GOOD MORNING, I WANT TO WELCOME YOU TO NIH OFFICE OF DISEASE PREVENTION MIND THE GAP SERIES. IT EXPLORES INTERSECTION OF RESEARCH AND CLINICAL PRACTICE. AREAS WHICH CONVENTIONAL WISDOM MAY BE CONTRADICTED BY RECENT EVIDENCE. FROM THE ROLE OF ADVOCACY AND RESEARCH AND POLICY TO THE IMPORTANCE OF BEHAVIOURAL INTERVENTIONS IT HOPES TO ENGAGE THE COMMUNITY IN THOUGHT PROVOKING DISCUSSIONS TO CHALLENGE WHAT WE THINK WE KNOW AND THINK CRITICALLY ABOUT OUR ROLE IN TODAY'S RESEARCH ENVIRONMENT. BEFORE I BEGIN I HAVE HOUSEKEEPING ITEMS. TO PARTICIPATE BY TWITTER, FOLLOW US AT NIHPREVENTS AND SUBMIT HASH TAG. AT THE CONCLUSION OF TODAY'S TALK WE WILL OPEN THE FLOOR TO QUESTIONS THAT HAVE BEEN SUBMITTED VIA EMAIL AND TWITTER. VISIT PREVENTION CLICK THE LINK TO THE EVALUATION UNDER THE RESOURCES SECTION TO SUBMIT YOUR FEEDBACK ABOUT THE SEMINAR. AT THIS TIME IT'S MY PLEASURE TO INTRODUCE OUR SPEAKER TODAY. DR. KARINA DAVIDSON IS CARDIOVASCULAR HEALTH AND VICE DEAN AT COLUMBIA UNIVERSITY MEDICAL CENTER. SHE RECEIVED HER Ph.D. IN CLINICAL PSYCHOLOGY AND MASTERS FROM UNIVERSITY OF WATERLOO CANADA. SHE IS CONDUCTED RANDOMIZED CONTROL TRIALS OF ANGER MANAGEMENT. STRESS REDUCTION AND DEPRESSION TREATMENT FOR HEALTHY, HYPER TENSIVE AND POST MYOCARDIAL INFARCTION PATIENTS. SHE HAS WON MANY AWARDS AS WELL AS TEACHING AND MENTORING AWARDS FOR HER WILLINGNESS TO TRAIN THE NEXT LEADERS. SHE HAS RECENTLY APPOINTED TO THE STATE'S PREVENTION SERVICES TASK FORCE WHERE SHE IS HONOR TODAY HELP EVALUATE A BROAD RAICHK OF PREVENTIVE HEALTH CARE SERVICES. SHE HAS AUTHORED OVER 200 PEER REVIEW ARTICLES BOOK CHAPTERS. SERVED AS EDITORS AND SERVED ON EDITORIAL BOARDS. HER CURRENT RESEARCH INTERESTS INCLUDE N-OF-1 TRIAL DESIGNS FOR HEALTH RESEARCH. AT THIS TIME I WOULD LIKE TO WELCOME DR. DAVIDSON AND TURN THE SESSION OVER TO HER AT COLUMBIA UNIVERSITY. >> THANK YOU. I'M PLEASED TO BE HERE AND TO TALK ABOUT AN INTERESTING METHODOLOGY THAT MAY HAVE MANY APPLICATIONS TO AREAS YOU ARE INTERESTED IN. I WOULD FIRST LIKE TO START BY ACKNOWLEDGING THE GREAT SUPPORT THAT I HAVE RECEIVED FROM NUMEROUS INSTITUTES. I DO HAVE A K-24. I THINK THAT'S A VITAL GRANT FOR ME TO HAVE FROM NHLBI TO HELP ME TEACH AND MENTOR THE NEXT GENERATION OF PHYSICIAN SCIENTISTS IN THIS AS WELL AS A NUMBER OF OTHER METHODOLOGIES AND INTERVENTIONAL DESIGNS THEY ARE USING FOR HEALTH SERVICES RESEARCH. I ALSO RECEIVED AN ALL-OF-1 FOR N-OF-1 CORRELATIONAL DEVELOPMENT. I THOUGHT WAS QUITE CRITICAL IN FORMING THE INTERVENTION DESIGNS I WILL TALK TO YOU TODAY. AND I HAVE A NATIONAL CANCER INSTITUTE CONTRACT TO DEVELOP THIS N-OF-1 HEALTH SERVICE OR INTERVENTION FOR PATIENTS WHO SURVIVE CANCER WHO HAVE DEPRESSIVE SYMPTOMS. AND PCORI HAS PROVIDED FUNDING TO WORK WITH PATIENTS AND PRIMARY CARE CLINICIANS TO UNDERSTAND HOW THIS TRIAL DESIGN COULD BE USED IN CLINICAL PRACTICE. SO WITH THAT I WILL TELL YOU ABOUT SOME OF THE QUESTIONS ASSUMPTIONS OF RUNNING MOST OF OUR TRADITIONAL INTERVENTION DESIGNS AND WHY THAT LEAD ME TO MY INTEREST IN N-OF-1 TRIAL DESIGN. THOUGH SOME ASSUMPTIONS WE STARTED TO THINK ABOUT STATISTICALLY AND METHODOLOGY IS TREATING COMPLEX RELAPSING DISEASES OR SYMPTOMS ARE OFTEN PRESUMED AT SOME CORE LEVEL THAT THE PROBLEM IS BINARY. DIABETES CAN BE PRESENT OR ABSENT BUT YOU COULD HAVE VARYING LEVELS OF GLUCOSE CONTROLS ACROSS THE DAY, WEEK, SEASONS, ACROSS THE PARADIGM. THAT MEANS YOU HAVE TO BE THINKING ABOUT IT CONTINUOUSLY RATHER THAN BINARILY. I OFTEN WORK ON DEPRESSIVE SYMPTOMS OR STRESS SYMPTOMS OR ANGER SYMPTOMS. SOMETIMES I SOMEWHAT UNWILLINGLY GET PULLED INTO WEIGHT, OR SMOKING OR EXERCISE AS AREAS WE NEED INTERVENTION. THOSE OF COURSE ARE ENDURING, TIME VARYING PHENOMENON RATHER THAN BEING BINARY PRESENT OR ABSENT. MY CENTER HAS BEEN DEDICATED TO THE STUDY OF BLOOD PRESSURE FOR YEARS AND THAT'S MEANT SOME STATISTICAL MODELS AND INTERVENTIONS AGAIN HAVE THAT PROBLEM THAT THEY ARE NOT BINARY AND I HAVE MANY COLLEAGUES WHO WORK ON MIGRAINE, AS I MENTIONED GLUCOSE CONTROL. CANCER CELL PROLIFERATION, ALL OF WHICH ACROSS TIME VARY CONTINUOUSLY. A SECOND ASSUMPTION IS THE TREATMENT TARGET IDENTIFICATION IS BEST CONDUCTED BY AVERAGING ACROSS PERSONS. IF WE ARE TRYING TO FIGURE OUT IF SOMETHING IS A REASONABLE TREATMENT TARGET WE TAKE IN PHASE 1 FIVE OR SIX PEOPLE, ASSUME THAT'S A UNIVERSAL IDENTIFICATION PROCESS THAT WE CAN DISCOVER A TREATMENT THAT WILL WORK FOR MOST PEOPLE. WE ASSUME THE SAME ABOUT DOSE, IT'S BEST IDENTIFIED BY AVERAGING ACROSS PERSONS. THE PROBLEM CLINICALLY IS THERE MAY BE PERSON-SPECIFIC DOSE LEVELS. MOST OF OUR METHODOLOGICAL DOSE. THE NEXT THERE MAY BE PERSON-SPECIFIC RESPONSE CURVES SO THE TIME LAG BETWEEN DOSE EXPOSURE AND RESPONSE IN ONE PERSON DIFFERS FROM THE TIME LAG FOUND IN ANOTHER. THIS COULD LEAD TO A QUANDARY AT MY STATISTICIAN SAID WHEN I FIRST STARTED TALKING TO HIM ABOUT THESE THINGS. HE SAID IS