Principles of Scientific Writing for an International Audience


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Principles of Scientific Writing for an International Audience

  1. 1. Successful  Scien+fic  Wri+ng   Eugene  Elbert,  MS  (Johns  Hopkins     University,  U.S.)   Special  thanks  to  :  Paul  Siegel  MD,  MPH   9-­‐10  August  2012  
  2. 2. Biological  Threat  Reduc+on  Program     of  the   Defense  Threat  Reduc+on  Agency   (DTRA)     2  
  3. 3. Biological  Threat  Reduc+on  Program    •  Consolidate  especially  dangerous  pathogens   (EDPs)  into  one  or  two  safe,  secure  central   reference  laboratories  or  repositories  •  Build  and  sustain  long-­‐term  partnerships  through   interna+onal  scien+fic  engagement  and   coopera+on  •  Improve  capacity  to  detect,  diagnose  and  report   outbreaks  and  poten+al  pandemics  by  providing   training  to  personnel  of  the  appropriate  facili+es   3  
  4. 4. Biological  Threat  Reduc+on  Program  (BTRP)   •  EDPs  for  human  and  animal  health  include:   o  Avian  and  pandemic  influenza  (influenza  viruses)   o  Crimean-­‐Congo  Hemorrhagic  Fever  (CCHF  virus)   o  Anthrax  (Bacillus  anthracis)   o  Brucella  (Brucella  species)   o  Tularemia  (Francisella  tularensis)   o  Botulism  (Clostridium  botulinum)   o  Tick  Borne  Encephali+s  (TBE  virus)   o  Plague  (Yersinia  pes6s)   o  Foot  and  Mouth  Disease  (FMD)   o  Glanders   o  Newcastle  Disease  Virus   o  Rinderpest   o  Pox  viruses  (goat  and  sheep  pox)   o  Swine  fevers  (African  and  Classical  Swine  Fever)   •  Although   the   BTRP-­‐provided   training   focus   on   these   pathogens,   the  knowledge  and  skills  learned  and  prac+ced  are  applicable  to  a   broad   range   of   other   infec+ous   diseases   and   public   and   animal   health  concerns       4  
  5. 5. 5  
  6. 6. BTRP-­‐Provided  Training  Courses  include:     •  Disease  recogni+on;     •  Laboratory  equipment  use  and  maintenance;     •  Biosafety  and  security;     •  Laboratory  safety;     •  Laboratory  quality  systems;     •  Respiratory  protec+on  program;     •  Purchasing  and  inventory  control;     •  Introduc+on  to  microbiology;     •  Introduc+on  to  molecular  biology;     •  Introduc+on  to  immunology/serology;     •  Diagnos+c  assays  for  specific  EDPs;     •  Laboratory  management;     •  Sample  collec+on  and  processing;     •  Basics  of  epidemiology;  and  others   6  
  7. 7. Conceptual  design  of  approved  TIPME   Training  Facility   7  
  8. 8. BTRP  Summary  •  Enhancement  of  exis+ng  surveillance  capacity   through  expansion  of  generic  skills  •  Development  of  capacity  for  rapid  detec+on  (PCR   and  ELISA),  which  contributes  to  public  health  •  Improved  biosafety  and  biosecurity  for   laboratory  personnel  •  BTRP-­‐provided  training  complements  the   Ministry  training  requirements  for  specialists   8    
  9. 9. Successful  Scien+fic  Wri+ng   9  
  10. 10. Introduc+on  Objec+ves  of  the  workshop:    •  To    introduce  basic  concepts  of  scien+fic  approach  •  To  detail  the  structure  and  format  of  scien+fic  papers.  •  To  compare  examples  of  different  research  designs.  •  To  examine  components  of  a  scien+fic  paper.  •  To  cri+cally  examine  published  examples  of  scien+fic   wri+ng.  •  To  apply  new  wri+ng  skills  to  draging  an  abstract.  •  To  learn  about  the  submission  process  for  publica+ons,   funding  proposals,  and  presenta+ons   10  
  11. 11. Why  do  we  publish?  •  Presen+ng  research  •  Reaching  global  scien+fic  community  •  Advancing  science  •  Educa+on  •  Funding  and  credibility     11  
  12. 12. 12  
  13. 13. Repor+ng  Scien+fic  Research  •  Hypothesis  or  research  ques+on  •  Planned  research  •  Ethics     –  Plagiarism   –  Misuse  of  data  and  informa+on   –  Conflict  of  interest   –  Integrity   –  Human  subject  research       13  
  14. 14. Process  of  scien6fic  wri6ng   Submiing   Hypothesis   Wri+ng     Study  plan   ar+cle  Having     Experiment  journal,  audience    in  mind   Results   Data  processing   genera+on   14  
  15. 15. General  Guidelines  for  Scien+fic   Papers:  Style  and  Content  EASE  guidelines  •  Complete,  concise  and  clear  •  For  effec+veness  of  interna+onal   coopera+on  all  publica+ons  should  be:  •  COMPLETE,  CONCISE  AND   CLEAR!  •  IMPORTANT     15  
  16. 16. General  Guidelines  for  Scien+fic   Papers:  Style  and  Content  •  Do  not  include  irrelevant  informa+on  •  Informa+on  should  not  be  repeated  •  Include  only  necessary  tables  and  figures  •  Cap+ons  –  informa+ve  but  concise  •  Delete  redundancies  •  Define  abbrevia+on  at  first  use  •  Do  not  over-­‐generalize  •  Numbers  for  all  numerals   16  
  17. 17. Content  •  Study  should  be  planned  in  advance  •  The  journal  and  the  audience  should  be   chosen  •  Informa+on  should  be  organized  •  All  the  components  of  scien+fic  ar+cle   should  be  present  and  sa+sfy  the   guidelines  for  a  chosen  journal   17  
  18. 18. Repor+ng  Guidelines:  Content  •  Dis+nguish  your  original  ideas  •  Paraphrase  text  from  other  sources  •  Proper  terms  (plant  community  vs.  phytocoenosis)  •  Define  every  uncommon  term    •  Avoid  ambiguity  •  Be  clear  what  you  regard  as  100%  when  repor+ng  %  •  SI  units  (interna+onal  system  of  units;  metric)  •  Decimal  point    •  Remember  that  the  text  will  be  read  by  foreigners   18  
  19. 19. Repor+ng  Guidelines:  Content  •  Make  posi+ve,  objec+ve  asser+ons,  directly  supported  by  the   results,    with  necessary  qualifica+ons  and  caveats  •  Don’t  oversell:    “This  result  clearly  proves  that  the  neural   network  approach  is  superior  and  will  revolu+onize  research   methods”.  •  Don’t  base  substan+al  claims  on  unpublished  data  or  on   “experience”  without  objec+ve  suppor+ng  evidence.        •  If  you  rely  on  a  reference  to  draw  a  conclusion,  be  sure  the   reference  supports  the  idea,  and  say  where  the  support  may   be  found  in  the  reference.   19  
