Coll Abbottabad. 2884 Apr-NunM 28"2$: @,2. -3. <ang D' 0ong <' 5ilson :' :oxman B' :o/ler B' :o/ler A&' Marrs C:' Ca#e MD and Bates N&. )dentification of risk factors for extra-pulmonary tuberculosis. Clin )nfect Dis 288@M,4:-66-287. -4. &ill P' *illa! DN' Donkor *A' +ut N' Adegbola A and Fien!ardt C. isk factors for pulmonary tuberculosis: a clinic based case control study in T!e Eambia' BMC Public &ealt! 2882M2:-72. -6. Arca#i F' (eal F and infection.288@M-2@:2282-22-2. Beno/it. MD. Cigarette smoking and

28. Feung CC' Fi T and Fam T& et al. *moking and tuberculosis among elderly in &ong 0ong. Am N espir Crit care Med 288@M -38: -823--8,,. 21. Earcia- odrigue.a N:' Al#are.-Dia.a &' Foren.o-Earciab MH' MariVno-Calle;oa A' :ernande.- ialc A and *esma-*anc!e.c P. Extrapulmonary tuberculosis: epidemiology and risk factors Enferm )nfecc Microbiol Clin. 28--M26"3$:782 786. 22. )lga.li A' Boyaci &' Basyigit ) and <ildi. :. Extrapulmonary tuberculosis: clinical and epidemiologic spectrum of 2,2 cases. Arc! Med es. 288@ *ep+ctM,7"7$:@,7-@-. 2,. :ader T' Parks N' 0!an (' Manning ' *tokes * and (asir (A. Extrapulmonary tuberculosis in 0abul' Afg!anistan:A !ospital-based retrospecti#e re#ie/. )nternational Nournal of )nfectious Diseases. 28-8M-@' e-82We--8 2@. Malte.ou & C' *pyridis P and 0afet.is D A. Extra-pulmonary tuberculosis in c!ildren.Arc! Dis C!ild 2888M4,:,@2U,@2. 27. Eunal *' <ang D' Agar/al M' 0oroglu M' 0a.gan D and Durma. . Demograp!ic and microbial c!aracteristics of extrapulmonary tuberculosis cases diagnosed in Malatya' Turkey' 288--2883. BMC Public &ealt! 28--' --:-7@. 22. +t!man EX' )bra!im M)M and a;aa <A. Comparison of clinical and sociodemograp!ical factors in pulmonary and extrapulmonary tuberculosis patient

in <emen.Nournal of Clinical and Diagnostic esearc!. 28-- April' Hol-7"2$:-6--67. 23. 0im MN' 0im & ' &/ang **' 0im <5' &an *0' *!im <*' and <im NN. Pre#alence and )ts Predictors of Extrapulmonary )n#ol#ement in Patients /it! Pulmonary Tuberculosis. N 0orean Med *ci. 2886M 2@: 2,3-@-. 24. &ussain M5' &aIue MA' Banu *A' Ekram *A and a!man M:. Extrapulmonary Tuberculosis: Experience in a;s!a!i C!est Disease Clinic and C!est Disease &ospital. T!e Nournal of Teac!ers Association' MC' a;s!a!i. TAN 288@M -3"-$ : -2--6.

PART D Budget I. Total Budget: Tk 500, 000 (Five lacs only Sl. No. Item 1 Personnel cost 1.1 Principal Investigator PI! 1.& 'o-Investigator 'o-I! 1.% )esearch *++icer )*! 1.( Support Sta++ M-SS! & .iel/ 01penses &.1 2onorarium +or )esource Person +or Training o+ )*3 4olunteers an/ /ata collectors &.& 'ost o+ Data 'ollection &.% -ocal supervision cost &.( 'ompensation +or research Participants % Supplies an/ Materials ( Patient 'ost Travel " 'ost ".1 Non-local +iel/ cost +or PI 8 'o-I ".& Non-local +iel/ cost +or )* ".% -ocal +iel/ cost +or PI 8 'o-I ".( -ocal +iel/ cost +or )*/ Data Unit cost "### (### 1&### 1### ("# $### 1### 1"# Months/ times $ ( % $ % & % 1

Number 1 & & 1 % $ ( $##

BDT %#### %&### ,&### $### (#"# ,&### 1&### 5####

Sub-total

1(####

1,6#"# Not 7pplicable Not 7pplicable %### 1### %## 1"# % 1 % 1 1 ( &# 1## 5### (### 16### 1"###