THE TREATMENT ONE FOR EVERYONE? THREE OF FOUR? ONE FOR DIFFERENT SUBGROUPS? THREE OR FOUR FOR DIFFERENT SUBGROUPS. ONE FOR ONE PERSON, OR THREE OR FOUR FOR ONE PERSON. HE THOUGHT IT WAS GOING TO BE PROBLEMATIC FOR US, THINKING OF ALL THE PLACES WHICH YOU COULD BE THINKING AT THE INDIVIDUAL LEVEL FOR FIXING A PARAMETER OR UNDERSTANDING THE RANGE OF RESPONSES AND THERE WOULD BE NO GENERALIZABILITY. I WILL SHOW YOU TOWARD THE END OF THE TALK HOW I THINK WE CAN BUILD BACK UP TO GENERALIZABILITY FROM THIS DESIGN. JUST TO MAKE THIS MORE CONCRETE FOR YOU, I KNOW I HAVE GONE OVER THOSE ASSUMPTIONS QUICKLY. I WILL SHOW YOU FOUR THINGS THAT ARE TIME VARYING. THAT IS THEY MOVE ACROSS TIME AND IN THIS CASE I WILL SHOW YOU A COUPLE EXAMPLES FOR DEPRESSIVE SYMPTOMS. SO IF WE TAKE DEPRESSIVE SYMPTOMS AT TIME ONE, TIME TWO, TIME THREE AND FOUR REPRESENTED BY THE BIG Z'S ACROSS THE TOP WE COULD BE LOOKING AT AN IRON SUPPLEMENT OR STRESS REDUCTION OR EXERCISE LEVELS AND START TO UNDERSTAND ACROSS AVERAGING ACROSS PEOPLE, WHAT IS THE AVERAGE RESPONSE TO ANY OF THOSE KINDS OF INTERVENTIONS. WE COULD WONDER ABOUT THE DOSE RESPONSE, THE RESPONSE TO IRON FOR REDUCING SYMPTOMS MIGHT BE FAIRLY SHORT BUT WE MIGHT HAVE HERE, WE MIGHT HAVE FOR A DIFFERENT TYPE OF TREATMENT A LONGER TIME RESPONSE, LIKE A YEAR. WE WOULD AGAIN AVERAGE ACROSS PEOPLE TO GO THE AVERAGE RESPONSIBLE IS ONE MONTH WHEN FOR SOME PEOPLE THERE IS A RESPONSE BUT IT'S YEAR LONG AND FOR ONE THERE'S A RESPONSE BUT IT'S A DAY LONG. AND THE QUESTION I POSED TO THE STATISTICIANS I WORK WITH, IS WOULD WE GET THE SAME ANSWER FROM AN N-OF-1 MODEL. HERE YOU HAVE PERSON ONE INDICATING THEY HAVE A RESPONSE TO A VITAMIN D SUPPLEMENT. IN ONE DAY. AND HERE IS ANOTHER PERSON WHO MAYBE IT TAKES FOUR DAYS AND WE ALL THINK ABOUT THAT AS VARIABILITY, CONFIDENCE, INTERVAL OR STANDARD ERROR AROUND THE AVERAGE POINT RESPONSE. BUT MAYBE THE WAY WE NEED TO START THINKING ABOUT IT IS DIFFERENTLY. THIS IS ACTUALLY FROM ONE OF MY PROGRAM PROJECTS WITH NHLBI. I LOOKED AT THE PREVALENCE OF POSSIBLE CAUSES FOR DEPRESSION IN PATIENTS WHO HAD A MYOCARDIAL INFARCTION AND REPRESENTING THE NUMBER OF PEOPLE WHO WERE DEPRESSED. I HAD 119 IN THIS SAMPLE AND WHAT VARIOUS POSSIBLE CAUSES OF DEPRESSION THEY HAD. YOU COULD SEE WE HAD VERY FEW WITH B 12 DEFICIENCY. ONE WHO HAD HYPER THYROIDISM, SOME WHO HAD HYPO -- SOME WITH A POSSIBLE SLEEP DISORDER. A VERY LARGE OVERLAP OF ANEMIA WITH A COUPLE OF OTHER SYMPTOMS. STRAIGHT ANEMIA AND WHAT WE CONSIDERED ESSENTIAL. PEOPLE WHO HAD NO KNOWN MEDICAL CAUSE WE HAD MEASURED FOR THEIR DEPRESSION. WHICH COULD HAVE BEEN STRESS OR A NUMBER OF THINGS WE DIDN'T HAVE A MEASURE ON. THE MOST TYPICAL WAY THAT WE RUN AN INTERVENTION AND THIS IS CERTAINLY AS A PERSON WHO HAS WON MANY INTERVENTIONS, THIS IS IMPLICITLY THE MODEL THAT WE USE WHEN WE ARE FIRST STARTING TO INTERVENE ON A PHENOMENON. REGARDLESS OF WHAT THE ACTUAL PORTION OF PUTATIVE CAUSES MIGHT BE FOR SOMEONE ENDING UP WITH HIGH DEPRESSIVE SYMPTOMS WE TRY A TREATMENT FOR REDUCING THAT SYMPTOM LEVEL. WE TRY AN SSRI OR TRY INCREASED SLEEP OR TRY SLEEP HYGIENE. WE TRY SOMETHING AND WE DON'T MATCH THAT TREATMENT TO NECESSARILY THAT PARTICULAR PERSON HAVING THAT PARTICULAR DEFICIT. NOW IN SOME AREAS THAT WORKS WELL. SO FOR PEOPLE WHO HAVE HYPER LITHEMIA WE DON'T LOOK IF THEY ENDED UP WITH HIGH CHOLESTEROL BECAUSE OF GENETICS, OR HIGH FAT DIET OR NOT EXERCISING OR OVERWEIGHT. WE LOOK AT ONE INTERVENTION THAT WORKS UNIVERSALLY FOR ALL TO GET THE CHOLESTEROL LEVEL OR DEPRESSION SYMPTOM DOWN OR BLOOD PRESSURE DOWN. THAT'S A NORMATIVE DESIGN WE USE AND IT ANSWERS THE QUESTION DOES A GENERIC DEPRESSION INTERVENTION WORK FOR THE HYPOTHETICAL AVERAGE PERSON. WE HAVE A SECOND COMMON DESIGN WE USE THAT IS STILL NORMATIVE. WE ACTUALLY MEASURE ONE PUTATIVE CAUSE FOR THE SYMPTOM OR THE DISEASE THAT WE ARE INTERESTED IN AND WE ONLY SELECT INTO OUR TRIALS PEOPLE WHO HAVE THAT. SO IN THIS CASE I'M SHOWING YOU LOOKING FOR PEOPLE WHO HAVE LOW VITAMIN D AND THEN WE RANDOMIZE THOSE PEOPLE IN THIS CASE TO PERHAPS CONTROL CONDITION IN VITAMIN D SUPPLEMENTATION AND THEN WE MEASURE DEPRESSION. AND THE SECOND DESIGN SUBGROUPS THOSE FIRST AT RISK BY THE PUTATIVE CAUSE, THE DEFICIENCY IN THIS CASE. WE RANDOMIZE ONLY THOSE PEOPLE AND WHAT IS PERSONALIZED COMES BY GROUPING THE PATIENTS INTO SMALLER AND SMALLER GROUPS. IT'S STILL A NORMATIVE DESIGN BUT ANSWERS THE QUESTION IN THE GROUP OF THE KNOWN CAUSE OR MECHANISM. THIS IS INTERVENTION IMPROVED DEPRESSION FOR THE HYPOTHETICAL AVERAGE PERSON. NOW I'M GOING TO MOVE TO N-OF-1 INTERVENTION DESIGN. SO IF FOR EXAMPLE WE ARE INTERESTED, AND I'VE CHANGED THINGS AROUND FROM THE PREVIOUS EXAMPLES IN SOMEBODY WHO, I'M SORRY THIS SHOULD SAY N-OF-1, SOMEBODY WHO HAS DEPRESSION AND PERHAPS THE MAJORITY OF THEIR DEPRESSION IS VITAMIN D DEFICIENCY BECAUSE WE HAVE MEASURED IT