  20. 20. A  Dic+onary  of  Useful  Research  Phrases    •  "It  has  long  been  known..."     •  I  didnt  look  up  the  original  •  "It  is  believed  that..."   references  •  "It  is  generally  believed   •  I  think   that..."   •  My  friends  think  so,  too  •  "A  sta+s+cally  oriented     projec+on..."   •  Wild  guess  •  “Typical  results  are  shown”   •  Best  results  are  shown  •  “Obviously,  we  will  need   •  I  don’t  understand  anything   addi+onal  studies”    •  “Authors  thanks  Joe  in   •  Joe  did  the  work  and   conduc+ng  experiment  and   George  explained  it  to  me   George  for  helpful     comments”   20  
  21. 21. Example  “In   order   to   provide   analy+c   control   during   forensic-­‐chemical   inves+ga+on,   it   is   customary   to   use   highly  sensi+ve  and  specific  analysis  methods.  Very  popular  in   the   prac+ce   of   chemic-­‐toxic   studies   is   the   TLC  method   in   view   of   its   accessibility,   ease   of   conduc+ng  and  expressiveness.  Due  to  the  possibility  of  changing  not   only   sorbents   but   also   solvents,   it   is   possible   to  quickly  solve  the  problems  of  separa+on”   21  
  22. 22. Repor+ng  Guidelines:  Text  Structure  •  Simple  sentences,  should  not  be  very  long  •  Avoid  passive  voice  •  Text  should  be  cohesive,  logically  organized  •  Each  paragraph  should  start  with  a  topic  sentence  •  Use  text  tables  •  Make  figures  and  tables  understandable  by  themselves  •  Explain  your  figures  and  charts,  and  jus+fy  their   inclusion.    Do  not  just  show  them  with  no  stated   reason.   22  
  23. 23. Text  tables  Original  sentence:  •  Iron  concentra+on  means  (±standard  devia+on)  were  as   follows:  11.2±0.3  mg/dm3  in  sample  A,  12.3±0.2  mg/ dm3  in  sample  B,  and  11.4±0.9  mg/dm3  in  sample  C.  Modified:   •  Iron  concentra+on  means  (±standard  devia+on,  in   mg/dm3)  were  as  follows:   •  sample  B    12.3±0.2   •  sample  C    11.4±0.9   •  sample  A    11.2±0.3   23  
  24. 24. Replace  phrases  with  a  single  word  •  Considering  this  fact  •  In  the  rela+on  to    •  Exceeding  number  •  In  the  previous  case  •  In  the  absence  •  In  large  number  of  cases   24  
  25. 25. Passive  Voice  “Have  you  ever  been  told  to  use  passive  voice”          or  “Did  anyone  tell  you  to  use  passive  voice”  Examples:  •  “James  Watson  was  awarded  the  Nobel  Prize  for   discovering  the  molecular  structure  of  DNA.“  vs.  •  "The  Nobel  CommiSee  awarded  James  Watson   the  Nobel  Prize  for  discovering  the  molecular   structure  of  DNA."   25  
  26. 26. Passive  voice  Nobody  takes  responsibility  in  passive  voice:    “Mistakes  were  made  during  the  experiment”  vs.  We  made  mistakes  during  the  experiment    “It  is  shown  in  the  table”  vs.  The  table  shows       26  
  27. 27. Example  Common  dysfunc+on  of  the  immune  system  was  shown  in  the  trials  on  humans  and  animals  __________________________________  Trials  on  humans  and  animals  show  a  common  dysfunc+on  of  the  immune  system   27  
  28. 28. Correct  Use  of  Passive  Voice  •  When  the  ac+on  is  more  important  than  the   agent  of  it  (as  in  Materials  and  Methods)    •  In  order  to  emphasize  somebody  other  than   the  ac+ng    agent    •  When  the  agent  is  unknown   28  
  29. 29. Repor+ng  Guidelines:  Language  •  Use  commonly  known  words,  but  not   idioma+c  expressions  •  Define  abbrevia+ons  (avoid  them  in  abstract)  •  Spelling    •  Past  tense  in  body,  present  in  general   statements  •  Refer  to  the  author  as  “we”  or  “I”  not  “the   author”   29  
  30. 30. Repor+ng  Guidelines:  Language  Transforma2on  of  verbs  into  nouns    Obtained  es+mates  –  es+mated  Gained  improvement-­‐  improved  Showed  growth  –  grew  Made  a  decision  –  decided       30  
  31. 31. Common  Fallacies  in  Wri+ng    •  Non  Causa  Pro  Causa  Fallacies  —  No  Cause   for  Cause  •  Asempts  to  establish  a  causal  rela+onship   –  Cum  Hoc,  Ergo  Propter  Hoc     –  Post  Hoc,  Ergo  Propter  Hoc     –  The  Regression  Fallacy     –  Texas  Sharpshooter  Fallacy   31  
  32. 32. Fallacies  in  Wri+ng    Cum  Hoc,  Ergo  Propter  Hoc  —  With  This,  Therefore  •  African  American  popula+on  is  more  likely  to  experience  metabolic   consequences  of  Chronic  Kidney  Disease  (CKD)  before  reaching  the   eGFR  <60  ml/min  threshold  …  that  these  observa+ons  support  a   need  to  adapt  clinical  prac+ce  guidelines  shiging  screening  for  CKD   to  a  higher  eGFR  threshold  specifically  for  African  Americans  (1)    •  The  assump6on  that  the  measured  clinical  parameters  in  this   representa6ve  popula6on  are  physiologically  linked  to  CKD  in   African  Americans  is  simplis6c  and  ignores  the  effects  of  a   combina6on  of  gene6c  and  physiologic  adapta6ons  superimposed   on  a  background  of  social  and  environmental  factors  that  account   for  minority  health  dispari6es  (2)    •  Lesson:  Adjustment  for  possible  confounders  and  other  sources  of   bias     32  
  33. 33. Fallacies  in  Wri+ng    Post  Hoc,  Ergo  Propter  Hoc  —  AAer  This,    Therefore    Because  of  This    •  “Since  that  event  followed  this  one,  this  event  must   have  caused  that  one.”  It  also  is  referred  to  as  “false   cause”  or  “coincidental  correla+on.”  •  7  women  in  California  developed  ovarian  cysts  taking   the  new  mul+phasic  oral  contracep+ve  pills  which  led   to  case  series  report  and  media  prin+ng  the  story  [1].    •  No  associa6on  was  shown  in  follow-­‐up  studies  [2]    •  Lesson:  Checking  for  possible  confounders,  conduc+ng   valida+on  studies  before  jumping  to  conclusions,   repor+ng  on  it  in  wri+ng   33  
  34. 34. Fallacies  in  Wri+ng    Texas  Sharpshooter  Fallacy       Outbreak  foci?      •  In  medical  research,  this  fallacy  occurs  when  inves6gators  select   certain  data  to  demonstrate  a  cause-­‐effect  rela6onships.   34  
  35. 35. Fallacies  in  Wri+ng    The  Art  of  Argumenta   –  Argumentum  ad  Ignoratum  (Appeal  to  Ignorance):   Absence  of  evidence  is  not  evidence  of  absence   Width  of  Confidence  Interval(±w)   Sample  Size(n)     0.01   9612   0.02   2403   0.03   1068   0.05   384   0.10   96   0.15   43   Sample  sizes  required  to  es2mate  a  true  prevalence  of  0.50  with  95%  confidence   intervals  of  different  widths  (±w)    Lesson:  Making  sure  that  the  sample  size  is  large  enough.  Recognizing  beneficence  and  non-­‐maleficence   35  