($###

collectors *++ice Stationeries $.1 Toner $.& *++set paper Bag/Pen/pencil/eraser/measuring $.% tape/ umbrella etc. Data processing an/ computer charges ,.1 Data entr93 co/ing3 cleaning

$### "## -ump sum -ump sum -ump sum -ump sum -ump sum -ump sum -ump sum

1 $

1 1

$### %### 1(### &"### &"### $3### 1&### $### 1#### &(### 1#### "#### &%###

,.& Data anal9sis Printing an/ repro/uction//issemination 6.1 6.& 6.% Printing o+ :uestionnaire )eport preparation/ printing Photocop9

5 1# 11

5.1 Dissemination Miscellaneous Telephone3 internet3 postage etc.! 47T 8 Income Ta1 (;! <ran/ Total

65"# 65"# &#### &#### BDT "#####.## =Ta>a +ive lacs onl9?

1ational Institute o Preventive and %ocial (edicine )irectorate General o 0ealt! %ervices Application or /t!ical Clearance 1. Principal Investigator(s): Dr. Md. Anisur a!man Professor % &ead' Dept. of Epidemiology. (ational )nstitute of Pre#enti#e and *ocial Medicine "()P*+M$ ,. Co-Investigator(s): Dr. Md. i./anul 0arim Asst. Professor' Department of Epidemiology' ()P*+M Dr. 1mmul 0!air Alam Medical +fficer' Population Dynamics' ()P*+M.

-. Place o t!e %tud"#Institution(s): *ixteen 1p.illa D+T* centers

.. Title o %tud": Predicting risk indicators for Pulmonary and Extra-pulmonary


Tuberculosis in rural areas

$. T"pe o %tud": Case control study ;. )uration: <. Total Cost: =. 4unding Agenc":
2 "six$ Mont!s Tk.788'8889J 'anglades! (edical Researc! Council ('(RC)

Circle t!e appropriate ans9er to eac! o t!e ollo9ing '(f not "&&licable )rite *"+ 1. %ource o Population : "a$ )ll *ub;ects "b$ (onY )ll *ub;ects "c$ Minors or persons under guardians!ip ,. )oes t!e stud" involve : "a$ P!ysical risks to t!e sub;ects "b$ *ocial isks "c$ Psyc!ological risks to sub;ects <es <es <es (o (o (o "a$ 1se of records' "!ospital' medical' deat!' birt! or ot!er$ <es (o <es <es <es (o (o (o "e$ )n#asion of t!e body "f$ )n#asion of Pri#acy <es <es (o (o (o "d$ Discomfort to sub;ects <es (o

"g$ Disclosure of <es information damaging to sub;ect or ot!ers -. )oes t!e stud" involve :

"b$ 1se of fetal tissue or abortus "c$ 1se of organs or body fluids

<es <es

(o (o ;. Aill precautions &e ta6en to protect anon"*it" o su&jects <es (o

.. Are su&jects clearl" in or*ed a&out: "a$ (ature and purposes of study "b$ Procedures to be follo/ed including alternati#es used "c$ P!ysical risks "d$ Pri#ate Iuestions "e$ )n#asion of t!e Body "f$ "g$ Benefits to be deri#ed ig!t to refuse to participate or to /it!dra/ from study <es <es (o (o

(ot applicable <es (o

(ot applicable <es <es (o (o

"!$ Confidential !andling of data "i$

<es

(o (o

Compensation <es /!ere t!ere are risks or loss of /orking time or pri#acy is in#ol#ed in any particular procedure

$. Aill signed consent or*#ver&al consent &e re7uired : "a$ :rom *ub;ects "b$ :rom parent or guardian "if sub;ects are minors$ <es (o

(ot applicable

T!e /t!ical Revie9 Co**ittee (/RC)


TB remains one of t!e leading causes of adult mortality and morbidity in Banglades! t!at causing persistent crisis in !ealt! and de#elopment. Banglades! ranks sixt! among !ig!er TB burden countries /!ere extra-pulmonary TB patients /ere -2G of all TB cases in 2884. Age' education' income' occupation' race' sex' malnutrition "Hit D deficiency$' &)H positi#ity' diabetes' renal disease' drinking unpasteuri.ed milk' all are t!oug!t to be important predictors of extra-pulmonary tuberculosis. A case control study /ill be conducted in eig!teen upa.illas of D!aka di#ision. A total of 744 samples "26@ cases and 26@ controls$ /ill be recruited from t!e treatment register of t!e D+T* centers of t!e selected upa.illas. *ociodemograp!ic and disease profile /ill be collected by a inter#ie/er administered semistructured Iuestionnaire. Before t!e inter#ie/' t!e detail of t!e study /ill be explained to t!e eligible respondents. )nformed #erbal consent /ill be obtained from e#ery respondent and inter#ie/s /ill be !eld in pri#ate. Risk factors for EPTB in Bangladesh may be different to those in low-burden countries. This study will help us identifying the risk factors that predispose to EPTB !nd will lead policymakers adopting targeted strategies to pre#ent it and decrease its national burden.