ACROSS TIME AND AS THEIR VITAMIN D DEFICIENCY REMEDIATES OR ACCELERATES THEY ARE HAVING A LATE RESPONSE WHICH THEIR DEPRESSION SYMPTOMS ARE GETTING BETTER OR WORSE. MAYBE A BIT WE DON'T KNOW WHAT IT IS. AND WE COULD TRY AN OPEN LABEL WITH THAT PERSON THAT JUST LOOKS LIKE A DOSE ESCALATION. WE GIVE THEM A LOW LEVEL SUPPLEMENT AND THEN WE GIVE HIGH, MAYBE WE HAVE RANDOMIZED AND MAYBE A HIGHER ONE STILL UNTIL WE SEE THE DOSE WHICH WE START TO SEE THEY ARE ACTUALLY HAVING A DEPRESSIVE SYMPTOM RESPONSE. IF WE WERE TO CONTROL WE MIGHT NOT KNOW AS WE ARE DOING THIS WHEN THEY ARE RECEIVING PLACEBO AND WHEN THEY ARE RECEIVING ACTIVE TREATMENT, SO WE WERE BLINDED, BOTH OURSELVES AND THE PATIENT AS TO WHETHER OR NOT THEY WERE RECEIVING WHAT WE THOUGHT WAS THE CAUSE. THE MODIFIABLE CAUSE OF THEIR DEPRESSION IN ORDER TO SEE WHETHER AS WE DO REPEATED MEASURES OF THEIR DEPRESSION, IF IN FACT WE WILL HELP THEM BY CONTINUING THEM ON THIS SUPPLEMENT. IN THE OPEN LABEL, RANDOMIZING WITHIN THE PATIENT TO AN INDIVIDUALIZED DOSE OF TREATMENT. IN THE CONTROL YOU ADDED A PLACEBO OR SHAM, LINED THE PATIENT, EXPERIMENTER OR BOTH. IT'S TAYLORED. DID YOU IMPROVE DEPRESSION IN THAT PERSON? NOW A FOURTH VARIANT OF A DESIGN AND SECOND ONE IN THE N-OF-1 WOULD BE ACTUALLY TO MEASURE ACROSS TIME ALL THE POSSIBLE PUTATIVE CAUSES FOR THE PARTICULAR DISEASE OR SYMPTOM THAT YOU ARE INTERESTED IN. SO YOU MIGHT MEASURE EXERCISE AND STRESS AND ANEMIA AND ESSENTIAL AND MAYBE YOU LOOKED AT IRON AND VITAMIN D AND SOME OF THE OTHER ONE'S I HAD, HYPOTHYROIDISM AND YOU MIGHT FIENT IN ONE PATIENT THIS SEEMS TO BE THE PATTERN OF TIME-LAGGED CORRELATION BETWEEN NOT EXERCISING AND DEPRESSION GOING UP. OR STRESS BEING PRESENT. STRESS GOING UP AND DEPRESSION GETTING WORSE. IN THIS ONE YOU MIGHT END UP TRYING IN AN OPEN LABEL FIRST SUPPLEMENTING FOR THEIR DEFICIENCY, THEN THE STRESS MANAGEMENT AND THEN THE EXERCISE TO SEE WHICH OF THESE REMEDIATES THE DEPRESSION IN THAT ONE PERSON. SO YOU ARE ONLY EXPOSING ONE PERSON TO THESE. AND YOU COULD ALSO DO THESE AS A CONTROLLED VARIANT IN WHICH THEY ARE GETTING IRON OR A PLACEBO OR A SUPPLEMENT OR, YOU KNOW, ATTENTION CONTROL AS A SHAM FOR THE STRESS MANAGEMENT. AND YOU ARE GAIN RANDOMIZING WITHIN THE PATIENT RATHER THAN ACROSS TIME OR ACROSS PATIENT. YOU ARE RANDOMIZING ACROSS THE PATIENTS TO SHAMS OR ALTERNATIVE TREATMENTS THAT ARE NOT PART OF YOUR HYPOTHESIS ABOUT WHAT ACTUALLY IS CAUSING THE DISEASE. AND YOU COULD AGAIN THEN BLIND BOTH THE PATIENT AND THE EXPERIMENTER IN SOME CASES. IT'S AN INDIVIDUALIZED DESIGN. AND IT'S TAILORED TO PATIENTS SPECIFIC CAUSES OR MECHANISMS FOR THEIR PARTICULAR DISEASE. IN THIS CASE DEPRESSION. IT ANSWERS THE QUESTION IF YOU INTERVENE ON IDEOGRAPHIC CAUSES OR MECHANISMS PRESENT IN EACH PATIENT, CAN YOU IMPROVE DEPRESSION IN THAT PERSON? SO I'M GOING TO GIVE YOU A CONCRETE EXAMPLE OF THE FOURTH VARIANT OF RCT AND THEN I WILL END UP TALKING ABOUT HOW YOU COULD MOVE TO GENERALIZED CASE OUT OF THIS INFORMATION ONCE YOU HAVE CONDUCTED A NUMBER OF THESE. SO AS IS THE CASE WITH MOST CLINICAL DECISIONS, PREDICTIONS ARE NECESSARY ABOUT A SINGLE CONCRETE PATIENT RATHER THAN HYPOTHETICAL NORMATIVE OR AVERAGE ONE. AND I'M GOING TO TELL YOU ABOUT A KID. SO FOR EXAMPLE RESEARCH HAS SHOWN RITALIN AFFECTS APPETITE ACROSS THE AVERAGE IDEALIZED OR NORMATIVE KID. THIS IS THE CASE OF RICHARD, 7 AND A HALF-YEAR-OLD 34 POUND INABILITY TO THRIVE, OPPOSITIONAL DEFIANT CHILD. ALREADY ON 60 GRAMS OF RITALIN. HOSPITALIZED TO INCREASE RITALIN PAST THE MAXIMUM DOSE, BEING FOR HIS AGE, NOT HIS WEIGHT. AND SO IF YOU WERE TO BE CONDUCTING A DESIGN NUMBER 4 AS I SHOWED YOU IN THEORY WHAT IT LOOKS LIKE. YOU MIGHT FIRST COME UP WITH PUTATIVE REASONS OR HYPOTHESES FOR THIS ONE CHILD ABOUT WHY HE MIGHT NOT BE HAVING EXTREME DIFFICULTIES HE WAS EXPERIENCING. AS WELL AS MANY OTHER DIFFICULT BEHAVIORS WHICH HE WAS NOT EATING. HE WAS THREATENING TO KILL OTHERS AND THREATENING TO KILL SELF. HE WAS ATTEMPTING BOTH OF THOSE LATTER BEHAVIORS. THE PEDIATRICIAN HYPOTHESIS WAS LACK OF SUFFICIENT MEDICATION WE HADN'T GOT TO THE RIGHT DOSE FOR THIS PARTICULAR TRIAL SO THAT'S N-OF-1 DOSE ESCALATION DESIGN HE WAS PROPOSING. AS I WAS A PSYCHOLOGIST ON THE CASE WE THOUGHT OF LACK OF STRUCTURE BEHAVIOURAL HYPOTHESIS ABOUT WHAT MIGHT BE GOING ON. LACK OF SLEEP RAISED BY CLINICAL STAFF OBSERVING THIS TRIAL. LACK OF FOOD, HE IS STARVING AS HE IS ONLY 34 POUNDS. THAT MAY BE AFFECTING HIS BEHAVIOR. FROM A MORE PSYCHO DYNAMIC EXPRESSION IT COULD BE EXPOSURE TO MOTHER OR AGAIN FROM MORE BEHAVIOURAL FRAMEWORK AND EXPOSURE TO FAILURE. FOR EVERY 2 HOUR PERIOD DURING THE DAY FOR FOUR WEEKS HE WAS IN THE HOSPITAL AND AT THE SCHOOL, SCHOOL AND HOSPITAL STAFF COMPLETED A BEHAVIOURAL ANALYSIS SHEET WHICH THE PRESENCE OR ABSENCE OF PROBLEMATIC BEHAVIORS ARE RECORDED ALONG WITH PRESENCE OR ABSENCE OF CAUSAL VARIABLES. DURING