  36. 36. Fallacies  in  Wri+ng    Argumentum  ad  Verecundiam  (Appeal  to  Authority):  Users  of  this  fallacy  ogen  call  upon  the  published  works  of  others  to  bolster  their  arguments,  without  ques+oning  the  accuracy,  reliability,  or  validity  of  those  sources  •  Quote  from  an  editor  as  a  condi+on  for  publica+on  highlights   the  problem:  “you  cite  Leukemia  [once  in  42  references].   Consequently,  we  kindly  ask  you  to  add  references  of  ar6cles   published  in  Leukemia  to  your  present  ar6cle”  (1)  •  Editors  incen+ve  to  inflate  impact  factors  through  self-­‐ cita+on  •  Survey  found  that  having  a  tenure  posi6on  also  increased   coercion  •  Lesson:    Being  true  to  your  work   36  
  37. 37. Fallacies  in  Wri+ng    Argumentum  ad  An;quitatem  (Appeal  to    Tradi2on  or  History)    “(Talking  about  acupuncture)  I  think  it  is  insul+ng  to  say  that  Chinese  people  would  carry  on  with  some  sort  of  mys+cal  belief  when  it  didn’t  work”   “Well,  you  know  –  acupuncture  is  one  of  those  amazing   things.  I  mean  it  has  been  around    for  several  thousand   years  .  .  .  there  is  a  huge  amount  of  validity  to  what  it   represents,     and  there  has  to  be  –  or  it  wouldn’t  have  survived  such  a  long   +me  “     Lesson:    Not  making  unsupported  claims   37  
  38. 38. Fallacies  in  wri+ng    •  Argumentum  ad  Populum  (Appeal  to  the  People  or  Popularity)    •  4  from  5  den+sts  recommend  sugar-­‐ free  “Trident”“  chewing-­‐gum!  •  The  adver+sement  “forgot”  to  men+on  “If  pa+ents  INSIST  to   use  chewing-­‐gum”.  They  also  hid  each  5th  den+st   recommended  to  avoid  the  use  of  chewing-­‐gum.  •  «Thus  based  on  the  assessment  of  leading  Russian  clinics   “Sangviri+n”  is  one  of  the  effec+ve  modern  an+microbial  drug   of  local  and  common-­‐  resorp+ve  ac+on  for  preven+on  and   treatment  of  different  infec+ous  diseases  [14–17].»  7/28/2012  
  39. 39. Fallacies  in  Wri+ng  Myths  of  Beneficence    An  analysis  of  60  adver+sements  that  had  appeared  in  the  Bri+sh  Medical  Journal  between  1999  and  2001  demonstrated  that  drug  adver+sing  uses  strong  imagery  to  fabricate  mythical  associa+ons  between  medical  condi+ons  and  branded  drugs,  and  that  drug  adver+sing  manipulates  readers’  percep+ons  by  subtle  appeal  to  ancient  and  modern  mythological  founda+ons  of  humanism  and  Western  psychology.     39  
  40. 40. Fallacies  in  Wri+ng  False  Dichotomy    This  is  also  called  a  false  dilemma,  an  either-­‐or  fallacy,  fallacy  of  false  choice,  or  black-­‐and-­‐white  thinking.    Most  wide-­‐spread  false  dichotomy  in  scien+fic  repor+ng:      Sta+s+cal  significance  P  =  0.049  vs.  P  =  0.051     40  
  41. 41. Fallacies  in  Wri+ng  Essen2alism    Some  argument  in  print  or  spoken  word,  some  “essen+al  feature”  is  proposed  as  a  defining  characteris+c  of  an  otherwise  complex  issue  or  larger  problem    Each  scien+fic  specialty  looks  at  disease  differently.  For  example,  cancer  from  the  perspec+ve  of  a  general  surgeon,  a  pathologist  or  an  acupuncturist  are  completely  different.      Lesson:  To  be  aware  of  specialized  terminology  and  body  of  knowledge  when  repor+ng   41  
  42. 42. Fallacies  in  Wri+ng  Редукционизм  Efforts  to  simplify  the  problem  to  the  simple  rela+ons    (O’Connor  et  al.  2011):  “Reduc+onist  methods  of  disease  control  involve  the  removal  of  infec+on  or  the  infec+ous  agent,  implemen+ng  barriers  to  direct  and  indirect  transmission  or  by  increasing  inherent  or  acquired  immunity  to  the  infec+ous  agent.  However,  for  those  diseases  which  evade  such  methods  of  conven+onal  control,  a  more  comprehensive  understanding  of  the  complex  interac+ons  amongst  biological  (agent  and  host(s)),  environmental,  economic  and  social  factors  which  can  affect  the  emergence  and  spread  of  an  infec+ous  disease  is  required.”   42  
  43. 43. Things  to  avoid:  •  Plagiarism    •  Fishing  expedi+ons  –  research  must  be  hypothesis  driven  •  Do  not  plan  your  study  in  order  to  use  your  results  to  pool   evidence  against  the  same  problem  (e.g.  meta-­‐analyses.    •  Do  not  fail  to  take  into  account  heterogeneity,  uncertainty   and  dependence  •  Do  not  fail  to  have  a  robust  exploratory  data  analysis  (EDA)   before  proceeding  into  any  confirmatory  tes+ng  (John   Tukey  teachings)  •  Do  not  discount  the  importance  of  internal  and  external   validity  when  interpre+ng  results  •  Do  not  underes+mate  the  sta+s+cs.    The  absence  of   evidence  is  not  the  evidence  of  absence  –  your  study  may   not  have  enough  power  to  detect  anything  unless  you  have   large  numbers   43  
  44. 44. Things  that  annoy  reviewers  –  Poor  English  –  Repe++on  –  Lack  of  structure  in  the  text  –  Sentences  that  are  too  convoluted  and  long    –  Lack  of  asen+on  to  detail  (a  premature  drag  with   typographical  errors,  etc.)  –  Not  well  thought  out  statements  (make  each  word   count)  –  Obscure  methods  or  not  well  described  –  Oversta+ng  the  results  –  Too  long  of  a  paper   44  
  45. 45. Repor+ng  Guidelines:  Structure  •  IMRaD  standard  (Introduc+on,  Methods,  Results,  and   Discussion)  •  Design  Specific  –  EQUATOR  network  •  Journal  -­‐specific  •  General:   –  Title  Page   –  Conflict  of  Interest  No+fica+on  Page   –  Abstract   –  Introduc+on   –  Methods   –  Results     –  Discussion   –  References   45  
  46. 46. Standardizing  Health  Repor+ng  EQUATOR  (Enhancing  Quality  and  Transparency  of  Health   Research)  network:  “Too  oaen,  good  research  evidence  is  undermined  by  poor   quality  repor6ng”  •  Raising  awareness  of  the  crucial  importance  of  good   repor+ng  of  research    •  Becoming  the  recognized  global  center  providing  resources,   educa+on  and  training  rela+ng  to  the  repor+ng  of  health   research  and  use  of  repor+ng  guidelines  •  Assis+ng  in  the  development,  dissemina+on  and   implementa+on  of  repor+ng  guidelines  •  Monitoring  the  status  of  the  quality  of  repor+ng  across   health  research  literature  •  Conduc+ng  research  rela+ng  to  the  quality  of  repor+ng     46    