)ocu*ents su&*itted !ere9it! to co**ittee: 1mbrella proposal Proposal *ummary Abstract for Et!ical e#ie/ Committee as per attac!ment )nformed consent form for sub;ects Procedure for maintaining confidentiality )nter#ie/ sc!edule and c!ecklist

We agree to obtain approval of the Ethical Review Committee for any changes involving the rights and welfare of subjects or any changes of the Methodology before making any such changes.

Principal )n#estigator

+t!er )n#estigator "s$

Predicting ris6 indicators or Pul*onar" and /5tra-pul*onar" Tu&erculosis in rural areas


T!ese issues /ill be kept in concern /!ile conducting researc! process:

-. Any group /!ose ability to gi#e #oluntary informed consent assumes Iuestionable /ill not be
included 2. (o potential risks exists in designing t!is study

,. By follo/ing under mentioned steps confidentiality /ill be maintained: esearc! data /ill be coded
Data /ill be stored in a locked cabinets +nly researc! personnel /ill be allo/ed to access data. T!ere is no p!ysical' psyc!ological' social and legal risk. During p!ysical examination' proper consent /ill be taken. :or safeguarding confidentiality and protecting anonymity eac! of t!e patient /ill be gi#en a special )D no. t!at pri#acy of t!e patient /ill be maintained and !e9s!e /ill be compensated for loss of /ork time if t!ey /ants

A signed informed consent /ill be taken from t!e patient9patientLs guardians con#incing A data collection s!eet s!ould "enclosed$ be prepared for /!ic! a s!ort inter#ie/ of 27-,8
minutes /ill be reIuired

(o drug /ill be used for t!is study (o experimental ne/ drug /ill be administrated (o placebo /ill be used !ere 1se of !ospital records "outdoor$ /ill be needed to fill up t!e patientLs data s!eet.

@. Consent form /ill be a /ritten statement 7. A brief inter#ie/ regarding study #ariables /ill be collected from t!e participants. 2. T!e study result /ill accrue t!e benefit to t!e society by pro#iding information regarding
exploration and identification of important risk factors and t!eir distribution among pulmonary and extra-pulmonary tuberculosis cases in rural areas of Banglades!. 3. (o experimental drug' placebo /ill be used.

Principal )n#estigator

I14+R( C+1%/1T 4+R( 4+R %@'8/CT%

Title o researc! stud": Predicting ris6 indicators or Pul*onar" and /5trapul*onar" Tu&erculosis in rural areas
----------------------------------------------------------------------------------------------1a*e o Participant: ----------------------------------------------------------------------------------------------1a*e o Investigator: -----------------------------------------------------------------------------------------------

-. ) consent to participate in t!e researc! titled RPredicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areasS' t!e particulars of /!ic!-including details of inter#ie/s and Iuestionnaires !a#e been explained to me. A /ritten copy of t!e information !as been gi#en to me to keep. 2. ) aut!ori.e t!e researc!er to use /it! me t!e inter#ie/s and Iuestionnaires referred to under "-$ abo#e. ,. ) ackno/ledge t!at: a. T!e possible effects of t!e inter#ie/s and Iuestionnaires !a#e been explained to me to my satisfaction b. ) !a#e been informed t!at ) am free to /it!dra/ from t!e researc! at any time /it!out explanation or pre;udice and to /it!dra/ any unprocessed data pre#iously suppliedM c. T!e pro;ect is for t!e purpose of researc! d. ) !a#e been informed t!at t!e confidentiality of t!e information ) pro#ide /ill be safeguarded sub;ect to any legal reIuirements e. ) !a#e been informed regarding t!e inter#ie/s. ) !a#e also been informed t!at because of t!e number of people to be inter#ie/s is smallM it is possible t!at someone may still be able to identify me on t!e basis of any references to personal information t!at mig!t allo/ someone to guess my identity. &o/e#er' ) /ill be referred by pseudonym or identified by a different name in any publications arising from t!e researc!.
*ignature Date ----------------------------------------------------------------------------------------"Participant$ *ignature Date ----------------------------------------------------------------------------------------"5itness to consent$

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Title o t!e stud": Predicting risk indicators for Pulmonary and Extra-pulmonary Tuberculosis in rural areas

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