THIS TIME HE WAS EITHER RECEIVING RITALIN AT 60 MILLIGRAMS, RITALIN AT 30 MILLIGRAMS, 120 MILLIGRAMS OR A PLACEBO AND THAT WAS ONLY KNOWN TO THE HOSPITAL PHARMACIST. I THE PSYCHOLOGIST AS WELL AS OTHERS WERE BLINDED TO THIS. HE WAS EATING APPROXIMATELY 1,000 CALORIES WHEN HE WAS EXPOSED TO ANY DOSE OF RITALIN AND 1250 WHEN NOT ON RITALIN. FROM 60 TO THE 120 BOTH OF THOSE DOSES THERE WAS AN INCREASE IN NERVOUS MOVEMENTS EVEN THOUGH WE HADN'T ASKED ANYONE TO RECORD THOSE. BECAUSE WE WERE INTERESTED IN OTHER OUTCOME VARIABLES FOR THIS PARTICULAR CHILD A BRIEF SET OF THE PERCENT OF VARIANCE EXPLAINED BY VARIOUS DIFFERENT CATEGORIES AND I WILL WALK YOU THROUGH THIS BRIEFLY. WHEN HE WAS ON THE RITALIN HE HAD AN 8% DECREASE IN HIS DISTRACTABLE BEHAVIOR. STATEMENTS HE WANTED TO KILL HIMSELF OR MADE ATTEMPTS. HIS CALORIE INTAKE SHOULD SAY NEGATIVE AS NOTED BEFORE WENT DOWN SIGNIFICANTLY. LACK OF STRUCTURE WAS ONLY RELATED IN 18% TO THREATENING TO HURT OTHERS. THE PRESENCE OF HIS MOTHER WAS SIGNIFICANTLY RELATED TO AN INCREASE IN HIS DISTRACTABLE BEHAVIOR, INCREASE IN SUICIDE ALABI HAIFOR AND INCREASE IN HIS CALORIIC INTAKE. SORRY NEGATIVE ASSOCIATION BETWEEN PRESENCE AND CALORIC INTAKE. THESE WERE THE SIGNIFICANT CORRELATIONS WE SAW IN THE DATA ACROSS THIS TRIAL AND JUST BECAUSE PEOPLE ALWAYS ASK ME WHEN I PRESENT THIS CASE WHAT ACTUALLY HAPPENED, I COULD TELL YOU WE WENT TO THE COURT WITH THIS DATA RATHER THAN WITH PHYSICAL ABUSE AND HE WAS REMOVED FROM HIS MOTHER'S CARE AND PUT BACK ON 30 MILLIGRAMS OF RITALIN. SIX MONTHS LATER WHEN HE CAME BACK TO THE HOSPITAL HE GAINED 22 POUNDS AND HAD BEEN NO SUICIDAL OR HOMICIDAL THREATS. THIS SOUNDS LIKE A FAIRYTALE AND MADE UP CASE THAT WAS A CASE. A VERY HIGH PUBLIC HEALTH COST FOR NOT MANAGING THIS FAMILY DIFFERENT OR CHANGE SUPPORTS THAT MIGHT HAVE AFFECTED THE OUTCOME. DO WE NEED TO CHANGE THE PREVALENCE OF CAUSES OR PUTATIVE CAUSES FOR THE DISEASES AND SYMPTOMS WE ARE INTERESTED IN. I BELIEVE YES. I THINK WE NEED MORE RESEARCH THAT LOOKS AT NORMATIVE OR COMMON CORE OF THE PUTATIVE CAUSES THAT WE ARE BELIEVED RELATED TO CHOLESTEROL-BLOOD PRESSURE TO MIGRAINES TO PAIN TO BLOOD PRESSURE. WHEN I GO LOOKING FOR PREVALENCE OF THE PUTATIVE CAUSES, JUST WHAT IS THE ACTUAL PREVALENCE OF THOSE BEFORE HAVING A TREATMENT STUDY I'M SURPRISED HOW OFTEN WE SPEAK TO EACH OTHER ABOUT WHAT THOSE ARE. BUT A QUANTITATIVE ESTIMATE OF HOW PREVALENT THOSE PUTATIVE CAUSES ARE IN THE ACTUAL POPULATION IS SOMETIMES DIFFICULT TO FIND. DO WE NEED TO DETERMINE THE PREVALENCE OF THE ESSENTIAL OR SECONDARY DIFFICULT. YES. I THINK FOR THOSE RELAPSING REMITING SYMPTOMS OR COMPLEX CHRONIC DISEASES THAT HAVE RELAPSING REMITING COURSES WE NEED TO HAVE MORE WITHIN SUBJECT DATA WHICH THE NATURAL HISTORY OF WHAT PUTATIVE CAUSES ACTUALLY PROCEED IN ONE PERSON THE FLARE UPS IN RHEUMATOID ARTHRITIS, IN MIGRAINES, IN BLOOD PRESSURE, IN DEPRESSIVE SYMPTOMS WOULD GIVE US INVALUABLE INFORMATION ABOUT WHAT ARE ACTUAL TREATMENTS THAT WE SHOULD BE CONTINUING TO DEVELOP. SHOULD WE TRY THAT FIRST NORMATIVE DESIGN, DESIGN 1. I THINK YES. WE SHOULD START TREATING BY OFFERING A UNIVERSAL TREATMENT TO ALL PEOPLE. KEEPING IN MIND WE COULD BE COLLECTING THE PREVALENCE INFORMATION IN THOSE KIND OF NORMATIVE DESIGNS. AND I THINK WE SHOULD ALSO CONTINUE TO USE THE NORMATIVE DESIGN NUMBER 2 WHICH IS WHERE WE HAVE SOME CLEAR SUBGROUPS BASED ON THE CAUSE OR MECHANISM REASONABLY PREVALENT AND IF WE HAVE A TREATMENT THAT IS A SUSPECTED MODIFIABLE CAUSE WE SHOULD BE TRYING TO MODIFY JUST THOSE PERSONS, TREAT THAT PARTICULAR CAUSE AND SEE IF THAT OFFSETS THEIR SYMPTOMS OR DISEASE. SHOULD WE BE TRYING THESE NEW N-OF-1 DESIGNS? YES. IF WE SET UP A REGISTRY OF REASONBLY PREVENTIVE, PREVALENT PREVENTIVE CAUSES OR MECHANISM WE COULD ASK CLINICIANS TO RUN N-OF-1 FILES, OPEN OR CLOSE AND UPLOAD THOSE RESULTS TO A COMMON REGISTRY. THOUGH TO CLOSE, WHAT I'M GOING TO DO IS SHOW YOU THE ALGORITHM YOU WOULD MAKE AN INFORMED DISEASE WHEN YOU WOULD USE WHICH DESIGN WHERE. STARTING ON THE 4 LEFT IF THEY HAVE TREATMENT SUCCESSFUL IN SAY, SOMEWHAT ARBITRARILY 70 OR MORE PERCENT OF THE CASES PROBABLY YOU WANT TO GO AHEAD AND TREAT ALL CASES WITH THAT PARTICULAR STATIN OR SSRI BECAUSE YOU DON'T WANT TO SPEND A LOT OF WORK TRYING TO FIGURE OUT WHAT'S GOING ON WITH EVERYONE IF YOU KNOW YOU CAN TREAT THEM. AND THEN FOR THAT 30% OR SO WHO FAIL THE FIRST LINE TREATMENT, THEN YOU CAN START SUBGROUPING THEM ON HIGHLY PREVALENT SECONDARY CAUSES AND SEE IF YOU CAN'T DEVELOP A UNIVERSAL TREATMENT FOR THOSE PEOPLE SPECIFICALLY. IF YOU DON'T HAVE A SINGLE ALREADY IDENTIFIED TREATMENT FOR 70% OF THE CASES THEN MAYBE WE NEED TO GO BACK TO ESTABLISH THE PREVALENCE OF THE RISK MARKERS OR PUTATIVE CAUSES AND WHEN WE HAVE DONE THAT, IF ONE OF THEM HAS A PREVALENCE OF 70% OR MORE THEN WE GO AHEAD AND DEVELOP A TREATMENT AGAINST