  47. 47. Guidelines  for  Repor+ng  Common   Study  Types  •  CONSORT  –  Consolidate  Standards  of   Repor+ng  Trials  •  STROBE  –  Strengthening  the  Repor+ng  of   Observa+onal  studies  •  STARD  –  Standards  for  repor+ng  of  Diagnos+c   Accuracy  •  QUOROM  –  Quality  of  Repor+ng  of  Meta-­‐ analyses  (under  CONSORT)   47  
  48. 48. Example  –  STROBE  checklist     Item No RecommendationTitle and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract (b) Provide in the abstract an informative and balanced summary of what was done and what was foundIntroductionBackground/rationale 2 Explain the scientific background and rationale for the investigation being reportedObjectives 3 State specific objectives, including any prespecified hypothesesMethodsStudy design 4 Present key elements of study design early in the paperSetting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collectionParticipants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-up Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controls Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants (b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed Case-control study—For matched studies, give matching criteria and the number of controls per case 48  
  49. 49. Study  Designs  in  Public  Health  Experimental  (Interven2onal)  Studies   Observa2onal  Studies  Randomized  Trials   Case  reports  Community  Trials   Case  Series   Descrip+ve  Therapeu+c/Preven+ve  Trials   Cross-­‐sec+onal  Studies   Surveillance     Cohort  Studies     Analy+c   Case-­‐Control   49  
  50. 50. Observa+onal  Descrip+ve  Studies  •  Case  Reports  –  detailed  presenta+ons  of  a   single  case  or  a  handful  of  cases.     “Normal  Plasma  Cholesterol  in  an  88-­‐Year-­‐Old  Man  Who  Eats  25  Eggs  a   Day  —  Mechanisms  of  Adapta+on”  [Kern  J,  NEJM  1991;  324:896–899]  •  Case  Series  –survey  of  a  group  of  individuals   with  a  par+cular  disease  performed  at  a  single   point  of  +me.   “Pneumocy+s  pneumonia:  Los  Angeles”  [MMWR  Morbidity  and   Mortality  Weekly  Report  1981;30:250-­‐252]       50  
  51. 51. Cross-­‐Sec+onal  Studies  •  Describes  health  of  popula+ons  (both  exposed   and  non-­‐exposed)  •  Iden+fies  prevalent  cases  •  Finds  associa+on,  not  causa+on    •  Best-­‐suited  for  lisle  disability,  pre-­‐symptoma+c   studies  •  Surveys  •  Good  for  planning  health  care   –  Na+onal  Health  Surveys  are  a  good  example   51  
  52. 52. Surveillance  •  An  ongoing,  systema6c  collec6on,  analysis  and  interpreta6on  of   health-­‐related  data  essen6al  to  the  planning,  implementa6on,  and   evalua6on  of  public  health  prac6ce  •  Detec+on  and  no+fica+on  of  health  events  •  Collec+on  and  consolida+on  of  data  •  Inves+ga+on  of  cases  and  outbreaks  •  Rou+ne  Repor+ng    •  Feedback   U.S.  CDC:  Ears,  EWIDS,  NTSIP,  ESP,  NEDSS,  FluNet,  BRFSS,  FoodNet,  etc.   Australia:    NNDSS   U.S.:  ProMED,  HealthMap   Canada:  FluWatch,  GPHIN   France:  GPs  Sen+nelles  Network   Asia:  APEC  EINet   WHO:  GOARN   Europe:  MedlSys   52  
  53. 53. Case-­‐Control  Studies  •  Comparison  of  cases  versus  non-­‐cases   (controls)  •  Retrospec+ve  for  exposure  •  Matching  all  popula+on  characteris+cs  of   cases  to  those  of  controls  (including  biases)  •  Mostly  for  prevalent  cases  (but  could  be  for   incident  cases,  too)   53  
  54. 54. Cohort  Studies  •  To  support  the  rela+on  between  the  cause   and  disease  •  Presence  or  absence  of  risk  factor  is   determined  before  outcome  occurs  •  Longitudinal/prospec+ve/incidence  studies  •  Cohorts  are  free  of  disease  at  baseline  •  Cohorts  should  be  comparable  •  Diagnos+cs  and  eligibility  should  be  defined   54  
  55. 55. Cohort  vs.  Case-­‐Control   COHORT  STUDY  DATA  COLLECTION   Sick   Exposed   Sample  of   Not  Sick   disease-­‐free   individuals   Sick   Not   Exposed   Not  Sick   Exposed   Develop   Illness  Not  Exposed   Popula+on   Exposed   Don’t   Develop  Not  Exposed   Illness   Case-­‐Control  Data  Collec+on   55  
  56. 56. Experimental:  Control  Study    Controlled:   –  Inves+gator  decides  on  interven+on    Randomized:   –  Gold  Standard  in  Epidemiological  research   –  Controls  for  confounding   –  Prevents  selec+on  Bias  Therapeu+c  vs.  Preven+ve:              Pa+ents  with  Disease  vs.  Popula+on  at  Risk     56    
  57. 57. Experimental:  Controlled  Studies    DATA  COLLECTION   Exposure   COHORT  (Observa+onal)   occurs   naturally   Sick   Exposed   Sample  of   Not  Sick  disease-­‐free   individuals   Sick   Not   Exposed   Not  Sick   Inves+gator   CONTROLLED  (Interven+onal)   Determines   Exposure   57  
  58. 58. Randomized  Clinical  Trial  •   Sample  size  should  be  sufficient  •   Possibility  to  follow  up  during  the  trial  •   Par+cipants  should  be  informed  of  risks/  benefits/  blinding/  placebo  •   Inclusion  Criteria   Reference  Popula+on     Reference  Popula+on     Experimental   Experimental   Popula+on   Popula+on       Study   Popula+on   Internal  Validity   External  Validity   58  
  59. 59. Randomized  Clinical  Trial  •  Design   –  Simple   –  Cross-­‐over,  factorial    •  Sampling  •  Eligibility  criteria  •  Blinding:  single  vs.  double  •  Alloca+on:  Randomiza+on  •  Follow-­‐up  •  Analysis  •  Therapeu+c  vs.  Non-­‐therapeu+c   59  
  60. 60. Randomized  Trial:  CONSORT  Flow   Eligible     Non-­‐eligible   Declined   Alloca+on  using   randomiza+on   scheme   Follow-­‐up   Included  in   analysis   60  
  61. 61. Protocol of clinical study (typical errors)•  During  development  of  CS  protocol:   –  Fail  to  jus+fy  the  study  of  given  drug  by  the  given  indica+ons;   –  Absence  of  pre-­‐clinical  and  clinical  (if  applicable)  trials;   –  The  objec+ves  of  study  are  not  listed  (primary  and  secondary   objec+ves),  hypothesis  of  study;   –  Mixed  concep+on  of  primary  objec+ve  of  study  and  criteria  of   efficacy;   –  Sta+s+cs!  Instead  of  sample  size  jus+fica+on  and  sta+s+cal  power:   “the  assessment  will  be  performed  with  PC,  Excel,  Student’s   methods,  etc.”;   –  Vague  procedures  and  methods,  allowing  ambiguous  interpreta+on;   –  No  dates,  no  versions  