THAT TREATMENT TARGET AND WE MOVE BACK TO DESIGN ONE. ON THE OTHER HAND IF IT'S A MULTILOGICAL DISEASE WHICH MANY OF THE CHRONIC COMPLEX DISEASES AND SYMPTOMS ARE IF THERE'S ONE THAT IS AROUND 30% OR SO IT SEEMS REASONABLE TO SUBGROUP ON THAT ONE FACTOR AND SEE IF WE CAN TREAT THAT. IF WE ARE ALL THE WAY DOWN YOU HAVE A MULTIPLE EPIDEMIOLOGICAL DISEASE. OBVIOUSLY THERE ARE GOING TO BE SOME THAT'S NOT POSSIBLE. THEY AREN'T TIME VARYING THEMSELVES. YOU CAN EITHER DECIDE TO DOSE ESCALATE ON THE SINGLE OR TRY DIFFERENT TREATMENTS DIFFERENTLY. WITH THAT I WOULD LIKE TO CLOSE WITH A QUOTE THAT INSPIRED THIS RESEARCH BACK WHEN I WAS IN GRADUATE SCHOOL. JOHN NESSEL WROTE 1991 ONE SHOULD TRY REPEATED MEASURES ON PARTICULAR INDIVIDUALS AND TO REGULARITIES THAT CHARACTERIZE ALL INDIVIDUALS. AND I BELIEVE THAT IS A PATH WE SHOULD GO DOWN IN ORDER TO TREAT AND PREVENT COMPLEX CHRONIC RELAXING REMITING DISEASES. THANK YOU. >> THANK YOU, DR. DAVIDSON. THAT WAS A REALLY GOOD PRESENTATION. I WANT TO REITERATE TO EVERYONE PARTICIPATING THAT YOU CAN EMAIL YOUR QUESTIONS TO PREVENTION@MAIL.NIH.GOV. AND ALSO YOU CAN SUBMIT QUESTIONS AT TWITTER BY USING @NIHPREVENTS. #NIHTG DR. DAVIDSON, WE HAVE A COUPLE QUESTIONS WE HAVE RECEIVED ON YOUR PRESENTATION. ONE OF THE FIRST QUESTIONS WE RECEIVED, WHY HAS AN N-OF-1 OR SINGLE SUBJECT TRIALS BEEN WIDELY USED? >> I THINK THAT'S A GREAT QUESTION. AND SPEAKING BOTH FROM SOME MARKET SURVEY RESEARCH THAT'S BEEN PUBLISHED BY A GROUP HERE AT COLUMBIA AS WELL AS BY DISOPINION, WHEN GORDON TRIED TO SET UP AN N-OF-1 TRIAL SERVICE IN THE EARLY 1990'S AT McMASTER UNIVERSITY HE WAS DOING EVERYTHING BY HAND. ANY BEHAVIOURAL OR BLOOD PRESSURE RECORDING OR AMOUNT OF PAIN HAD TO BE HANDWRITTEN ON PIECES OF PAPER AND BROUGHT IN. THE STATISTICIAN WAS CALCULATING POWER BY HAND. THE CHEMIST WAS COMPOUNDING THE PLACEBOS AND THE PILLS BY HAND. AND HE MANAGED TO KEEP THAT UP FOR THREE YEARS BUT IT WAS AN INCREDIBLY LABOR INTENSIVE JOB JUST TO GET ONE PATIENT THROUGH ONE N-OF-1 TRIAL. I THINK ONE OF THE REASONS WE ARE SO BEAUTIFULLY POISED TO LAUNCH INTO THIS AS A LARGE SCALE OPERATION IS WE NOW HAVE ECOLOGICAL MOMENTARY ASSESSMENT. UNOBTRUSIVE WAYS OF MONITORING SYMPTOMS, BEHAVIORS, FEELINGS THROUGH MANY OF THE DEVICES PEOPLE CARRY. WE HAVE AUTOMATED WAYS OF POPULATING THE ELECTRONIC HEALTH RECORD AND OF CALCULATING THE POWER OF COLLECTING THE DATA IN WAYS THAT DON'T REQUIRE THE KIND OF MANUAL LABOR THAT WAS NEEDED IN THE EARLY 90'S. I THINK NOW WE CAN. WE DON'T HAVE A LOT OF PEOPLE TEACHING THIS METHOD, EITHER CONCRETELY TO THE CLINICIANS OR IN THEORY TO THE PEOPLE WHO COULD BE FURTHER DEVELOPING THIS STATISTICAL METHOD SOFTWARE PACKAGES, PLUG AND PLAY WAYS TO SET UP N-OF-1 TRIALS FOR PATIENTS TO START COMPLETING AND WE DON'T HAVE A SYSTEM FOR THEN COLLECTING THAT SO THAT WE HAVE MANY PATIENTS WHO HAVE GONE THROUGH THE SAME N-OF-1 SO WE COULD START TO SEE WHAT TYPES OF PHENOTYPES COME UP INDUCTIVELY FROM THE REPEATED MEASURE DATA TAKEN FROM MANY PEOPLE. >> THANK YOU SO MUCH. IN THIS AGE OF PERSONALIZED MEDICINE, N-OF-1 TRIALS HAVE BECOME PRETTY POPULAR. HAVE YOU FOUND PATIENTS WANT THIS TYPE OF TRIAL AS WELL? >> I THINK, STILL HAVE A WAYS TO GO IN COMING UP WITH THE LANGUAGE AND WAYS OF INTRODUCING PATIENTS TO THIS TYPE OF TRIAL. WE HAVE DONE EVEN THE LABEL, N-OF-1 ALTHOUGH IT MEANS SOMETHING TO ALL OF US WOULD BE EXPOSED TO THAT TYPE OF METHODOLOGY, IT SOUNDS LIKE AN EXPERIMENT AND NOT SOMETHING EASILY ACCESSIBLE TO A PATIENT. THEY SPENT SOME TIME DECIDING THEY WOULD RENAME IT, THEY CAME UP WITH THE TITLE PATIENT-CENTERED TRIAL. PATIENT CENTERED TREATMENT IDENTIFICATION, A BETTER WAY TO EXPLAIN TO PATIENTS WHAT IT IS WE ARE TRYING TO DO. PATIENTS HAVE SOME CONCERNS IT SHOULD BE THEIR PHYSICIAN WHO IS MONITORING ALL OF THEIR SYMPTOMS AND PHYSICIANS HAVE CONCERNS THAT PROVIDING THEM WITH YET MORE CONTINUOUS DATA AND PARTICULARLY DATA THAT'S COLLECTED 24 HOURS 7 DAYS A WEEK IS NOT GOING TO FIT WITH THEIR WORK SCHEDULE. SO WE ARE WORKING OUT SOME OF THE WAYS THIS COULD BE DONE INSIDE A PRIMARY CARE OFFICE IN A WAY THAT WORKS FOR A PHYSICIAN AND THAT MEETS THE NEEDS AND CONCERNS OF THE PATIENTS INTERESTED IN THIS KIND OF DESIGN. >> THANK YOU, WE RECEIVED ONE OTHER ADDITIONAL EMAIL. DR. DAVIDSON, NOT SURPRISINGLY YOUR IDEAS AND METHODS ARE WELL ARTICULATED AND N-OF-1 IS WELL POSITIONED WITHIN THE RESEARCH DESIGN OPTIONS. DO YOU PERHAPS HAVE A PUBLICATION ON THESE IDEAS ALREADY YOU CAN SHARE WITH COLLEAGUES, INSIGHT. >> ABSOLUTELY. WE HAVE A METHOD PIECE THAT I CAN SHARE PERHAPS AFTER THIS WEBCAST, THE FULL CITATIONS FOR. I CAN TELL YOU AHRQ DID A FULL REPORT ON IT WITHIN THE LAST TWO YEARS, I BELIEVE. TO CONSIDER ISSUES WE DIDN'T PUT IN OUR PUBLICATION WE THINK ARE ADDITIONALLY IMPORTANT. THINGS LIKE ETHICS. IS THIS RESEARCH OR CLINICAL PRACTICE. IF IT'S RESEARCH AND IT HAS TO