  62. 62. Protocol of clinical study (typical errors)•  While  repor+ng  of  CS:     –  Vague  descrip+on  of  study  popula+on,  that  unable  the  formula+on  of   conclusion  about  homoscendacity;     –  No  sta+s+cal  assessment  inclusion/exclusion  criteria  of  lost  follow-­‐up   pa+ents;     –  No  side  therapy  details  and  its  effect  in  sta+s+cal  analysis;     –  No  severity  and  resolving  of  side  effects  (e.g.  2  pa+ents  presented  the   head  ache  –  no  terms,  methods  od  treatment,  outcome,  etc.);     –  No  pa+ents’  compliance  data;     –  Separate  reports  from  each  center  instead  of  all-­‐centers  consolidated   report  …  
  63. 63. General  Guidelines  For  Selec+on  of  Study  Type   Study  objec2ve   Study  type   Study  of  rare  diseases   Case  control  studies   Study  of  rare  exposure,  such  as  exposure  to   Cohort  studies  in  a  popula+on  group  in   industrial  chemicals   which  there  has  been  exposure  (e.g.   industrial  workers)   Study  of  mul+ple  exposures,  such  as  the   Case  control  studies   combined  effect  of  oral  contracep+ves  and   smoking  on  myocardial  infarc+on   Study  of  mul+ple  end  points,  such  as   Cohort  studies   mortality  from  different  causes   Es+mate  of  the  incidence  rate  in  exposed   Exclusively  cohort  studies   popula+ons   Study  of  covariables  which  change  over   Preferably  cohort  studies   +me   Study  of  the  effect  of  interven+ons   Interven+on  studies   63  
  64. 64. Costs  of  different  types  of  bias  for  different  study  designs   Ecological   Cross-­‐ Case-­‐ Cohort   study   sec2onal   control   study(and   study   study   RCT)   Selec+on   N/A   2   3   1   bias   Recall  bias   N/A   3   3   1   Loss  to   N/A   N/A   1   3   follow-­‐up   Confounding   3   2   2   1   Time   1   2   2   3   Required   Costs   1   2   2   3   1-­‐slight;  2-­‐moderate;  3-­‐high;  N/A=  not  applicable   64  
  65. 65. Introduc+on  sec+on   Purpose:  to  convince  the  reader  that  your  study  will   yield  knowledge  or  know-­‐how  that  is  new  and  useful  •  Iden+fy  a  gap  in  knowledge  or  know-­‐how  (study   problem)   o  Provide  key  background  (scope/nature/magnitude  of  the  gap)   o  Be  clear  that  filling  this  gap  will  be  useful.   o  Describe  the  relevant  limita+ons  of  previous  studies  •  Present  your  approach  to  filling  the  gap  (study   purpose)   o  Be  clear  that  your  approach  is  new   o  Emphasize  that  your  approach  addresses  the  limita+ons  of   previous  studies  in  a  logical  and  compelling  way   Oaen  requires  just  three  paragraphs   65  
  66. 66. Introduc+on  Checklist  Background Statement: Scope nature magnitude of the gap Be clear that filling the gap is usefulProblem Statement Describe relevant limitationsStudy Statement Be clear that your approach is new Emphasize that your approach addresses limitationsSummary Statement Summarizes the study 66  
  67. 67. Introduc+on  sec+on    •  No  major  difference  in  introduc+on  sec+on   between  study  types  •  Some+mes  summary  statement  is  omised,  or   becomes  part  of  the  study  statement  •  STROBE:   Introduc+on Background/ra+onale 2 Explain  the  scien+fic  background  and  ra+onale  for   the  inves+ga+on  being  reported Objec+ves 3 State  specific  objec+ves,  including  any  pre-­‐specified   hypotheses 67  
  68. 68. Introduc+on  sec+on  The  next  four  slides  detail  the  introduc+on  checklist  process  for  four  separate  studies:    •  Background  statement  •  Problem  statement  •  Study  statement   –  General  descrip+on  of  the  surveillance  system  •  Summary  statement   68  
  69. 69. Background   The  treatment  of  human  immunodeficiency  virus  (HIV)  infec+on  has  undergone   Statement:   considerable  change.  Protease  inhibitors  and  non–nucleoside-­‐analogue     reverse-­‐transcriptase  inhibitors,  when  used  as  part  of  combina+on  drug   regimens,  can  profoundly  suppress  viral  replica+on,  with  consequent  reple+on   of  CD4+  cell  counts.   Mul+ple  clinical  trials  have  shown  the  virologic  and  immunologic  efficacy  of  the   newer,  highly  ac+ve  an+retroviral-­‐drug  combina+ons  by  measuring  the  plasma   load  of  HIV  RNA  and  CD4+  cell  counts.  In  addi+on,  prophylac+c  medica+ons  are   now  being  used  rou+nely  to  prevent  disseminated  Mycobacterium  avium   complex  infec+on Problem   Several  reports  have  described  reduc+ons  in  mortality  and  in  the  rate  of   Statement   hospitaliza+on  of  HIV  infected  pa+ents;  however,  such  reduc+ons  have  not       been  clearly  related  to  specific  therapeu+c  regimens.     Study  Statement   We  analyzed  data  collected  over  42  months  in  the  HIV  Outpa+ent  Study.  During   this  period,  rates  of  chemoprophylaxis  against  opportunis+c  infec+on  remained   rela+vely  constant  even  while  paserns  of  an+retroviral  therapy  were  changing Summary   This  report  outlines  the  changes  in  death  rates  and  the  incidence  of   Statement   opportunis+c  infec+ons  in  a  large  group  of  HIV-­‐infected  outpa+ents,  many  of   whom  had  previously  received  extensive  treatment. 69  
  70. 70. Background   Among  the  few  diseases  claimed  to  occur  more  ogen  in  non-­‐smokers  than   Statement:   smokers  1  2  that  of  greatest  poten+al  importance  is  Alzheimers  disease,  which     accounts  for  most  of  the  demen+as  of  later  life  in  Britain Problem   The  published  epidemiological  evidence,  although  sugges+ve  of  an  inverse   Statement   rela+on  with  smoking,  is  not  conclusive  either  about  Alzheimers  disease  or       demen+a  in  general.  Much  of  the  evidence  derives  from  small  retrospec+ve     studies  of  uncertain  reliability,  many  of  which  excluded  vascular  demen+a.   Prospec+ve  studies,  in  which  smoking  habits  are  recorded  before  the  onset  of   demen+a,  should  be  more  informa+ve  about  the  overall  effects  of  smoking,   par+cularly  if  they  concern  large  numbers  and  prolonged  follow  up.  Only  a  few   such  studies  have,  however,  been  properly  reported  (none  of  which  had   prolonged  follow  up) Study   We  sought  evidence  from  the  cohort  of  Bri+sh  doctors  who  have  been   Statement   followed  since  1951,  with  their  smoking  habits  reviewed  every  six  to  12  years.3   4  Many  have  died  from  or  with  some  type  of  demen+a  over  the  past  two   decades. Summary   Statement   70  
  71. 71. Background   Alcohol  was  first  implicated  as  a  possible  risk  factor  for  stroke  in  1725(1)   Statement:   Several  epidemiological  studies  now  suggest  a  U-­‐shaped  associa+on  between     alcohol  intake  and  stroke(2). Problem   Previous    studies  have  been  cri+cized  for  not  differen+a+ng  between   Statement   nondrinkers  who  were  lifelong  abstainers  and  those  who  had  given  up       drinking(3-­‐7)     By  asking  specifically  about  previous  regular  drinking  habits  we  have  been  able   to    dis+nguish  between  the  two  groups.  The  level  of  alcohol  consump+on  at   which  this  possible  protec+ve  effect  is  lost  and  alcohol  becomes  a  risk  factor   for  stroke  are  unknown. Study   We  report  the  findings  of  a  case-­‐control  study  that  examines  the  contribu+on   Statement   of  alcohol  to  the  risk  of  stroke  in  moderate  and  heavy  drinkers  (both  currently   and  previously),  lifelong  abstainers  (those  who  have  never  drunk  alcohol),  and   current  abstainers  (those  who  had  formerly  been  regular  drinkers  but  who   currently  do  not  drink  alcohol),  using  validated  measures  of  alcohol   consump+on. Summary   Statement   71  
  72. 72. Background   Between  May  2009  and  May  2010,  Greece  experienced  two  waves   Statement:   of  influenza  A(H1N1)2009  transmission   Problem   Given  the  poten+al  for  worsening  in  the  clinical  severity  of  influenza   Statement   during  the  post-­‐pandemic  influenza  season,  as  was  the  case  for       previous  influenza  pandemics  [7-­‐9],  it  was  cri+cal  to  con+nue     surveillance  with  a  focus  on  severe  cases  and  their  clinical   characteris+c Descrip2on  of   In  Greece,  influenza  is  annually  monitored  through  the  rou+ne   the   sen+nel  surveillance  system,  which  became  opera+onal  in  1999.  The   Surveillance   sen+nel  surveillance  system,  which  covers  approximately  three   System   percent  of  the  total  Greek  popula+on  in  the  2010/11  influenza   season,  provides  data  representa+ve  of  the  na+onal  popula+on Summary   This  report  summarises  data  from  influenza  surveillance  in  Greece   Statement   during  the  post-­‐pandemic  2010/11  influenza  season.   72  
  73. 73. Materials  and  Methods   Purpose:  to  describe  how  you  collected,  organized   and  analyzed  data  (relevant  to  the  study  purpose)  •  Clearly  present/define  all  analysis  variables  •  Organize  into  logical  subsec+ons  that  illustrate  the  steps   you  took  to  collect,  organize,  and  analyze  the  data:   o  Study  popula+on   o  Defini+on  of  variables   o  Laboratory  methods/  epidemiological  inves+ga+on   o  Interven+on  •  Describe  what  you  did,  not  what  you  found  (Results)  •  Respect  chronology  •  Describe  the  original  methods  in  detail;  otherwise  give   references   Length  varies  depending  on  originality  of  methods   73  
  74. 74. Materials  and  Methods  –  part1  MethodsStudy  design Present  key  elements  of  study  design  early  in  the  paperSeing Describe  the  seing,  loca+ons,  and  relevant  dates,  including  periods  of   recruitment,  exposure,  follow-­‐up,  and  data  collec+onPar+cipants  and   (a)  Cohort  study—Give  the  eligibility  criteria,  and  the  sources  and  Seing methods  of  selec+on  of  par+cipants.  Describe  methods  of  follow-­‐up   Case-­‐control  study—Give  the  eligibility  criteria,  and  the  sources  and   methods  of  case  ascertainment  and  control  selec+on.  Give  the  ra+onale   for  the  choice  of  cases  and  controls   Cross-­‐sec6onal  study—Give  the  eligibility  criteria,  and  the  sources  and   methods  of  selec+on  of  par+cipants (b)  Cohort  study—For  matched  studies,  give  matching  criteria  and   number  of  exposed  and  unexposed   Case-­‐control  study—For  matched  studies,  give  matching  criteria  and  the   number  of  controls  per  case 74  
  75. 75. Materials  and  Methods  –  part2   Clearly  define  all  outcomes,  exposures,  predictors,  poten+al  Variables confounders,  and  effect  modifiers.  Give  diagnos+c  criteria,  if   applicableData  sources/    For  each  variable  of  interest,  give  sources  of  data  and  details  of   methods  of  assessment  (measurement).  Describe  comparability  measurement of  assessment  methods  if  there  is  more  than  one  group Describe  any  efforts  to  address  poten+al  sources  of  biasBias Explain  how  the  study  size  was  arrived  atStudy  size (a)  Describe  all  sta+s+cal  methods,  including  those  used  to  Sta+s+cal   control  for  confoundingmethods (b)  Describe  any  methods  used  to  examine  subgroups  and   interac+ons (c)  Explain  how  missing  data  were  addressed (d)  Cohort  study—If  applicable,  explain  how  loss  to  follow-­‐up  was   addressed   Case-­‐control  study—If  applicable,  explain  how  matching  of  cases   and  controls  was  addressed   Cross-­‐sec6onal  study—If  applicable,  describe  analy+cal  methods   taking  account  of  sampling  strategy (e)  Describe  any  sensi+vity  analyses 75  
  76. 76. Study  Design  •  Observa+onal  or  Experimental  •  Retrospec+ve  or  Prospec+ve   76  
  77. 77. Seing  and  Par+cipants  •  Describe  the  study  popula+on  and  seing:  •  Descrip+on  should  involve  relevant   demographic,  environmental,  diagnos+c,   comorbid  factors  •  Defini+on  of  cohort/case  •  Exclusion/inclusion  criteria  •  How  was  consent  obtained?  •  Matching  (in  case-­‐control  study)   77  
  78. 78. Examples  of  seing  and  par+cipants  -­‐-­‐   cohort  Smoking  and  demen6a  in  male  Bri6sh  doctors:  prospec6ve  study    The  cohort  originally  comprised  34,439  male  doctors  on  the   Bri+sh   medical   register,   resident   in   the   United  Kingdom,   who   had   responded   to   a   ques+onnaire   about  their   smoking   habits   in   1951.   Changes   in   such   habits  were  sought  in  1957,  1966,  1972,  1978,  1990,  and  1998,  and   other   personal   informa+on   was   sought   in   1978,  1990,  and  1998.  In  1971,  follow  up  was  discon+nued  for  2459   subjects   (10.1%   of   the   survivors)   who   were   living  abroad   and   218   (0.9%)   for   other   reasons.   Almost   all   of  the   remaining   survivors   have   con+nued   to   provide  informa+on  about  their  smoking  habits*.   78  