GO THROUGH AN I.R.B. DO YOU HAVE TO PUT AN I.R.B. THROUGH EACH AND EVERY SINGLE PATIENT YOU MAY FIND ONE DOESN'T NEED IRON SUPPLEMENT FOR DEPRESSION TRIAL AND ANOTHER DOES. THEY WERE THINKING OF SOME OF THE REGULATORY AND COMPLEX ISSUES THAT WE ARE GOING TO HAVE TO WORK THROUGH IN ORDER TO GET THIS OUT MORE EXPEDITIOUSLY TO PATIENTS. >> THANK YOU FOR YOUR ANSWER. ONE OTHER QUESTION WE HAVE GOTTEN ONLINE. DR. DAVIDSON DO YOU THINK THERE'S A BENEFIT TO CREATING AN INTELLIGENT COMPUTER SYSTEM TO ASSIST A PHYSICIAN TO IMPLEMENT AN N-OF-1 PRACTICE. THE AUTHOR OF THIS EMAIL IS THINKING SOMETHING LIKE GOOGLE PLUS FOR THIS PARTICULAR PURPOSE. >> YES. I THINK THAT'S THE KIND OF EXCITING OPPORTUNITY THAT WE HAVE NOW, GIVEN THE DIGITAL AGE, THE COLLECTION OF M HEALTH DATA CONTINUOUSLY. AND THE INCREASED AWARENESS OF PATIENTS OF THE KINDS OF TREATMENTS THAT THEY WANT OR INTERESTED IN TRYING. SO YOU COULD SEE INTELLIGENT COMPUTER SYSTEMS THAT MIGHT ASK PATIENTS WHAT ARE THE SYMPTOMS THAT ARE BOTHERING YOU. ONE OF THE THINGS WE NOTICED A LONG TIME AGO PATIENTS WHO LOST THEIR PRIMARY CARE OFFICE WHAT DID YOU TALK ABOUT, WHAT GOT TREATED AND WHAT PROBLEMS DO YOU HAVE. IF YOU HAD OVERLAPPING VENN DIAGRAMS WHAT PROBLEMS THEY HAD IN THEIR DAILY LIFE RARELY CAME UP AS HEALTH CARE ISSUES. FOR EXAMPLE SLEEP PROBLEMS. PROBLEMS WITH DEPRESSION AND ANXIETY AND STRESS. WERE OFTEN MENTIONED AS DAILY PROBLEMS BUT NOT THINGS THEY DECIDED TO DISCUSS AS A HEALTH ISSUE WITH THEIR PHYSICIAN. A KIND OF GOOGLE PLUS COULD ALLOW A PATIENT TO SAY I WANT TO KNOW WHAT TO DO ABOUT IMSOMNIA, OR I WANT TO KNOW WHAT TO DO ABOUT MY LOW LEVEL HEADACHES THAT HAPPEN OFTEN. AND THEY MIGHT BE ABLE TO THEN START FIGURING OUT HOW TO ENTER DATA TO A FIGURE OUT WHAT THEIR TRIGGERS OR POSSIBLE ETIOLOGIES ARE OR SIGN UP FOR A TRIAL WHERE SOMEONE IS DELIVERING THE TREATMENT, EITHER OPEN CASE OR IF THEY WERE WILLING TO CONTROL WITH A POSSIBLE SHAM OR ALTERNATIVE TREATMENT. SO THOSE ARE THE KINDS OF THINGS I THINK COULD MAKE THIS SCALE UP IN A WAY THAT WAS JUST NOT POSSIBLE A COUPLE DECADES AGO. >> REMIND PARTICIPANTS IF YOU HAVE A QUESTION, EMAIL TO PREVENTION@NIH.GOV. OR TWITTER @NIHPREVENTS USING THE HASH TAG NIHTG. >> THE NEXT IS ABOUT TRAINING RESOURCES AND OPPORTUNITIES. THIS PARTICULAR RESEARCHER WANTS TO KNOW IF YOU CAN RECOMMEND ANY RESOURCES FOR THOSE RESEARCHERS WHO ARE INTERESTED IN LEARNING MORE ABOUT N-OF-1 DESIGNS IN TERMS OF OBSERVATIONS, HOW TO ANALYZE AND COLLECT DATA AND HOW TO ASSESS MEDIATION N-OF-1 DESIGNS. >> I THINK THOSE ARE EXCELLENT QUESTIONS AND THESE ARE NASCIENT AREAS. I HAVE WORKED WITH BIO STATS AT COLUMBIA UNIVERSITY, THEY HAVE WORKED OUT POWER ANALYSES FOR THIS. THAT IS THE NUMBER OF OBSERVATIONS GIVEN THE EXPECTED CORRELATION SIZE BETWEEN AN ETIOLOGY AND A SYMPTOM. AS THE PERSON ASKING THIS QUESTION IS PROBABLY AWARE IT'S FAIRLY COMPLICATED BECAUSE OF DEPENDENCY IN THE OB VERSATION. -- OBSERVATION. WE DON'T YET HAVE THAT IN A SOFTWARE PROGRAM OR SET OF SLIDES. BUT I'M DISCUSSING WITH BIO STATISTICIANS TO START A COURSE IN THE GRADUATE LEVEL AT COLUMBIA. I THINK THERE IS LITTLE TRAINING YET AVAILABLE. I THINK WE DON'T YET HAVE ENOUGH OF THESE TRIALS CONDUCTED IN ORDER TO START HAVING GOOD CASE EXAMPLES THAT HELP FLUSH OUT FOR PEOPLE SOME ASSUMPTIONS AND ISSUES THAT HAVE TO BE GRAPPLED WITH. IN THE AHRQ PUBLICATION FROM 2014, IT DOES HAVE GOOD CHECKLISTS AT THE END OF EACH CHAPTER ABOUT ETHICS, STATISTICAL CONCERNS, FINANCIAL CONCERNS AND SO THAT INFORMATION, I THINK IS USEFUL FOR TRAINING PURPOSES. BECAUSE TRYING TO GET PEOPLE TO SEE WHERE SOMETHING WOULD NOT WORK SO THAT YOU DON'T GO DOWN THE PATH TO TRYING ONE OF THESE IF YOU ARE NOT IN THE SPACE OF A SYMPTOM OR AN AREA WHERE IT'S GOING TO BE POSSIBLE TO DO. >> THANK YOU. THE NEXT QUESTION CENTERS MORE ALONG STATISTICAL BARRIERS AND TROUBLESHOOTING. THIS PARTICULAR RESEARCHER HAS A QUESTION ADDRESSING HOW WOULD YOU HANDLE STATISTICAL POWER IN N-OF-1 TRIAL. ARE THERE ANY BARRIERS WITH STATISTICAL POWER AND N-OF-1 TRIALS? >> THERE CERTAINLY ARE, YOU HAVE TO HAVE SOMETHING OF HIGH FREQUENCY SYMPTOMS. YOU HAVE TO SEE REPEATEDLY AND AS THE PERSON IS AWARE QUITE OF BIT OF VARIABILITY. WE TRIED CONDUCTING A POWER ANALYSIS FOR DETECTING TRIGGERS OF A-FIB AND IF THE AVERAGE PATIENT HAS 12-30 A-FIB EPISODES EVEN IF YOU COUNT THE SILENT ONE'S. THEY ARE WEARING A HALTER. COLLECT DATA OVER 18 MONTHS IN ORDER TO GET A STABLE ESTIMATE OF WHAT WERE THE TRIGGERS WHICH MOST PATIENTS TOLD US WAS TOO LONG TO WEAR AND TOO LONG TO FIND OUT WHAT MIGHT BE THE THING THEY SHOULD BE REMOVING FROM THEIR LIFE OR SUPPLEMENTING OR ALTERING IN ORDER TO AVOID THE A-FIB EPISODE. YOU WANT A VARIABLE LIKE BLOOD PRESSURE THAT COULD BE MEASURED MULTIPLE TIMES THAT IS HIGHLY VARIABLE IN THE PERSON AND THAT THE PUTATIVE CAUSE OF THEMSELVES ARE TIME VARYING. THERE ARE IN FACT MANY THINGS