  79. 79. Examples  of  seing  and  par+cipants  –     case  control   Alcohol  and  stroke.  A  case-­‐control  study  of  drinking  habits  past   and  present     Cases  Three  hundred  sixty-­‐four  consecu+ve  pa+ents  hospitalized  for   acute   stroke   in   Newcastle   upon   Tyne   between   August  1989   and   July   1990   formed   the   study   popula+on.   No  pa+ent   refused   to   take   part   in   the   study.   Pa+ents   were  iden+fied  by  daily  contact  with  the  resident  medical  officer  and  completeness  of  case  ascertainment  was  checked  with  data   from   the   medical   records   department   at   each   of   the  three   par+cipa+ng   hospitals   (Freeman   Hospital,   Royal  Victoria   Infirmary,   and   Newcastle   General   Hospital)  Pa6ents   with   primary   subarachnoid   hemorrhage   were  excluded.     79  
  80. 80. Examples  of  seing  and  par+cipants  –     case  control  (con+nued)     Controls  Three  hundred  sixty-­‐four  community  control  subjects  were  matched  for  age,  sex,  and  family  doctor.  Control  subjects  were  the  next  unrelated  matching  individual  to  the  case  in  the  family  doctor  register.  Control  subjects  with  a  previous  history  of  stroke  were  excluded.   80  
  81. 81. Examples  of  seing  and  par+cipants  –     cross  sec+onal   Breast  feeding  and  obesity:  cross  sec6onal  study  The   1997   obligatory   health   examina+on   before   school  entry   evaluated   134,577   children   in   Bavaria,   southern  Germany.   At   the   examina+on,   the   parents   of   13,345  children   seen   in   two   rural   regions   were   asked   to  complete   a   ques+onnaire   about   risk   factors   for   atopic  diseases.   Data   collected   by   this   ques+onnaire   were  linked   with   the   data   from   the   school   health  examina+on.   Our   analysis   was   confined   to   children  aged  5  and  6  who  had  German  na+onality.   81  
  82. 82. Examples  of  seing  and  par+cipants  –     cross  sec+onal   Supplementary  feeding  with  either  ready-­‐to-­‐use  for6fied  spread  or  corn-­‐soy  blend  in   wasted  adults  star6ng  an6retroviral  therapy  in  Malawi:  randomised,  inves6gator   blinded,  controlled  trial    The   study   took   place   at   the   an+retroviral   therapy   clinic   of   Queen  Elizabeth  Central  Hospital  in  Blantyre,  Malawi,  from  January  2006  to   April   2007.   Blantyre   is   the   major   commercial   city   of   Malawi,  with  a  popula+on  of  1,000,000  and  an  es+mated  HIV  prevalence  of   27%   in   adults   in   2004.Eligible   par+cipants   were   all   adults   aged  18   or   over   with   HIV   who   met   the   eligibility   criteria   for  an+retroviral   therapy   according   to   the   Malawian   na+onal   HIV  treatment   guidelines   (WHO   clinical   stage   III   or   IV   or   any   WHO  stage   with   a   CD4   count   <250/mm3)   and   who   were   star+ng  treatment   with   a   BMI   <18.5.   Exclusion   criteria   were   pregnancy  and   lacta6on   or   par6cipa6on   in   another   supplementary   feeding  program   82  
  83. 83. Seing  and  par+cipants-­‐Surveillance    ONGOING  OUTBREAK  OF  WEST  NILE  VIRUS  INFECTION  IN  HUMANS,  GREECE,  JULY   TO  AUGUST  2011  Case-­‐Defini2on  •   A  confirmed  case  is  defined  as  a  person  mee+ng  any  of  the   following  clinical  criteria:  encephali+s,  meningi+s,  fever   without  specific  diagnosis  and  at  least  one  of  the  four   laboratory  criteria:  (i)  isola+on  of  WNV  from  blood  or   cerebrospinal  fluid  (CSF),  (ii)  detec+on  of  WNV  nucleic  acid  in   blood  or  CSF,  (iii)  WNV-­‐specific  an+body  response  (IgM)  in   CSF,  and  (iv)  WNV  IgM  high  +tre,  and  detec+on  of  WNV  IgG,   and  confirma+on  by  neutralisa+on.   83  
  84. 84. Study  Variables  •  Specify  unit  of  measurement  (if  applicable)  •  Quan+fy  exposure  •  Variable  transforma+ons  •  Criteria  for  defini+ons  •  Units  of  +me  and  special  categories   84  
  85. 85. Study  Variables  (examples)  The   childrens   height   and   weight   were   measured   as  part  of  the  rou+ne  examina+on.  Body  mass  index  was  calculated   as   weight   (kg)/(height   (m)2).   The   age  specific  and  sex  specific  distribu+on  of  the  body  mass  index   among   all   children   with   German   na+onality   in  Bavaria,  which  had  been  inves+gated  during  the  1997  school  health  examina+on,  was  used  as  the  reference  for   being   overweight   (defined   as   body   mass   index  above  the  90th  cen6le)  or  obese  (defined  as  body  mass  index   above   the   97th   cen6le)   because   these   cen+les  were  higher  than  other  European  reference  values.     85  
  86. 86. Study  Variables  (examples)    Hypertension   was   iden6fied   by   medical   history   or  posi6ve  screening  results  (systolic  pressure  ≥140  mm  Hg).  Pre-­‐hypertension  (asystolic  pressure  of  120–139  mm   Hg)   and   pre-­‐diabetes   (a   fas6ng   blood   glucose  concentra6on   of   6.1–6.9   mmol/L)   were   defined   on  the   basis   of   screened   laboratory   results.   Individuals  were   regarded   as   regular   alcohol   drinkers   if   they  consumed   two   or   more   alcoholic   drinks   a   day   on  three  or  more  days  a  week,  and  occasional  drinkers  if  they  consumed  less  than  regular  drinkers.   86  
  87. 87. Study  Variables  (con+nued)  Data   from   clinic   visits   were   used   to   calculate   the   number   of   days   of  observa6on   per   quarter   for   each   pa+ent   in   each   of   four   categories   of  prescribed  an+retroviral  therapy.  These  categories,  in  increasing  order  of  intensity,  were  no  an+retroviral  therapy,  monotherapy,  combina+on  therapy   without   a   protease   inhibitor,   and   combina+on   therapy   that  included  a  protease  inhibitor.      The   data   collected   for   each   case,   using   a   standardised   form,   were:  demographic   characteris+cs   (age,   sex),   dates   of   admission   to   the  hospital   and   the   ICU,   the   +me   course   of   illness   including   the   date   of  symptom   onset,   underlying   condi+ons,   complica+ons,   use   of  mechanical   ven+la+on   support   (dates   of   intuba+on   and   extuba+on),  and  an+viral  treatment   87  
  88. 88. Data  Sources/Management  •  How  the  data  were  collected  •  If  it  was  part  of  the  registry,  describe:   –  Original  purpose  of  the  database   –  How  large  the  database  is,  +meliness   –  Valida+on,  quality  checks   –  Error  rate  •  Database  sogware/hardware  •  For  surveillance  paper  –  a  diagram  of  the   surveillance  system  is  preferred     88  
  89. 89. Data  Sources/Management  Pa+ents   (with   a   close   rela+ve   or   significant   other  when   possible)   were   interviewed   and   examined   by  H.R.   (79%)   or   P.D.A.   within   48   hours   of  hospitaliza+on.   Control   subjects   were   interviewed   in  their   homes   by   H.R.   (also   with   a   rela+ve   or   significant  other   when   possible).   Inter-­‐observer   valida+on  studies   between   the   two   interviewers   were   carried  out.   The   propor+on   of   agreement   between   two  observers,  K,  was  0.68.     89  
  90. 90. Data  Sources/Management  Drinking   frequency   was   recorded   as   a   categorical  variable,   whereas   past   and   present   amounts   of  alcohol   consump+on,   dura+on   of   abs+nence,   and  heavy   drinking   were   recorded   as   con+nuous  variables.   Data   were   transferred   to   Northumbrian  Universitys   Mul6ple   Access   Computer   (NUMAC).  Following   verifica6on   procedures   to   ensure   accurate  transcrip6on,  data  were  analyzed  using  spss-­‐x  (SPSS-­‐X  Batch  System,  SPSS  Inc.,  Chicago,  Illinois).   90  
  91. 91. Data  Sources/Management  •  Informa6on  in  five  general  categories  has  been  abstracted   from  the  chart  for  each  outpa6ent  visit  and  entered   electronically  by  trained  data  abstracters;  the  data  are   compiled  centrally,  reviewed,  and  corrected  before  being   included  in  the  data  base.  Because  the  study  physicians  are   the  source  of  primary  care  for  these  pa+ents,  all  symptoms,   diagnoses,  and  treatments  since  the  previous  visit,  are  noted   at  each  clinic  visit.  The  categories  of  informa+on  are  as   follows:  demographic  characteris+cs;  symptoms;  diagnosed   diseases;  medica+ons  prescribed;  and  laboratory  values.     91  
  92. 92. Data  Sources/Management   92  
  93. 93. Study  Size  •  Specify  the  null  hypothesis  and  whether  it  is   one  or  two-­‐sided  •  Specify  the  minimum  difference  in  response   variable  that  is  considered  to  be  clinically   important  •  Specify  power  and  alpha  level  for  calcula+ng   sample  size   93  
  94. 94. Examples  To   detect   a   reduc+on   in   PHS   (postopera+ve  hospital   stay)   of   3   days   (SD   5   days),   which   is   in  agreement   with   the   study   of   Lobo   et   al.   with   a  two-­‐sided   5%   significance   level   and   a   power   of  80%,   a   sample   size   of   50   pa+ents   per   group   was  necessary,   given   an   an+cipated   dropout   rate   of  10%.   To   recruit   this   number   of   pa+ents,   a   12-­‐month  inclusion  period  was  an+cipated   94  
  95. 95. Examples  Based   on   an   expected   incidence   of   the   primary  composite  endpoint  of  11%  at  2.25  years  in  the  placebo   group,   we   calculated   that   we   would  need  950  primary  endpoint  events  and  a  sample  size   of   9650   pa+ents   to   give   90%   power   to  detect   a   significant   difference   between  ivabradine   and   placebo,   corresponding   to   a   19%  reduc;on  of  rela;ve  risk  (with  a  two-­‐sided  type  1  error  of  5%)   95  
  96. 96. Randomiza+on  –     Randomized  controlled  trials  (RCT)  Par+cipants   should   be   assigned   to  comparison   groups   in   the   trial   on   the  basis   of   a   chance   (random)   process  characterized  by  unpredictability                 96  
  97. 97.   Randomized  controlled  trials  (RCT)  -­‐-­‐   examples  •  Independent  pharmacists  dispensed  either   ac+ve  or  placebo  inhalers  according  to  a   computer  generated  randomiza+on  list    •  For  alloca+on  of  the  par+cipants,  a   computer-­‐generated  list  of  random  numbers   was  used                 97  
  98. 98. Randomiza+on  (con+nued)  •  Randomiza+on  sequence  was  created  using   Stata  9.0  (StataCorp,  College  Sta+on,  TX)   sta+s+cal  sogware  and  was  stra+fied  by   center  with  a  1:1  alloca+on  using  random   block  sizes  of  2,  4,  and  6    •  Par+cipants  were  randomly  assigned  following   simple  randomiza+on  procedures   (computerized  random  numbers)  to  1  of  2   treatment  groups   98  
  99. 99. Randomiza+on  -­‐-­‐  Concealment  A   generated   alloca+on   schedule   should   be  implemented  by  using  alloca+on  concealment,  a   c r i + c a l   m e c h a n i s m   t h a t   p r e v e n t s  foreknowledge   of   treatment   assignment   and  thus  shields  those  who  enroll  par+cipants  from  being   influenced   by   this   knowledge.   The  decision   to   accept   or   reject   a   par+cipant  should  be  made,  and  informed  consent  should  be  obtained  from  the  par+cipant,  in  ignorance  of  the  next  assignment  in  the  sequence   99  
  100. 100. Randomiza+on  (concealment)  The  doxycycline  and  placebo  were  in  capsule  form  and  iden+cal  in  appearance.  They  were  prepackaged   in   bosles   and   consecu+vely  numbered  for  each  woman  according  to  the  randomiza+on   schedule.   Each   woman   was  assigned   an   order   number   and   received   the  capsules   in   the   corresponding   pre-­‐packed  bosle   100  
  101. 101. Blinding  (RCTs)  The   term   “blinding”   or   “masking”   refers   to  withholding   informa+on   about   the   assigned  interven+ons  from  people  involved  in  the  trial  who  may   poten+ally   be   influenced   by   this   knowledge.  Blinding   is   an   important   safeguard   against   bias,  par+cularly  when  assessing  subjec+ve  outcomes.  EXAMPLE:  Whereas   pa+ents   and   physicians   allocated   to   the  interven+on   group   were   aware   of   the   allocated  arm,   outcome   assessors   and   data   analysts   were  kept  blinded  to  the  alloca+on.   101  
  102. 102. Laboratory  Methods(Surveillance)  Serum  and  CSF  specimens  were  tested  for  the  presence  of  WNV-­‐specific  IgM  and  IgG  an+bodies  using  commercial  ELISA  kits  (WNV  IgM  capture  DxSelect  and  WNV  IgG  DxSelect,  Focus  Diagnos+cs  Inc,  Cypress,  CA,  USA).  WNV  posi+ve  specimens  were  also  tested  for  the  presence  of  other  flaviviruses:  +ck-­‐borne  encephali+s  virus  (TBEV)  and  dengue  virus  (DENV).   102