THAT MEET THOSE AND I THINK THE SHORTEST TIME PERIOD WE HAD ADEQUATE POWER FOR WAS SIX WEEKS. AND THAT WAS FOR A FAST-ACTING DRUG FOR BLOOD PRESSURE THAT WAS BEING DONE IN ONE WEEK BLOCKS. IT HAD A FAST-ACTING AND A SHORT HALF-LIFE. SO WE COULD POWER TO LOOK AT A PLACEBO VERSUS THAT SINGLE DRUG AND BE POWERED WITH A SIX-WEEK BLOCK. >> THANK YOU. THE NEXT QUESTION ADDRESSES ANOTHER BARRIER WHICH IS COST. THIS PARTICULAR RESEARCHER WANTED TO KNOW ARE THERE ANY DIFFERENCES IN TERMS OF MAYBE WHAT HAS BEEN ANALYZED THROUGH A COST ANALYSIS BETWEEN N-OF-1 EXPERIMENTS AND TRADITIONAL RCT'S. >> WE HAVE SEEN SOME COST ANALYSES THAT WERE HYPOTHETICAL. SO THOSE ARE SLIGHTLY PROBLEMATIC BECAUSE THEY ARE GUESSING WHAT THE COST WOULD BE. I THINK IT'S REASONABLE TO ONLY LOOK WITHIN ONE SYMPTOM OR WITHIN ONE TREATMENT WITHIN ONE SYMPTOM SO THAT IT'S A HEAD-TO-HEAD COMPARISON. IF YOU WERE TRYING TO FIGURE OUT FOR HYPERTENSION, IF A NEW DRUG WAS SUPERIOR TO A STANDARD-OF-CARE DRUG. WHAT KIND OF DESIGN ONE WOULD YOU HAVE TO CONDUCT, THAT IS HOW MANY SUBJECTS, VERSUS HOW MANY SUBJECTS WOULD YOU HAVE TO DO AT THE N-OF-1, IN ORDER TO SEE A BENEFIT FOR THE AVERAGE N-OF-1 PATIENT. I HAVE NOT SEEN PEOPLE YET CONSIDER THAT KIND OF HEAD-TO-HEAD COMPARISON AND SO I CAN'T ANSWER THE QUESTION DIRECTLY. WHAT I CAN SAY IS THAT WE OFTEN END UP RUNNING INCREDIBLY EXPENSIVE PHASE 3 TRIALS AND WE HAVE 5-30% WHO RESPOND POSITIVELY AND MAYBE 30% WHO RESPOND NOT AT ALL AND MAYBE 20-30% WHO HAVE HARM. IF THAT HAD BEEN RUN AS N-OF-1 TRIAL, THAT IS REPEATED MEASURES ACROSS TIME WITH TIME RANDOMIZED RATHER THAN SUBJECTS RANDOMIZED. I THINK YOU MIGHHAVE SOME CASES WHICH YOU WOULD END UP WITH BETTER POWER WITH FEWER SUBJECTS. AND YOU WOULD THEN BE ABLE TO LOOK AT THE PHENOTYPE OF WHO HAD HARMED AND WHO BENEFITED IN A WAY THAT WOULD BE MORE RICH IN THE DATA YOU WOULD HAVE FROM THAT SUBJECT COMPARISON TRIAL. >> IN YOUR EXPERIENCE, WHAT WOULD BE AN EXAMPLE OF A PREVENTIVE BEHAVIOURAL N-OF-1 TRIAL AND HAVE YOU CONDUCTED ANY OF THESE TYPES OF TRIALS BEFORE? >> FOR US DAILY EXERCISE R01 THAT JUST FINISHED RECENTLY AND WE ARE IN THE PROCESS OF ANALYZING IT, IT WAS PREVENTIVE, TAKING PATIENTS WHO INTERMITTENTLY EXERCISED AND CONSIDERED ABLE TO EXERCISE BUT DIDN'T ALWAYS. SO WE REMOVED PEOPLE WHO HAD A SCHEDULE THEY KEPT NO MATTER WHAT AND HAD A RUN-IN WITH PEOPLE WITH A VARIANCE HOW MUCH THEY EXERCISED EACH DAY WHICH WAS A REASONABLE AMOUNT, RATHER THAN SOMEONE WHO RUNS THREE DAYS A WEEK OR FIVE DAYS A WEEK. WE DID AN INDIVIDUAL STRESS FINGERPRINT. WE TRIED TO SEE WHAT WERE THE INDIVIDUAL PREDICTORS FROM STRESS RATINGS TAKEN RANDOMLY ACROSS THE DAY AS WELL AS SLEEP, AS WELL AS TEMPERATURE OUTSIDE, A NUMBER OF VARIABLES. WE RANDOMIZED PATIENTS TO RECEIVE INFORMATION ABOUT WHAT THEIR FACILITATORS AND BARRIERS OF DAILY 30 MINUTE BOUTS OF EXERCISE WAS OR NOT RECEIVE THAT AND CONTINUING THE OBSERVATIONAL ARM. THIS STRESS RO1 WAS INSPIRED BY THE IDEA IF YOU ARE A CAPABLE ADULT OF ENGAGING IN 30 MINUTES OF MODERATE EXERCISE AND YOU AREN'T DOING IT, PROBABLY THE HYPOTHESES ABOUT WHAT YOU HAVE ABOUT WHAT IS CAUSING YOU TO EXERCISE OR NOT EXERCISE ARE INCORRECT. CONCRETELY WHAT I MEAN BY THAT, I AM SUCH A PERSON. SOME WEEKS I MANAGE TO GO FOR MY THREE, 3-MILE RUNS AND OTHER WEEKS I DON'T. IF YOU ASK ME WHY IT IS I DON'T, I WOULD TELL YOU MAYBE STRESS AT WORK IS WHAT CAUSES ME TO NOT WORK OUT. OR FIGHTS WITH MY DAUGHTER. SO THOSE WERE THE HYPOTHESES I HAD GOING INTO THIS. I ALSO WOULD HAVE TOLD YOU I KNOW I SLEEP BETTER ON THE NIGHTS THAT I HAVE RUN DURING THE DAY, I SLEEP BETTER. AND SO I ALWAYS HAVE BEEN TELLING PEOPLE RUNNING FOR ME IS A TWO-FOR. CAUSING BETTER SLEEP WHICH IS A GOOD PREVENTION FOR CARDIOVASCULAR DISEASE AND RUNNING WHICH IS GOOD PREVENTION FOR CARDIOVASCULAR DISEASE. TURNS OUT I'M WRONG ON ALL THREE COUNTS. MY STRESS AT WORK HAD ZERO TIME-LAG CORRELATION TO WHETHER I EXERCISED OR NOT. AND FIGHTS WITH MY DAUGHTER HAD ZERO CORRELATION WITH WHETHER I EXERCISED OR NOT AND AMOUNT OF SLEPT AND QUALITY OF SLEEP ON THE NIGHTS I EXERCISED WAS ZERO WITH THE AMOUNT THAT I HAD EXERCISED DURING THE DAY. IT TURNED OUT FOR ME THE SINGLE BEST PREDICTOR WHETHER I EXERCISED IS WHETHER I HAD 7 HOURS OF SLEEP, NOT THE NIGHT BEFORE BUT TWO NIGHTS BEFORE. SO IF I WANT TO RUN ON THURSDAY, I HAVE TO SLEEP MORE THAN 7 HOURS ON TUESDAY NIGHT. AND THAT IS THE TYPE OF PUTATIVE CAUSE THAT HUMAN BEINGS ARE NOT LIKELY TO FIND. WE LOOK FOR PROXIMAL, SALIENT AND HYPOTHESIS CONGRUENT CAUSES. SO MUCH OF OUR PREVENTION AND MUCH OF THE BEHAVIOR WE ARE INTERESTED IN HAVING PEOPLE CHANGE, I BELIEVE, WE HAVE THE WRONG HYPOTHESES ABOUT. AND WE HAVE TO START COLLECTING DATA IN ORDER TO INFORM PEOPLE ABOUT WHAT IN FACT IS DRIVING THEIR BEHAVIOR AND THEN SEE IF THEY USE THAT IN ORDER TO IMPROVE THEIR BEHAVIOR. OR IN OTHER DESIGNS WE COULD DO IF WE THEN COULD CHANGE THOSE THINGS THAT WE FOUND WHETHER ETIOLOGIES OR PREDICTORS WAS EDUCATING THE PERSON. MAKING IT A DIFFERENT KIND OF LIFESTYLE FOR THEM THAT GETS THOSE KINDS OF TRIGGERS OR PROBLEMS OR BARRIERS OUT OF THEIR LIFE. THAT WAS A LONG-WINDED ANSWER. I'M SORRY ABOUT THAT. >> NO, IT WAS GOOD. I JUST WANT TO REMIND VIEWERS THAT YOU CAN EMAIL QUESTIONS TO PREVENTION@MAIL.NIH.GOV OR SUBMIT QUESTIONS VIA TWITTER @NIHPREVENTS USING NIHTMG. WHAT OTHER AREAS OF RESEARCH RATHER THAN BEHAVIOURAL INTERVENTIONS CAN N-OF-1 TRIALS BE USED FOR? >> I REALLY THINK FOR MOST OF THE COMPLEX CHRONIC RELAPSING, RECURRING DISEASES THAT WE HAVE TROUBLE TREATING, THAT WE DON'T ALREADY HAVE A KNOWN CURE FOR, OBESITY, EXERCISE, PAIN, MIGRAINES, A-FIB, ESTRADIOL LEVELS WE HAVEN'T HAD A UNIVERSAL CLEAR, SUCCESSFUL TREATMENT. SO FOR MOST OF THOSE I THINK WE COULD START THINKING ABOUT COLLECTING FIRST THE OBSERVATIONAL DATA TO GET THAT NORMATIVE PREVALENCE AND THEN WHEN SUBGROUPING DOESN'T WORK, IF IT DOESN'T WORK STARTING TO MOVE INTO THE N-OF-1 TRIAL SPACE. I CAN TELL YOU THAT THESE ARE SYMPTOMS HAVE TO BE CHRONIC, RELAPSING, REMITING. THEY HAVE TO BE MEASURABLE ON A WILDLY FREQUENT BASIS AND THEY HAVE TO HAVE SOME VARIATION TO THEM. IF THEY DON'T HAVE THOSE THEY AREN'T AMENABLE TO AN N-OF-1 TRIAL. I DO HAVE THE FULL CITATION FOR OUR ARTICLE IN WHICH WE HAVE WRITTEN UP SOME OF THIS INFORMATION I WAS SHARING WITH YOU. DAVIDSON PEACOCK CRONISH EDMONDSON, PUBLISHED IN 2014 IN SOCIAL PERSONALITY PSYCHOLOGICAL COMPASS PERSONALIZING PATIENTS THROUGH N-OF-1 TRIAL. AUGUST ISSUE 8 AND PAGE 408-421. >> THANK YOU SO MUCH FOR THE REFERENCE. THIS LAST TWO QUESTIONS, ONE OF THE LAST QUESTIONS, IN YOUR EXPERIENCE HAVE YOU HAD ANY EXPERIENCE INTEGRATING DATA FROM MULTIPLE N-OF-1 TRIALS AND HAVE YOU RUN INTO ANY BARRIERS AGGREGATING DATA FROM MULTIPLE N-OF-1'S? >> STRESS RO1 FUNDED BY SCIENCE OF BEHAVIOR CHANGE GROUP WE AGGREGATED THE 30 PATIENTS WHO WERE RANDOMIZED TO RECEIVE THEIR STRESS FINGERPRINT. WHAT WAS GREAT ABOUT THE AGGREGATION OF IT WE COULD LOOK AT THE 30 OF THEM AND REGARDLESS OF WHAT THEY WERE TOLD, DID THAT ACTUALLY CHANGE THE FREQUENCY OF THEIR EXERCISE 30 MINUTE BOUT OF EXERCISE. AND SECOND WE COULD FURTHER SUBGROUP THEM IN THE PEOPLE WHO SAY THERE WERE SOME PEOPLE FOR WHOM WORK STRESS OR HOMEWORK WAS CAUSING PROBLEMS SO WE COULD LOOK AT THOSE 17 PEOPLE. THERE WERE INTERESTINGLY A NUMBER OF PEOPLE FOR WHOM SLEEP IMPACTED ON THEIR EXERCISE SO WE COULD LOOK AT THAT SUBGROUP SEPARATELY. I HAVE AGGREGATED, IT JUST HAPPENED IN THE LAST MONTH OR SO BECAUSE THE GRANT IS FINISHING IN DECEMBER. AND WE BEING ABLE TO SORT OF START JUST EXAMINING HOW RICH THE AGGREGATION IS FOR LOOKING AT BOTH THE WHOLE GROUP AND FOR IDENTIFYING SUBGROUPS WITHIN THE WHOLE GROUP. >> THANK YOU. THE LAST QUESTION IS BASICALLY CENTERED AROUND LOOKING AT THE BROADER VIEW OF N-OF-1 TRIALS AND WHAT YOU THINK THE NEXT STEPS ARE IN THE DEVELOPMENT OF THIS METHOD'S APPROACH? >> SO I THINK NEXT STEP FOR MOVING THIS FIELD ALONG IS TO FIND, WHAT I CALL, THE LOW HANGING FRUIT. THAT'S WHY WE HAVE BEEN TALKING TO PATIENTS AND PRIMARY CARE CLINICIANS. WE ARE DOING A POLL TO ASK 500 PATIENTS WHAT ARE THE TOP CONDITIONS OR SYMPTOMS THEY WOULD LIKE TO TRY THIS KIND OF DESIGN. AND THEN WE ARE ASKING A SECOND PANEL OF 500 PATIENTS TAKEN FROM ACROSS THE NATION HOW LONG WOULD THEY BE WILLING TO WORK ON THAT SYMPTOM OR PROBLEM. HOW MANY MEASUREMENTS WOULD THEY BE WILLING TO TAKE. WOULD THEY BE WILLING TO HAVE IT BE CONTROLLED OR NOT. I THINK WE NEED TO HAVE ONE OR TWO CLEAR AREAS THAT EVERYBODY IS INTERESTED IN TACKLING WITH THIS AND WE NEED TO START GETTING SOME DATA IN THAT AREA TO HAVE A USE CASE THAT ALLOWS PEOPLE FROM OTHER AREAS OF SCIENCE OR OTHER AREAS OF PREVENTION OR OTHER TARGET ORGANS, QUITE FRANKLY TO START THINKING HOW THEY COULD APPLY THIS. I WILL TELL YOU THERE WAS A RECENT ANELS THAT HAD ONLY 12 PARTICIPANTS IN IT. EACH AND EVERYONE WAS CONCERNED ABOUT MUSCLE PAIN AS A RESULT OF THEIR STATIN. SO THEY RAN AN N-OF-1 FOR EACH PATIENT IN WHICH THEY REPORTED WHETHER THEY WERE HAVING MUSCLE PAIN INTERMITTENTLY THROUGH THE DAY AND THEY RECEIVED A STATIN OR A PLACEBO AND THEY SHOWED, I THINK NINE OUT OF THE 12 PATIENTS HAD NO MUSCLE PAIN ASSOCIATED WITH EXPOSURE TO STATIN AND EIGHT WERE WILLING TO GO BACK ON THEIR STATIN ON A DAILY BASIS IN ORDER TO PREVENT HEART DISEASE. THERE ARE MANY USE CASES FOR THIS DESIGN. WE ARE JUST STARTING REALLY RIGHT NOW TO START FIGURING OUT THE AREAS THIS WOULD BE A USEFUL DESIGN. >> DR. DAVIDSON, THANK YOU FOR ALL THIS USEFUL INFORMATION AND THANK YOU TO EVERYONE WHO PARTICIPATED IN TODAY'S WEBINAR. ON THE MIND THE GAP WEBSITE, PREVENTION.NIH.GOV/MINDTHEGAP. YOU WILL FIND SEVERAL RESOURCES INCLUDING SLIDES AND REFERENCES AND A LINK TO PROVIDE INFORMATION. THANK YOU AGAIN FOR YOUR TIME. >> THANK YOU, EVERYONE.